A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow.

PubMed

Wynn, Robert F; Hart, Claire A; Corradi-Perini, Carla; O'Neill, Liam; Evans, Caroline A; Wraith, J Ed; Fairbairn, Leslie J; Bellantuono, Ilaria

2004-11-01

Homing of bone marrow stromal cells (MSCs) to bone and bone marrow after transplantation, important for the correction of conditions such as metabolic storage disorders, can occur but with poor efficiency. Substantial improvements in engraftment will be required in order to derive a clinical benefit from MSC transplantation. Chemokines are the most important factors controlling cellular migration. Stromal-derived factor-1 (SDF-1) has been shown to be critical in promoting the migration of cells to the bone marrow, via its specific receptor CXCR4. The aim of our study was to investigate CXCR4 expression on MSCs and its role in mediating migration to bone marrow. We show that CXCR4, although present at the surface of a small subset of MSCs, is important for mediating specific migration of these cells to bone marrow.

Bone Marrow Sparing in Intensity Modulated Proton Therapy for Cervical Cancer: Efficacy and Robustness under Range and Setup Uncertainties

PubMed Central

Dinges, Eric; Felderman, Nicole; McGuire, Sarah; Gross, Brandie; Bhatia, Sudershan; Mott, Sarah; Buatti, John; Wang, Dongxu

2015-01-01

Background and Purpose This study evaluates the potential efficacy and robustness of functional bone marrow sparing (BMS) using intensity-modulated proton therapy (IMPT) for cervical cancer, with the goal of reducing hematologic toxicity. Material and Methods IMPT plans with prescription dose of 45 Gy were generated for ten patients who have received BMS intensity-modulated x-ray therapy (IMRT). Functional bone marrow was identified by 18F-flourothymidine positron emission tomography. IMPT plans were designed to minimize the volume of functional bone marrow receiving 5–40 Gy while maintaining similar target coverage and healthy organ sparing as IMRT. IMPT robustness was analyzed with ±3% range uncertainty errors and/or ±3mm translational setup errors in all three principal dimensions. Results In the static scenario, the median dose volume reductions for functional bone marrow by IMPT were: 32% for V5GY, 47% for V10Gy, 54% for V20Gy, and 57% for V40Gy, all with p<0.01 compared to IMRT. With assumed errors, even the worst-case reductions by IMPT were: 23% for V5Gy, 37% for V10Gy, 41% for V20Gy, and 39% for V40Gy, all with p<0.01. Conclusions The potential sparing of functional bone marrow by IMPT for cervical cancer is significant and robust under realistic systematic range uncertainties and clinically relevant setup errors. PMID:25981130

Deficiency of bone marrow beta3-integrin enhances non-functional neovascularization.

PubMed

Watson, Alan R; Pitchford, Simon C; Reynolds, Louise E; Direkze, Natalie; Brittan, Mairi; Alison, Malcolm R; Rankin, Sara; Wright, Nicholas A; Hodivala-Dilke, Kairbaan M

2010-03-01

beta3-Integrin is a cell surface adhesion and signalling molecule important in the regulation of tumour angiogenesis. Mice with a global deficiency in beta3-integrin show increased pathological angiogenesis, most likely due to increased vascular endothelial growth factor receptor 2 expression on beta3-null endothelial cells. Here we transplanted beta3-null bone marrow (BM) into wild-type (WT) mice to dissect the role of BM beta3-integrin deficiency in pathological angiogenesis. Mice transplanted with beta3-null bone marrow show significantly enhanced angiogenesis in subcutaneous B16F0 melanoma and Lewis lung carcinoma (LLC) cell models and in B16F0 melanoma lung metastasis when compared with tumours grown in mice transplanted with WT bone marrow. The effect of bone marrow beta3-integrin deficiency was also assessed in the RIPTAg mouse model of pancreatic tumour growth. Again, angiogenesis in mice lacking BM beta3-integrin was enhanced. However, tumour weight between the groups was not significantly altered, suggesting that the enhanced blood vessel density in the mice transplanted with beta3-null bone marrow was not functional. Indeed, we demonstrate that in mice transplanted with beta3-null bone marrow a significant proportion of tumour blood vessels are non-functional when compared with tumour blood vessels in WT-transplanted controls. Furthermore, beta3-null-transplanted mice showed an increased angiogenic response to VEGF in vivo when compared with WT-transplanted animals. BM beta3-integrin deficiency affects the mobilization of progenitor cells to the peripheral circulation. We show that VEGF-induced mobilization of endothelial progenitor cells is enhanced in mice transplanted with beta3-null bone marrow when compared with WT-transplanted controls, suggesting a possible mechanism underlying the increased blood vessel density seen in beta3-null-transplanted mice. In conclusion, although BM beta3-integrin is not required for pathological angiogenesis, our studies demonstrate a role for BM beta3-integrin in VEGF-induced mobilization of bone marrow-derived cells to the peripheral circulation and for the functionality of those vessels in which BM-derived cells become incorporated.

Modular flow chamber for engineering bone marrow architecture and function.

PubMed

Di Buduo, Christian A; Soprano, Paolo M; Tozzi, Lorenzo; Marconi, Stefania; Auricchio, Ferdinando; Kaplan, David L; Balduini, Alessandra

2017-11-01

The bone marrow is a soft, spongy, gelatinous tissue found in the hollow cavities of flat and long bones that support hematopoiesis in order to maintain the physiologic turnover of all blood cells. Silk fibroin, derived from Bombyx mori silkworm cocoons, is a promising biomaterial for bone marrow engineering, because of its tunable architecture and mechanical properties, the capacity of incorporating labile compounds without loss of bioactivity and demonstrated ability to support blood cell formation. In this study, we developed a bone marrow scaffold consisting of a modular flow chamber made of polydimethylsiloxane, holding a silk sponge, prepared with salt leaching methods and functionalized with extracellular matrix components. The silk sponge was able to support efficient platelet formation when megakaryocytes were seeded in the system. Perfusion of the chamber allowed the recovery of functional platelets based on multiple activation tests. Further, inhibition of AKT signaling molecule, which has been shown to be crucial in regulating physiologic platelet formation, significantly reduced the number of collected platelets, suggesting the applicability of this tissue model for evaluation of the effects of bone marrow exposure to compounds that may affect platelet formation. In conclusion, we have bioengineered a novel modular system that, along with multi-porous silk sponges, can provide a useful technology for reproducing a simplified bone marrow scaffold for blood cell production ex vivo. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms.

PubMed

Herroon, Mackenzie K; Rajagurubandara, Erandi; Hardaway, Aimalie L; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-11-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

PubMed Central

Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-01-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease. PMID:24240026

Bone and fat connection in aging bone.

PubMed

Duque, Gustavo

2008-07-01

The fat and bone connection plays an important role in the pathophysiology of age-related bone loss. This review will focus on the age-induced mechanisms regulating the predominant differentiation of mesenchymal stem cells into adipocytes. Additionally, bone marrow fat will be considered as a diagnostic and therapeutic approach to osteoporosis. There are two types of bone and fat connection. The 'systemic connection', usually seen in obese patients, is hormonally regulated and associated with high bone mass and strength. The 'local connection' happens inside the bone marrow. Increasing amounts of bone marrow fat affect bone turnover through the inhibition of osteoblast function and survival and the promotion of osteoclast differentiation and activation. This interaction is regulated by paracrine secretion of fatty acids and adipokines. Additionally, bone marrow fat could be quantified using noninvasive methods and could be used as a therapeutic approach due to its capacity to transdifferentiate into bone without affecting other types of fat in the body. The bone and fat connection within the bone marrow constitutes a typical example of lipotoxicity. Additionally, bone marrow fat could be used as a new diagnostic and therapeutic approach for osteoporosis in older persons.

Circulating hematopoietic progenitor cells in patients affected by Chornobyl accident.

PubMed

Bilko, N M; Dyagil, I S; Russu, I Z; Bilko, D I

2016-12-01

High radiation sensitivity of stem cells and their ability to accumulate sublethal radiation damage provides the basis for investigation of hematopoietic progenitors using in vivo culture methodology. Unique samples of peripheral blood and bone marrow were derived from the patients affected by Chornobyl accident during liquidation campaign. To investigate functional activity of circulating hematopoietic progenitor cells from peripheral blood and bone marrow of cleanup workers in early and remote periods after the accident at Chornobyl nuclear power plant (CNPP). The assessment of the functional activity of circulating hematopoietic progenitor cells was performed in samples of peripheral blood and bone marrow of 46 cleanup workers, who were treated in the National Scientific Center for Radiation Medicine of the Academy of Medical Sciences of Ukraine alongside with 35 non radiated patients, who served as a control. Work was performed by culturing peripheral blood and bone marrow mononuclear cells in the original gel diffusion capsules, implanted into the peritoneal cavity of CBA mice. It was shown that hematopoietic progenitor cells could be identified in the peripheral blood of liquidators of CNPP accident. At the same time the number of functionally active progenitor cells of the bone marrow was significantly decreased and during the next 10 years after the accident, counts of circulating progenitor cells in the peripheral blood as well as functionally active hematopoietic cells in bone marrow returned to normal levels. It was shown that hematopoietic progenitor cells are detected not only in the bone marrow but also in the peripheral blood of liquidators as a consequence of radiation exposure associated with CNPP accident. This article is a part of a Special Issue entitled "The Chornobyl Nuclear Accident: Thirty Years After".

Development, regulation, metabolism and function of bone marrow adipose tissues.

PubMed

Li, Ziru; Hardij, Julie; Bagchi, Devika P; Scheller, Erica L; MacDougald, Ormond A

2018-05-01

Most adipocytes exist in discrete depots throughout the body, notably in well-defined white and brown adipose tissues. However, adipocytes also reside within specialized niches, of which the most abundant is within bone marrow. Whereas bone marrow adipose tissue (BMAT) shares many properties in common with white adipose tissue, the distinct functions of BMAT are reflected by its development, regulation, protein secretion, and lipid composition. In addition to its potential role as a local energy reservoir, BMAT also secretes proteins, including adiponectin, RANK ligand, dipeptidyl peptidase-4, and stem cell factor, which contribute to local marrow niche functions and which may also influence global metabolism. The characteristics of BMAT are also distinct depending on whether marrow adipocytes are contained within yellow or red marrow, as these can be thought of as 'constitutive' and 'regulated', respectively. The rBMAT for instance can be expanded or depleted by myriad factors, including age, nutrition, endocrine status and pharmaceuticals. Herein we review the site specificity, age-related development, regulation and metabolic characteristics of BMAT under various metabolic conditions, including the functional interactions with bone and hematopoietic cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of Spaceflight on Cells of Bone Marrow Origin

PubMed Central

Özçivici, Engin

2013-01-01

Once only a subject for science fiction novels, plans for establishing habitation on space stations, the Moon, and distant planets now appear among the short-term goals of space agencies. This article reviews studies that present biomedical issues that appear to challenge humankind for long-term spaceflights. With particularly focus on cells of bone marrow origin, studies involving changes in bone, immune, and red blood cell populations and their functions due to extended weightlessness were reviewed. Furthermore, effects of mechanical disuse on primitive stem cells that reside in the bone marrow were also included in this review. Novel biomedical solutions using space biotechnology will be required in order to achieve the goal of space exploration without compromising the functions of bone marrow, as spaceflight appears to disrupt homeostasis for all given cell types. Conflict of interest:None declared. PMID:24385745

Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases

PubMed Central

Hardaway, Aimalie L.; Herroon, Mackenzie K.; Rajagurubandara, Erandi

2014-01-01

Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease. PMID:24398857

Treatment of stroke with (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1, 2-diolate and bone marrow stromal cells upregulates angiopoietin-1/Tie2 and enhances neovascularization.

PubMed

Cui, X; Chen, J; Zacharek, A; Roberts, C; Savant-Bhonsale, S; Chopp, M

2008-09-22

Neovascularization may contribute to functional recovery after neural injury. Combination treatment of stroke with a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1, 2-diolate (DETA-NONOate) and bone marrow stromal cells promotes functional recovery. However, the mechanisms underlying functional improvement have not been elucidated. In this study, we tested the hypothesis that combination treatment upregulates angiopoietin-1 and its receptor Tie2 in the ischemic brain and bone marrow stromal cells, thereby enhancing cerebral neovascularization after stroke. Adult wild type male C57BL/6 mice were i.v. administered PBS, bone marrow stromal cells 5x10(5), DETA-NONOate 0.4 mg/kg or combination DETA-NONOate with bone marrow stromal cells (n=12/group) after middle cerebral artery occlusion. Combination treatment significantly upregulated angiopoietin-1/Tie2 and tight junction protein (occludin) expression, and increased the number, diameter and perimeter of blood vessels in the ischemic brain compared with vehicle control (mean+ or -S.E., P<0.05). In vitro, DETA-NONOate significantly increased angiopoietin-1/Tie2 protein (n=6/group) and Tie2 mRNA (n=3/group) expression in bone marrow stromal cells. DETA-NONOate also significantly increased angiopoietin-1 protein (n=6/group) and mRNA (n=3/group) expression in mouse brain endothelial cells (P<0.05). Angiopoietin-1 mRNA (n=3/group) was significantly increased in mouse brain endothelial cells treated with DETA-NONOate in combination with bone marrow stromal cell-conditioned medium compared with cells treated with bone marrow stromal cell-conditioned medium or DETA-NONOate alone. Mouse brain endothelial cell capillary tube-like formation assays (n=6/group) showed that angiopoietin-1 peptide, the supernatant of bone marrow stromal cells and DETA-NONOate significantly increased capillary tube formation compared with vehicle control. Combination treatment significantly increased capillary tube formation compared with DETA-NONOate treatment alone. Inhibition of angiopoietin-1 significantly attenuated combination treatment-induced tube formation. Our data indicated that combination treatment of stroke with DETA-NONOate and bone marrow stromal cells promotes neovascularization, which is at least partially mediated by upregulation of the angiopoietin-1/Tie2 axis.

Spaceflight alters immune cell function and distribution

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald; Mandel, Adrian D.; Konstantinova, Irina V.; Berry, Wallace D.; Taylor, Gerald R.; Lesniak, A. T.; Fuchs, Boris B.; Rakhmilevich, Alexander L.

1992-01-01

Experiments are described which were performed onboard Cosmos 2044 to determine spaceflight effects on immunologically important cell function and distribution. Results indicate that bone marrow cells from flown and suspended rats exhibited a decreased response to a granulocyte/monocyte colony-stimulating factor compared with the bone marrow cells from control rats. Bone marrow cells showed an increase in the percentage of cells expressing markers for helper T-cells in the myelogenous population and increased percentages of anti-asialo granulocyte/monocyte-1-bearing interleulin-2 receptor bearing pan T- and helper T-cells in the lymphocytic population.

Characterization of neutrophils and macrophages from ex vivo cultured murine bone marrow for morphologic maturation and functional responses by imaging flow cytometry

PubMed Central

Pelletier, Margery G. H.; Szymczak, Klaudia; Barbeau, Anna M.; Prata, Gianna N.; O’Fallon, Kevin S.; Gaines, Peter

2016-01-01

Neutrophils and macrophages differentiate from common myeloid progenitors in the bone marrow, where they undergo nuclear morphologic changes during maturation. During this process, both cell types acquire critical innate immune functions that include phagocytosis of pathogens, and for neutrophils the release of nuclear material called nuclear extracellular traps (NETs). Primary cells used to study these functions are typically purified from mature mouse tissues, but bone marrow-derived ex vivo cultures provide more abundant numbers of progenitors and functionally mature cells. Routine analyses of these cells use conventional microscopy and flow cytometry, which present limitations; microscopy is laborious and subjective, whereas flow cytometry lacks spatial resolution. Here we describe methods to generate enriched populations of neutrophils or macrophages from cryopreserved mouse bone marrow cultured ex vivo, and to use imaging flow cytometry that combines the resolution of microscopy with flow cytometry to analyze cells for morphologic features, phagocytosis, and NETosis. PMID:27663441

PPARγ antagonist attenuates mouse immune-mediated bone marrow failure by inhibition of T cell function

PubMed Central

Sato, Kazuya; Feng, Xingmin; Chen, Jichun; Li, Jungang; Muranski, Pawel; Desierto, Marie J.; Keyvanfar, Keyvan; Malide, Daniela; Kajigaya, Sachiko; Young, Neal S.

2016-01-01

Acquired aplastic anemia is an immune-mediated disease, in which T cells target hematopoietic cells; at presentation, the bone marrow is replaced by fat. It was reported that bone marrow adipocytes were negative regulators of hematopoietic microenvironment. To examine the role of adipocytes in bone marrow failure, we investigated peroxisomal proliferator-activated receptor gamma, a key transcription factor in adipogenesis, utilizing an antagonist of this factor called bisphenol-A-diglycidyl-ether. While bisphenol-A-diglycidyl-ether inhibited adipogenesis as expected, it also suppressed T cell infiltration of bone marrow, reduced plasma inflammatory cytokines, decreased expression of multiple inflammasome genes, and ameliorated marrow failure. In vitro, bisphenol-A-diglycidyl-ether suppressed activation and proliferation, and reduced phospholipase C gamma 1 and nuclear factor of activated T-cells 1 expression, as well as inhibiting calcium flux in T cells. The in vivo effect of bisphenol-A-diglycidyl-ether on T cells was confirmed in a second immune-mediated bone marrow failure model, using different strains and non-major histocompatibility antigen mismatched: bisphenol-A-diglycidyl-ether ameliorated marrow failure by inhibition of T cell infiltration of bone marrow. Our data indicate that peroxisomal proliferator-activated receptor gamma antagonists may attenuate murine immune-mediated bone marrow failure, at least in part, by suppression of T cell activation, which might hold implications in the application of peroxisomal proliferator-activated receptor gamma antagonists in immune-mediated pathophysiologies, both in the laboratory and in the clinic. Genetically “fatless” mice developed bone marrow failure with accumulation of marrow adipocytes in our model, even in the absence of body fat, suggesting different mechanisms of systematic and marrow adipogenesis and physiologic versus pathophysiologic fat accumulation. PMID:26589913

The bone marrow is not only a primary lymphoid organ: The critical role for T lymphocyte migration and housing of long-term memory plasma cells.

PubMed

Pabst, Reinhard

2018-05-22

In immunology and anatomy textbooks the bone marrow is described as a typical "primary lymphoid organ" producing lymphoid cells independent of antigens. The hematopoietic bone marrow is largely age-dependent organ with great anatomical and functional differences among various species. There are estimates that about 12% of all lymphoid cells in the human body are found in the bone marrow at any given time (2% in the peripheral blood). Enormous numbers of T lymphocytes migrate to the bone marrow and partly return later to the blood. Many of these lymphocytes are memory CD4 + and CD8 + T cells. A few days after immunization a wave of plasma cells and their precursors migrate to the bone marrow where they lose their migratory response to CXCL-12 and CXCL9. There is a relative enrichment of CD19 + B cells in the bone marrow outnumbering those in the blood and secondary lymphoid organs. This is not due to local production. The proliferation and migration kinetics of these lymphoid cells in the bone marrow have to be studied in more detail as this is of major clinical relevance. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bone marrow invasion in multiple myeloma and metastatic disease.

PubMed

Vilanova, J C; Luna, A

2016-04-01

Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Copper-64 Labeled Liposomes for Imaging Bone Marrow

PubMed Central

Lee, Sang-gyu; Gangangari, Kishore; Kalidindi, Teja Muralidhar; Punzalan, Blesida; Larson, Steven M.; Pillarsetty, Naga Vara Kishore

2016-01-01

Introduction Bone marrow is the soft tissue compartment inside the bones made up of hematopoietic cells, adipocytes, stromal cells, phagocytic cells, stem cells, and sinusoids. While [18F]-FLT has been utilized to image proliferative marrow, to date, there are no reports of particle based positron emission tomography (PET) imaging agents for imaging bone marrow. We have developed copper-64 labeled liposomal formulation that selectively targets bone marrow and therefore serves as an efficient PET probe for imaging bone marrow. Methods Optimized liposomal formulations were prepared with succinyl PE, DSPC, cholesterol, and mPEG-DSPE (69:39:1:10:0.1) with diameters of 90 and 140 nm, and were doped with DOTA-Bn-DSPE for stable 64Cu incorporation into liposomes. Results PET imaging and biodistribution studies with 64Cu-labeled liposomes indicate that accumulation in bone marrow was as high as 15.18 ± 3.69 %ID/g for 90 nm liposomes and 7.01 ± 0.92 %ID/g for 140 nm liposomes at 24 h post-administration. In vivo biodistribution studies in tumor-bearing mice indicate that the uptake of 90 nm particles is approximately 0.89 ± 0.48 %ID/g in tumor and 14.22 ± 8.07 %ID/g in bone marrow, but respective values for Doxil® like liposomes are 0.83 ± 0.49 %ID/g and 2.23 ± 1.00 %ID/g. Conclusion Our results indicate that our novel PET labeled liposomes target bone marrow with very high efficiency and therefore can function as efficient bone marrow imaging agents. PMID:27694056

Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy.

PubMed

Kini Bailur, Jithendra; Mehta, Sameet; Zhang, Lin; Neparidze, Natalia; Parker, Terri; Bar, Noffar; Anderson, Tara; Xu, Mina L; Dhodapkar, Kavita M; Dhodapkar, Madhav V

2017-11-28

Altered number, subset composition, and function of bone marrow innate lymphoid cells are early events in monoclonal gammopathies.Pomalidomide therapy leads to reduction in Ikzf1 and Ikzf3 and enhanced human innate lymphoid cell function in vivo.

Maintenance of Host Leukocytes in Peripheral Immune Compartments Following Lethal Irradiation and Bone Marrow Reconstitution: Implications for Graft Versus Host Disease

PubMed Central

Staley, Elizabeth M.; Tanner, Scott M.; Daft, Joseph G.; Stanus, Andrea L.; Martin, Steven M.; Lorenz, Robin G.

2013-01-01

Bone marrow reconstitution is utilized as a tool for disease treatment and as a research technique to elucidate the function of bone marrow derived cells. Clinically successful engraftment is indicated by the development of a functioning immune repertoire. In research, reconstitution is considered successful if >85% of splenic leukocytes are of donor origins. Previous work suggests that splenic reconstitution may not be indicative of reconstitution in the mucosa. We sought to evaluate mucosal reconstitution in animals following a standard bone marrow eradication and reconstitution technique. Bone marrow was harvested from adult B6.SJL donor mice (CD45.1) and injected via either the retro-orbital or intraperitoneal route into lethally irradiated B6 (CD45.2) adult or neonatal recipients respectively. Expression of CD45 by flow cytometry was used to calculate reconstitution with respect to immune compartment and cell type. In reconstituted adult animals 93.2±1.5% of splenic leukocytes expressed the donor CD45.1 antigen thus meeting the standard definition of reconstitution, however only 58.6±13.6% of intestinal lamina propria lymphocytes and 52.4±16.0% of intestinal intraepithelial lymphocytes were of donor origin, confirming splenic reconstitution fails to represent peripheral immune reconstitution. T-cells in the gastrointestinal tract are the most poorly reconstituted, while B-cells appear to be almost universally replaced by donor cells. The inadequate mucosal reconstitution was not corrected by evaluating later timepoints or by performing the bone marrow transfer during the neonatal period. This demonstration that substantial host T-cells remain in the intestinal mucosa after a “successful” bone marrow transplantation should cause a re-evaluation of data from research bone marrow chimera experiments, as well as the mechanisms for complications after clinical bone marrow transplantation. PMID:23334064

Maintenance of host leukocytes in peripheral immune compartments following lethal irradiation and bone marrow reconstitution: implications for graft versus host disease.

PubMed

Staley, Elizabeth M; Tanner, Scott M; Daft, Joseph G; Stanus, Andrea L; Martin, Steven M; Lorenz, Robin G

2013-03-01

Bone marrow reconstitution is utilized as a tool for disease treatment and as a research technique to elucidate the function of bone marrow derived cells. Clinically successful engraftment is indicated by the development of a functioning immune repertoire. In research, reconstitution is considered successful if >85% of splenic leukocytes are of donor origins. Previous work suggests that splenic reconstitution may not be indicative of reconstitution in the mucosa. We sought to evaluate mucosal reconstitution in animals following a standard bone marrow eradication and reconstitution technique. Bone marrow was harvested from adult B6.SJL donor mice (CD45.1) and injected via either the retro-orbital or intraperitoneal route into lethally irradiated B6 (CD45.2) adult or neonatal recipients respectively. The expression of CD45 by flow cytometry was used to calculate reconstitution with respect to immune compartment and cell type. In reconstituted adult animals 93.2±1.5% of splenic leukocytes expressed the donor CD45.1 antigen thus meeting the standard definition of reconstitution, however only 58.6±13.6% of intestinal lamina propria lymphocytes and 52.4±16.0% of intestinal intraepithelial lymphocytes were of donor origin, confirming splenic reconstitution fails to represent peripheral immune reconstitution. T-cells in the gastrointestinal tract are the most poorly reconstituted, while B-cells appear to be almost universally replaced by donor cells. The inadequate mucosal reconstitution was not corrected by evaluating later time points or by performing the bone marrow transfer during the neonatal period. This demonstration that substantial host T-cells remain in the intestinal mucosa after a "successful" bone marrow transplantation should cause a re-evaluation of data from research bone marrow chimera experiments, as well as the mechanisms for complications after clinical bone marrow transplantation. Copyright © 2013 Elsevier B.V. All rights reserved.

Concise Review: Bone Marrow Mononuclear Cells for the Treatment of Ischemic Syndromes: Medicinal Product or Cell Transplantation?

PubMed Central

Rico, Laura; Herrera, Concha

2012-01-01

In November of 2011, the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA) published two scientific recommendations regarding the classification of autologous bone marrow-derived mononuclear cells (BM-MNCs) and autologous bone marrow-derived CD133+ cells as advanced therapy medicinal products (ATMPs), specifically tissue-engineered products, when intended for regeneration in ischemic heart tissue on the basis that they are not used for the same essential function (hematological restoration) that they fulfill in the donor. In vitro and in vivo evidence demonstrates that bone marrow cells are physiologically involved in adult neovascularization and tissue repair, making their therapeutic use for these purposes a simple exploitation of their own essential functions. Therefore, from a scientific/legal point of view, nonsubstantially manipulated BM-MNCs and CD133+ cells are not an ATMP, because they have a physiological role in the processes of postnatal neovascularization and, when used therapeutically for vascular restoration in ischemic tissues, they are carrying out one of their essential physiological functions (the legal definition recognizes that cells can have several essential functions). The consequences of classifying BM-MNCs and CD133+ cells as medicinal products instead of cellular transplantation, like bone marrow transplantation, in terms of costs and time for these products to be introduced into clinical practice, make this an issue of crucial importance. Therefore, the recommendations of EMA/CAT could be reviewed in collaboration with scientific societies, in light of organizational and economic consequences as well as scientific knowledge recently acquired about the mechanisms of postnatal neovascularization and the function of bone marrow in the regeneration of remote tissues. PMID:23197819

Loss of c-Kit function impairs arteriogenesis in a mouse model of hindlimb ischemia.

PubMed

Hernandez, Diana R; Artiles, Adriana; Duque, Juan C; Martinez, Laisel; Pinto, Mariana T; Webster, Keith A; Velazquez, Omaida C; Vazquez-Padron, Roberto I; Lassance-Soares, Roberta M

2018-04-01

Arteriogenesis is a process whereby collateral vessels remodel usually in response to increased blood flow and/or wall stress. Remodeling of collaterals can function as a natural bypass to alleviate ischemia during arterial occlusion. Here we used a genetic approach to investigate possible roles of tyrosine receptor c-Kit in arteriogenesis. Mutant mice with loss of c-Kit function (Kit W/W-v ), and controls were subjected to hindlimb ischemia. Blood flow recovery was evaluated pre-, post-, and weekly after ischemia. Foot ischemic damage and function were assessed between days 1 to 14 post-ischemia while collaterals remodeling were measured 28 days post-ischemia. Both groups of mice also were subjected to wild type bone marrow cells transplantation 3 weeks before hindlimb ischemia to evaluate possible contributions of defective bone marrow c-Kit expression on vascular recovery. Kit W/W-v mice displayed impaired blood flow recovery, greater ischemic damage and foot dysfunction after ischemia compared to controls. Kit W/W-v mice also demonstrated impaired collateral remodeling consistent with flow recovery findings. Because arteriogenesis is a biological process that involves bone marrow-derived cells, we investigated which source of c-Kit signaling (bone marrow or vascular) plays a major role in arteriogenesis. Kit W/W-v mice transplanted with bone marrow wild type cells exhibited similar phenotype of impaired blood flow recovery, greater tissue ischemic damage and foot dysfunction as nontransplanted Kit W/W-v mice. This study provides evidence that c-Kit signaling is required during arteriogenesis. Also, it strongly suggests a vascular role for c-Kit signaling because rescue of systemic c-Kit activity by bone marrow transplantation did not augment the functional recovery of Kit W/W-v mouse hindlimbs. Copyright © 2017 Elsevier Inc. All rights reserved.

Obesity-driven disruption of haematopoiesis and the bone marrow niche.

PubMed

Adler, Benjamin J; Kaushansky, Kenneth; Rubin, Clinton T

2014-12-01

Obesity markedly increases susceptibility to a range of diseases and simultaneously undermines the viability and fate selection of haematopoietic stem cells (HSCs), and thus the kinetics of leukocyte production that is critical to innate and adaptive immunity. Considering that blood cell production and the differentiation of HSCs and their progeny is orchestrated, in part, by complex interacting signals emanating from the bone marrow microenvironment, it is not surprising that conditions that disturb bone marrow structure inevitably disrupt both the numbers and lineage-fates of these key blood cell progenitors. In addition to the increased adipose burden in visceral and subcutaneous compartments, obesity causes a marked increase in the size and number of adipocytes encroaching into the bone marrow space, almost certainly disturbing HSC interactions with neighbouring cells, which include osteoblasts, osteoclasts, mesenchymal cells and endothelial cells. As the global obesity pandemic grows, the short-term and long-term consequences of increased bone marrow adiposity on HSC lineage selection and immune function remain uncertain. This Review discusses the differentiation and function of haematopoietic cell populations, the principal physicochemical components of the bone marrow niche, and how this environment influences HSCs and haematopoiesis in general. The effect of adipocytes and adiposity on HSC and progenitor cell populations is also discussed, with the goal of understanding how obesity might compromise the core haematopoietic system.

Radionuclide imaging of bone marrow disorders

PubMed Central

Agool, Ali; Glaudemans, Andor W. J. M.; Boersma, Hendrikus H.; Dierckx, Rudi A. J. O.; Vellenga, Edo

2010-01-01

Noninvasive imaging techniques have been used in the past for visualization the functional activity of the bone marrow compartment. Imaging with radiolabelled compounds may allow different bone marrow disorders to be distinguished. These imaging techniques, almost all of which use radionuclide-labelled tracers, such as 99mTc-nanocolloid, 99mTc-sulphur colloid, 111In-chloride, and radiolabelled white blood cells, have been used in nuclear medicine for several decades. With these techniques three separate compartments can be recognized including the reticuloendothelial system, the erythroid compartment and the myeloid compartment. Recent developments in research and the clinical use of PET tracers have made possible the analysis of additional properties such as cellular metabolism and proliferative activity, using 18F-FDG and 18F-FLT. These tracers may lead to better quantification and targeting of different cell systems in the bone marrow. In this review the imaging of different bone marrow targets with radionuclides including PET tracers in various bone marrow diseases are discussed. PMID:20625724

A STUDY OF PREDICTED BONE MARROW DISTRIBUTION ON CALCULATED MARROW DOSE FROM EXTERNAL RADIATION EXPOSURES USING TWO SETS OF IMAGE DATA FOR THE SAME INDIVIDUAL

PubMed Central

Caracappa, Peter F.; Chao, T. C. Ephraim; Xu, X. George

2010-01-01

Red bone marrow is among the tissues of the human body that are most sensitive to ionizing radiation, but red bone marrow cannot be distinguished from yellow bone marrow by normal radiographic means. When using a computational model of the body constructed from computed tomography (CT) images for radiation dose, assumptions must be applied to calculate the dose to the red bone marrow. This paper presents an analysis of two methods of calculating red bone marrow distribution: 1) a homogeneous mixture of red and yellow bone marrow throughout the skeleton, and 2) International Commission on Radiological Protection cellularity factors applied to each bone segment. A computational dose model was constructed from the CT image set of the Visible Human Project and compared to the VIP-Man model, which was derived from color photographs of the same individual. These two data sets for the same individual provide the unique opportunity to compare the methods applied to the CT-based model against the observed distribution of red bone marrow for that individual. The mass of red bone marrow in each bone segment was calculated using both methods. The effect of the different red bone marrow distributions was analyzed by calculating the red bone marrow dose using the EGS4 Monte Carlo code for parallel beams of monoenergetic photons over an energy range of 30 keV to 6 MeV, cylindrical (simplified CT) sources centered about the head and abdomen over an energy range of 30 keV to 1 MeV, and a whole-body electron irradiation treatment protocol for 3.9 MeV electrons. Applying the method with cellularity factors improves the average difference in the estimation of mass in each bone segment as compared to the mass in VIP-Man by 45% over the homogenous mixture method. Red bone marrow doses calculated by the two methods are similar for parallel photon beams at high energy (above about 200 keV), but differ by as much as 40% at lower energies. The calculated red bone marrow doses differ significantly for simplified CT and electron beam irradiation, since the computed red bone marrow dose is a strong function of the cellularity factor applied to bone segments within the primary radiation beam. These results demonstrate the importance of properly applying realistic cellularity factors to computation dose models of the human body. PMID:19430219

A study of predicted bone marrow distribution on calculated marrow dose from external radiation exposures using two sets of image data for the same individual.

PubMed

Caracappa, Peter F; Chao, T C Ephraim; Xu, X George

2009-06-01

Red bone marrow is among the tissues of the human body that are most sensitive to ionizing radiation, but red bone marrow cannot be distinguished from yellow bone marrow by normal radiographic means. When using a computational model of the body constructed from computed tomography (CT) images for radiation dose, assumptions must be applied to calculate the dose to the red bone marrow. This paper presents an analysis of two methods of calculating red bone marrow distribution: 1) a homogeneous mixture of red and yellow bone marrow throughout the skeleton, and 2) International Commission on Radiological Protection cellularity factors applied to each bone segment. A computational dose model was constructed from the CT image set of the Visible Human Project and compared to the VIP-Man model, which was derived from color photographs of the same individual. These two data sets for the same individual provide the unique opportunity to compare the methods applied to the CT-based model against the observed distribution of red bone marrow for that individual. The mass of red bone marrow in each bone segment was calculated using both methods. The effect of the different red bone marrow distributions was analyzed by calculating the red bone marrow dose using the EGS4 Monte Carlo code for parallel beams of monoenergetic photons over an energy range of 30 keV to 6 MeV, cylindrical (simplified CT) sources centered about the head and abdomen over an energy range of 30 keV to 1 MeV, and a whole-body electron irradiation treatment protocol for 3.9 MeV electrons. Applying the method with cellularity factors improves the average difference in the estimation of mass in each bone segment as compared to the mass in VIP-Man by 45% over the homogenous mixture method. Red bone marrow doses calculated by the two methods are similar for parallel photon beams at high energy (above about 200 keV), but differ by as much as 40% at lower energies. The calculated red bone marrow doses differ significantly for simplified CT and electron beam irradiation, since the computed red bone marrow dose is a strong function of the cellularity factor applied to bone segments within the primary radiation beam. These results demonstrate the importance of properly applying realistic cellularity factors to computation dose models of the human body.

Long-term survival of donor bone marrow multipotent mesenchymal stromal cells implanted into the periosteum of patients with allogeneic graft failure.

PubMed

Kuzmina, L A; Petinati, N A; Sats, N V; Drize, N J; Risinskaya, N V; Sudarikov, A B; Vasilieva, V A; Drokov, M Y; Michalzova, E D; Parovichnikova, E N; Savchenko, V G

2016-09-01

The present study involved three patients with graft failure following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We obtained multipotent mesenchymal stromal cells (MSCs) from the original hematopoietic cell donors and implanted these cells in the periosteum to treat long-term bone marrow aplasia. The results showed that in all patients endogenous blood formation was recovered 2 weeks after MSC administration. Donor MSCs were found in recipient bone marrow three and 5 months following MSC implantation. Thus, our findings indicate that functional donor MSCs can persist in patient bone marrow.

Secretome within the bone marrow microenvironment: A basis for mesenchymal stem cell treatment and role in cancer dormancy.

PubMed

Eltoukhy, Hussam S; Sinha, Garima; Moore, Caitlyn; Gergues, Marina; Rameshwar, Pranela

2018-05-31

The secretome produced by cells within the bone marrow is significant to homeostasis. The bone marrow, a well-studied organ, has multiple niches with distinct roles for supporting stem cell functions. Thus, an understanding of mediators involved in the regulation of stem cells could serve as a model for clinical problems and solutions such as tissue repair and regeneration. The exosome secretome of bone marrow stem cells is a developing area of research with respect to the regenerative potential by bone marrow cell, particularly the mesenchymal stem cells. The bone marrow niche regulates endogenous processes such as hematopoiesis but could also support the survival of tumors such as facilitating the cancer stem cells to exist in dormancy for decades. The bone marrow-derived secretome will be critical to future development of therapeutic strategies for oncologic diseases, in addition to regenerative medicine. This article discusses the importance for parallel studies to determine how the same secretome may compromise safety during the use of stem cells in regenerative medicine. Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Human bone marrow harbors cells with neural crest-associated characteristics like human adipose and dermis tissues

PubMed Central

Coste, Cécile; Neirinckx, Virginie; Sharma, Anil; Agirman, Gulistan; Rogister, Bernard; Foguenne, Jacques; Lallemend, François

2017-01-01

Adult neural crest stem-derived cells (NCSC) are of extraordinary high plasticity and promising candidates for use in regenerative medicine. Several locations such as skin, adipose tissue, dental pulp or bone marrow have been described in rodent, as sources of NCSC. However, very little information is available concerning their correspondence in human tissues, and more precisely for human bone marrow. The main objective of this study was therefore to characterize NCSC from adult human bone marrow. In this purpose, we compared human bone marrow stromal cells to human adipose tissue and dermis, already described for containing NCSC. We performed comparative analyses in terms of gene and protein expression as well as functional characterizations. It appeared that human bone marrow, similarly to adipose tissue and dermis, contains NESTIN+ / SOX9+ / TWIST+ / SLUG+ / P75NTR+ / BRN3A+/ MSI1+/ SNAIL1+ cells and were able to differentiate into melanocytes, Schwann cells and neurons. Moreover, when injected into chicken embryos, all those cells were able to migrate and follow endogenous neural crest migration pathways. Altogether, the phenotypic characterization and migration abilities strongly suggest the presence of neural crest-derived cells in human adult bone marrow. PMID:28683107

The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function

PubMed Central

Isern, Joan; García-García, Andrés; Martín, Ana M; Arranz, Lorena; Martín-Pérez, Daniel; Torroja, Carlos; Sánchez-Cabo, Fátima; Méndez-Ferrer, Simón

2014-01-01

Mesenchymal stem cells (MSCs) and osteolineage cells contribute to the hematopoietic stem cell (HSC) niche in the bone marrow of long bones. However, their developmental relationships remain unclear. In this study, we demonstrate that different MSC populations in the developing marrow of long bones have distinct functions. Proliferative mesoderm-derived nestin− MSCs participate in fetal skeletogenesis and lose MSC activity soon after birth. In contrast, quiescent neural crest-derived nestin+ cells preserve MSC activity, but do not generate fetal chondrocytes. Instead, they differentiate into HSC niche-forming MSCs, helping to establish the HSC niche by secreting Cxcl12. Perineural migration of these cells to the bone marrow requires the ErbB3 receptor. The neonatal Nestin-GFP+ Pdgfrα− cell population also contains Schwann cell precursors, but does not comprise mature Schwann cells. Thus, in the developing bone marrow HSC niche-forming MSCs share a common origin with sympathetic peripheral neurons and glial cells, and ontogenically distinct MSCs have non-overlapping functions in endochondrogenesis and HSC niche formation. DOI: http://dx.doi.org/10.7554/eLife.03696.001 PMID:25255216

Distinct bone marrow blood vessels differentially regulate haematopoiesis.

PubMed

Itkin, Tomer; Gur-Cohen, Shiri; Spencer, Joel A; Schajnovitz, Amir; Ramasamy, Saravana K; Kusumbe, Anjali P; Ledergor, Guy; Jung, Yookyung; Milo, Idan; Poulos, Michael G; Kalinkovich, Alexander; Ludin, Aya; Kollet, Orit; Shakhar, Guy; Butler, Jason M; Rafii, Shahin; Adams, Ralf H; Scadden, David T; Lin, Charles P; Lapidot, Tsvee

2016-04-21

Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols.

Combinatorial Gata2 and Sca1 expression defines hematopoietic stem cells in the bone marrow niche

PubMed Central

Suzuki, Norio; Ohneda, Osamu; Minegishi, Naoko; Nishikawa, Mitsuo; Ohta, Takayuki; Takahashi, Satoru; Engel, James Douglas; Yamamoto, Masayuki

2006-01-01

The interaction between stem cells and their supportive microenvironment is critical for their maintenance, function, and survival. Whereas hematopoietic stem cells (HSCs) are among the best characterized of tissue stem cells, their precise site of residence (referred to as the niche) in the adult bone marrow has not been precisely defined. In this study, we found that a Gata2 promoter directs activity in all HSCs. We show that HSCs can be isolated efficiently from bone marrow cells by following Gata2-directed GFP fluorescence, and that they can also be monitored in vivo. Each individual GFP-positive cell lay in a G0/G1 cell cycle state, in intimate contact with osteoblasts beside the endosteum, at the edge of the bone marrow. We conclude that the HSC niche is composed of solitary cells and that adult bone marrow HSC are not clustered. PMID:16461905

Selection, proliferation and differentiation of bone marrow-derived liver stem cells with a culture system containing cholestatic serum in vitro.

PubMed

Cai, Yun-Feng; Zhen, Zuo-Jun; Min, Jun; Fang, Tian-Ling; Chu, Zhong-Hua; Chen, Ji-Sheng

2004-11-15

To explore the feasibility of direct separation, selective proliferation and differentiation of the bone marrow-derived liver stem cells (BDLSC) from bone marrow cells with a culture system containing cholestatic serum in vitro. Whole bone marrow cells of rats cultured in routine medium were replaced with conditioning selection media containing 20 mL/L, 50 mL/L, 70 mL/L, and 100 mL/L cholestatic sera, respectively, after they attached to the plates. The optimal concentration of cholestatic serum was determined according to the outcome of the selected cultures. Then the selected BDLSC were induced to proliferate and differentiate with the addition of hepatocyte growth factor (HGF). The morphology and phenotypic markers of BDLSC were characterized using immunohistochemistry, RT-PCR and electron microscopy. The metabolic functions of differentiated cells were also determined by glycogen staining and urea assay. Bone marrow cells formed fibroblast-like but not hepatocyte-like colonies in the presence of 20 mL/L cholestatic serum. In 70 mL/L cholestatic serum, BDLSC colonies could be selected but could not maintain good growth status. In 100 mL/L cholestatic serum, all of the bone marrow cells were unable to survive. A 50 mL/L cholestatic serum was the optimal concentration for the selection of BDLSC at which BDLSC could survive while the other populations of the bone marrow cells could not. The selected BDLSC proliferated and differentiated after HGF was added. Hepatocyte-like colony-forming units (H-CFU) then were formed. H-CFU expressed markers of embryonic hepatocytes (AFP, albumin and cytokeratin 8/18), biliary cells (cytokeratin 19), hepatocyte functional proteins (transthyretin and cytochrome P450-2b1), and hepatocyte nuclear factors (HNF-1alpha and HNF-3beta). They also had glycogen storage and urea synthesis functions, two of the critical features of hepatocytes. The selected medium containing cholestatic serum can select BDLSC from whole bone marrow cells. It will be a new way to provide a readily available alternate source of cells for clinical hepatocyte therapy.

Transplantation of autologous bone marrow-derived mesenchymal stem cells for traumatic brain injury☆

PubMed Central

Jiang, Jindou; Bu, Xingyao; Liu, Meng; Cheng, Peixun

2012-01-01

Results from the present study demonstrated that transplantation of autologous bone marrow-derived mesenchymal stem cells into the lesion site in rat brain significantly ameliorated brain tissue pathological changes and brain edema, attenuated glial cell proliferation, and increased brain-derived neurotrophic factor expression. In addition, the number of cells double-labeled for 5-bromodeoxyuridine/glial fibrillary acidic protein and cells expressing nestin increased. Finally, blood vessels were newly generated, and the rats exhibited improved motor and cognitive functions. These results suggested that transplantation of autologous bone marrow-derived mesenchymal stem cells promoted brain remodeling and improved neurological functions following traumatic brain injury. PMID:25806058

Methods for Studying the Role of RAAS in the Modulation of Vascular Repair-Relevant Functions of Stem/Progenitor Cells.

PubMed

Jarajapu, Yagna P R

2017-01-01

In recent years, previously unknown functions have been conferred to the RAAS and have been explored in mechanistic studies and disease models. Implication of bone marrow stem/progenitor cells in the cardiovascular protective or detrimental effects of RAAS is a prominent advancement because of the translational significance. Selected members of RAAS are now known to modulate migration, proliferation, and mobilization of bone marrow cells in response to ischemic insult, which are sensitive indicators of vascular repair-relevant functions. In this Chapter, protocols for most frequently used, in vitro, ex vivo, and in vivo assays to explore the potential of RAAS members to stimulate vascular repair-relevant functions of bone marrow stem/progenitor cells of human and murine origin.

Clinical Evaluation of Decellularized Nerve Allograft with Autologous Bone Marrow Stem Cells to Improve Peripheral Nerve Repair and Functional Outcomes

DTIC Science & Technology

2016-07-01

AWARD NUMBER: W81XWH-15-2-0026 TITLE: Clinical Evaluation of Decellularized Nerve Allograft With Autologous Bone Marrow Stem Cells To Improve...5b. GRANT NUMBER W81XWH-15-2-0026 CClinical Evaluation of Decellularized Nerve Allograft With Autologous Bone Marrow Stem Cells To Improve...co- treatments of a commercially available decellularized processed peripheral nerve allograft scaffold (Avance® Nerve Graft, AxoGen, Alachua FL) with

Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis.

PubMed

Cheung, Laurence C; Strickland, Deborah H; Howlett, Meegan; Ford, Jette; Charles, Adrian K; Lyons, Karen M; Brigstock, David R; Goldschmeding, Roel; Cole, Catherine H; Alexander, Warren S; Kees, Ursula R

2014-07-01

Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis. Copyright© Ferrata Storti Foundation.

Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis

PubMed Central

Cheung, Laurence C.; Strickland, Deborah H.; Howlett, Meegan; Ford, Jette; Charles, Adrian K.; Lyons, Karen M.; Brigstock, David R.; Goldschmeding, Roel; Cole, Catherine H.; Alexander, Warren S.; Kees, Ursula R.

2014-01-01

Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis. PMID:24727816

Bone marrow aspiration

MedlinePlus

Iliac crest tap; Sternal tap; Leukemia - bone marrow aspiration; Aplastic anemia - bone marrow aspiration; Myelodysplastic syndrome - bone marrow aspiration; Thrombocytopenia - bone marrow aspiration; Myelofibrosis - bone marrow aspiration

Bone marrow osteoblast vulnerability to chemotherapy

PubMed Central

Gencheva, Marieta; Hare, Ian; Kurian, Susan; Fortney, Jim; Piktel, Debbie; Wysolmerski, Robert; Gibson, Laura F.

2013-01-01

Osteoblasts are a major component of the bone marrow microenvironment which provide support for hematopoietic cell development. Functional disruption of any element of the bone marrow niche, including osteoblasts, can potentially impair hematopoiesis. We have studied the effect of two widely used drugs with different mechanisms of action, etoposide (VP16) and melphalan, on murine osteoblasts at distinct stages of maturation. VP16 and melphalan delayed maturation of preosteoblasts and altered CXCL12 protein levels, a key regulator of hematopoietic cell homing to the bone marrow. Sublethal concentrations of VP16 and melphalan also decreased the levels of several transcripts which contribute to the composition of the extracellular matrix (ECM) including osteopontin (OPN), osteocalcin (OCN) and collagen 1A1 (Col1a1). The impact of chemotherapy on message and protein levels for some targets was not always aligned, suggesting differential responses at the transcription and translation or protein stability levels. Since one of the main functions of a mature osteoblast is to synthesize ECM of a defined composition, disruption of the ratio of its components may be one mechanism by which chemotherapy affects the ability of osteoblasts to support hematopoietic recovery coincident with altered marrow architecture. Collectively, these observations suggest that the osteoblast compartment of the marrow hematopoietic niche is vulnerable to functional dysregulation by damage imposed by agents frequently used in clinical settings. Understanding the mechanistic underpinning of chemotherapy-induced changes on the hematopoietic support capacity of the marrow microenvironment may contribute to improved strategies to optimize patient recovery post-transplantation. PMID:23551534

Rad GTPase is essential for the regulation of bone density and bone marrow adipose tissue in mice.

PubMed

Withers, Catherine N; Brown, Drew M; Byiringiro, Innocent; Allen, Matthew R; Condon, Keith W; Satin, Jonathan; Andres, Douglas A

2017-10-01

The small GTP-binding protein Rad (RRAD, Ras associated with diabetes) is the founding member of the RGK (Rad, Rem, Rem2, and Gem/Kir) family that regulates cardiac voltage-gated Ca 2+ channel function. However, its cellular and physiological functions outside of the heart remain to be elucidated. Here we report that Rad GTPase function is required for normal bone homeostasis in mice, as Rad deletion results in significantly lower bone mass and higher bone marrow adipose tissue (BMAT) levels. Dynamic histomorphometry in vivo and primary calvarial osteoblast assays in vitro demonstrate that bone formation and osteoblast mineralization rates are depressed, while in vitro osteoclast differentiation is increased, in the absence of Rad. Microarray analysis revealed that canonical osteogenic gene expression (Runx2, osterix, etc.) is not altered in Rad -/- calvarial osteoblasts; instead robust up-regulation of matrix Gla protein (MGP, +11-fold), an inhibitor of extracellular matrix mineralization and a protein secreted during adipocyte differentiation, was observed. Strikingly, Rad deficiency also resulted in significantly higher marrow adipose tissue levels in vivo and promoted spontaneous in vitro adipogenesis of primary calvarial osteoblasts. Adipogenic differentiation of wildtype calvarial osteoblasts resulted in the loss of endogenous Rad protein, further supporting a role for Rad in the control of BMAT levels. These findings reveal a novel in vivo function for Rad and establish a role for Rad signaling in the complex physiological control of skeletal homeostasis and bone marrow adiposity. Copyright © 2017 Elsevier Inc. All rights reserved.

Hematopoietic Stem Cells in Neural-crest Derived Bone Marrow.

PubMed

Jiang, Nan; Chen, Mo; Yang, Guodong; Xiang, Lusai; He, Ling; Hei, Thomas K; Chotkowski, Gregory; Tarnow, Dennis P; Finkel, Myron; Ding, Lei; Zhou, Yanheng; Mao, Jeremy J

2016-12-21

Hematopoietic stem cells (HSCs) in the endosteum of mesoderm-derived appendicular bones have been extensively studied. Neural crest-derived bones differ from appendicular bones in developmental origin, mode of bone formation and pathological bone resorption. Whether neural crest-derived bones harbor HSCs is elusive. Here, we discovered HSC-like cells in postnatal murine mandible, and benchmarked them with donor-matched, mesoderm-derived femur/tibia HSCs, including clonogenic assay and long-term culture. Mandibular CD34 negative, LSK cells proliferated similarly to appendicular HSCs, and differentiated into all hematopoietic lineages. Mandibular HSCs showed a consistent deficiency in lymphoid differentiation, including significantly fewer CD229 + fractions, PreProB, ProB, PreB and B220 + slgM cells. Remarkably, mandibular HSCs reconstituted irradiated hematopoietic bone marrow in vivo, just as appendicular HSCs. Genomic profiling of osteoblasts from mandibular and femur/tibia bone marrow revealed deficiencies in several HSC niche regulators among mandibular osteoblasts including Cxcl12. Neural crest derived bone harbors HSCs that function similarly to appendicular HSCs but are deficient in the lymphoid lineage. Thus, lymphoid deficiency of mandibular HSCs may be accounted by putative niche regulating genes. HSCs in craniofacial bones have functional implications in homeostasis, osteoclastogenesis, immune functions, tumor metastasis and infections such as osteonecrosis of the jaw.

Identification, characterization and isolation of a common progenitor for osteoclasts, macrophages and dendritic cells from murine bone marrow and periphery

PubMed Central

Jacome-Galarza, Christian E.; Lee, Sun-Kyeong; Lorenzo, Joseph A.; LeonardoAguila, Hector

2012-01-01

Osteoclasts are specialized bone resorbing cells that derive from monocyte precursors. We have identified three populations of cells with high osteoclastogenic potential in murine bone marrow, which expressed the phenotype: B220−CD3−CD11b−/low CD115+ and either CD117hi, CD117intermediate or CD117low. We have evaluated these populations for their ability to also generate macrophages and dendritic cells. At a single cell level, the population expressing higher CD117 levels was able to generate bone-resorbing osteoclasts, phagocytic macrophages and antigen-presenting dendritic cells in vitro with efficiencies of over 90 percent, indicating that there exists a common developmental pathway for these cell types. Cells with osteoclastogenic potential also exist in blood and peripheral hematopoietic organs. Their functional meaning and/or their relationship with bone marrow progenitors is not well established. Hence, we characterized murine peripheral cell populations for their ability to form osteoclasts, macrophages and dendritic cells in vitro. The spleen and peripheral blood monocyte progenitors share phenotypic markers with bone marrow progenitors, but differ in their expression of CD11b, which was low in bone marrow but high in periphery. We propose that circulating monocyte progenitors are derived from a common bone marrow osteoclasts/macrophage/dendritic cell progenitor (OcMDC), which we have now characterized at a clonal level. However, the lineage relationship between the bone marrow and peripheral monocyte progenitors has yet to be defined. PMID:23165930

CHARACTERIZATION OF FATTY ACID COMPOSITION IN BONE MARROW FLUID FROM POSTMENOPAUSAL WOMEN: MODIFICATION AFTER HIP FRACTURE

PubMed Central

Miranda, Melissa; Pino, Ana María; Fuenzalida, Karen; Rosen, Clifford J.; Seitz, Germán; Rodríguez, J. Pablo

2016-01-01

Bone marrow adipose tissue (BMAT) is associated with low bone mass, although the functional consequences for skeletal maintenance of increased BMAT are currently unclear. BMAT might have a role in systemic energy metabolism, and could be an energy source as well as an endocrine organ for neighboring bone cells, releasing cytokines, adipokines and free fatty acids into the bone marrow microenvironment. The aim of the present report was to compare the fatty acid composition in the bone marrow supernatant fluid (BMSF) and blood plasma of postmenopausal women women (65 to 80 years old). BMSF was obtained after spinning the aspirated bone marrow samples; donors were classified as control, osteopenic or osteoporotic after dual-energy X-ray absorptiometry. Total lipids from human bone marrow fluid and plasma were extracted, converted to the corresponding methyl esters, and finally analyzed by a gas chromatographer coupled with a mass spectrometer. Results showed that fatty acid composition in BMSF was dynamic and distinct from blood plasma, implying significance in the locally produced lipids. The fatty acid composition in the BMSF was enriched in saturated fatty acid and decreased in unsaturated fatty acids as compared to blood plasma, but this relationship switched in women who suffered a hip fracture. On the other hand, there was no relationship between BMSF and bone mineral density. In conclusion, lipid composition of BMSF is distinct from the circulatory compartment, most likely reflecting the energy needs of the marrow compartment. PMID:27416518

T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments.

PubMed

Hawkins, Edwin D; Duarte, Delfim; Akinduro, Olufolake; Khorshed, Reema A; Passaro, Diana; Nowicka, Malgorzata; Straszkowski, Lenny; Scott, Mark K; Rothery, Steve; Ruivo, Nicola; Foster, Katie; Waibel, Michaela; Johnstone, Ricky W; Harrison, Simon J; Westerman, David A; Quach, Hang; Gribben, John; Robinson, Mark D; Purton, Louise E; Bonnet, Dominique; Lo Celso, Cristina

2016-10-27

It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. Here we studied a mouse model of human T-cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single-cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting that a stochastic mechanism underlies these processes. Yet, although T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells while perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment, rather than specific bone marrow stroma, to combat the invasion by and survival of chemo-resistant T-ALL cells.

Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation.

PubMed

Capasso, Stefania; Alessio, Nicola; Di Bernardo, Giovanni; Cipollaro, Marilena; Melone, Mariarosa Ab; Peluso, Gianfranco; Giordano, Antonio; Galderisi, Umberto

2014-01-01

Bone marrow adipose tissue (BMAT) is different from fat found elsewhere in the body, and only recently have some of its functions been investigated. BMAT may regulate bone marrow stem cell niche and plays a role in energy storage and thermogenesis. BMAT may be involved also in obesity and osteoporosis onset. Given the paramount functions of BMAT, we decided to better clarify the human bone marrow adipogenesis by analyzing the role of the retinoblastoma gene family, which are key players in cell cycle regulation. Our data provide evidence that the inactivation of RB1 or RB2/P130 in uncommitted bone marrow stromal cells (BMSC) facilitates the first steps of adipogenesis. In cultures with silenced RB1 or RB2/P130, we observed an increase of clones with adipogenic potential and a higher percentage of cells accumulating lipid droplets. Nevertheless, the absence of RB1 or RB2/P130 impaired the terminal adipocyte differentiation and gave rise to dysregulated adipose cells, with alteration in lipid uptake and release. For the first time, we evidenced that RB2/P130 plays a role in bone marrow adipogenesis. Our data suggest that while the inactivation of retinoblastoma proteins may delay the onset of last cell division and allow more BMSC to be committed to adipocyte, it did not allow a permanent cell cycle exit, which is a prerequisite for adipocyte terminal maturation.

Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation

PubMed Central

Capasso, Stefania; Alessio, Nicola; Di Bernardo, Giovanni; Cipollaro, Marilena; Melone, Mariarosa AB; Peluso, Gianfranco; Giordano, Antonio; Galderisi, Umberto

2014-01-01

Bone marrow adipose tissue (BMAT) is different from fat found elsewhere in the body, and only recently have some of its functions been investigated. BMAT may regulate bone marrow stem cell niche and plays a role in energy storage and thermogenesis. BMAT may be involved also in obesity and osteoporosis onset. Given the paramount functions of BMAT, we decided to better clarify the human bone marrow adipogenesis by analyzing the role of the retinoblastoma gene family, which are key players in cell cycle regulation. Our data provide evidence that the inactivation of RB1 or RB2/P130 in uncommitted bone marrow stromal cells (BMSC) facilitates the first steps of adipogenesis. In cultures with silenced RB1 or RB2/P130, we observed an increase of clones with adipogenic potential and a higher percentage of cells accumulating lipid droplets. Nevertheless, the absence of RB1 or RB2/P130 impaired the terminal adipocyte differentiation and gave rise to dysregulated adipose cells, with alteration in lipid uptake and release. For the first time, we evidenced that RB2/P130 plays a role in bone marrow adipogenesis. Our data suggest that while the inactivation of retinoblastoma proteins may delay the onset of last cell division and allow more BMSC to be committed to adipocyte, it did not allow a permanent cell cycle exit, which is a prerequisite for adipocyte terminal maturation. PMID:24281253

Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment

PubMed Central

Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Fahey, Frederic; Daley, George Q.

2009-01-01

Osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC) in mammalian bone marrow (BM) 1,2,3 . Adult BM also contains adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. Fatty infiltration of hematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia 4. To explore whether adipocytes influence hematopoiesis or simply fill marrow space, we compared the hematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. By flow cytometry, colony forming activity, and competitive repopulation assay, HSCs and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes8, and in mice treated with the PPARγ inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE), which inhibits adipogenesis9, post-irradiation marrow engraftment is accelerated relative to wild type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone marrow microenvironment, and suggest that antagonizingmarrow adipogenesis may enhance hematopoietic recovery in clinical bone marrow transplantation. PMID:19516257

Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells.

PubMed

Laurent, Julien; Touvrey, Cédric; Botta, Francesca; Kuonen, François; Ruegg, Curzio

2011-01-01

Cancer-related inflammation has emerged in recent years as a major event contributing to tumor angiogenesis, tumor progression and metastasis formation. Bone marrow-derived and inflammatory cells promote tumor angiogenesis by providing endothelial progenitor cells that differentiate into mature endothelial cells, and by secreting pro-angiogenic factors and remodeling the extracellular matrix to stimulate angiogenesis though paracrine mechanisms. Several bone marrow-derived myelonomocytic cells, including monocytes and macrophages, have been identified and characterized by several laboratories in recent years. While the central role of these cells in promoting tumor angiogenesis, tumor progression and metastasis is nowadays well established, many questions remain open and new ones are emerging. These include the relationship between their phenotype and function, the mechanisms of pro-angiogenic programming, their contribution to resistance to anti-angiogenic treatments and to metastasis and their potential clinical use as biomarkers of angiogenesis and anti-angiogenic therapies. Here, we will review phenotypical and functional aspects of bone marrow-derived myelonomocytic cells and discuss some of the current outstanding questions.

Association between Activated Partial Thromboplastin Time and the Amount of Infused Heparin at Bone Marrow Transplantation.

PubMed

Kusuda, Machiko; Kimura, Shun-Ichi; Misaki, Yukiko; Yoshimura, Kazuki; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Akahoshi, Yu; Ugai, Tomotaka; Kameda, Kazuaki; Wada, Hidenori; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Nakasone, Hideki; Kako, Shinichi; Tanihara, Aki; Kanda, Yoshinobu

2018-03-27

The actual heparin concentration of harvested allogeneic bone marrow varies among harvest centers. We monitor the activated partial thromboplastin time (APTT) of the patient during bone marrow infusion and administer prophylactic protamine according to the APTT. We retrospectively reviewed the charts of consecutive patients who underwent bone marrow transplantation without bone marrow processing at our center between April 2007 and March 2016 (n = 94). APTT was monitored during marrow transfusion in 52 patients. We analyzed the relationship between the APTT ratio and several parameters related to heparin administration. As a result, the weight-based heparin administration rate (U/kg/hour) seemed to be more closely related to the APTT ratio (r = .38, P = .005) than to the total amount of heparin. There was no significant correlation between the APTT ratio and renal or liver function. Bleeding complications during and early after infusion were seen in 3 of 52 patients, and included intracranial, nasal, and punctured-skin bleeding. The APTT ratio during transfusion was over 5.88 in the former 2 patients and 2.14 in the latter. All of these patients recovered without sequelae. In conclusion, slow bone marrow infusion is recommended to decrease the weight-based heparin administration rate when the heparin concentration per patient body weight is high. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Human gingiva-derived mesenchymal stem cells are superior to bone marrow-derived mesenchymal stem cells for cell therapy in regenerative medicine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomar, Geetanjali B.; Srivastava, Rupesh K.; Gupta, Navita

2010-03-12

Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation into multiple cell lineages. Presently, bone marrow is considered as a prime source of MSCs; however, there are some drawbacks and limitations in use of these MSCs for cell therapy. In this study, we demonstrate that human gingival tissue-derived MSCs have several advantages over bone marrow-derived MSCs. Gingival MSCs are easy to isolate, homogenous and proliferate faster than bone marrow MSCs without any growth factor. Importantly, gingival MSCs display stable morphology and do not loose MSC characteristic at higher passages. In addition, gingival MSCs maintain normal karyotype and telomerase activitymore » in long-term cultures, and are not tumorigenic. Thus, we reveal that human gingiva is a better source of MSCs than bone marrow, and large number of functionally competent clinical grade MSCs can be generated in short duration for cell therapy in regenerative medicine and tissue engineering.« less

Use of G-CSF-stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review.

PubMed

Chang, Ying-Jun; Huang, Xiao-Jun

2011-01-01

In recent years, several researchers have unraveled the previously unrecognized effects of granulocyte colony-stimulating factor (G-CSF) on hematopoiesis and the immune cell functions of bone marrow in healthy donors. In human leukocyte antigen-matched or haploidentical transplant settings, available data have established the safety of using G-CSF-stimulated bone marrow grafts, as well as the ability of this source to produce rapid and sustained engraftment. Interestingly, G-CSF-primed bone marrow transplants could capture the advantages of blood stem cell transplants, without the increased risk of chronic graft-versus-host disease that is associated with blood stem cell transplants. This review summarizes the growing body of evidence that supports the use of G-CSF-stimulated bone marrow grafts as an alternative stem cell source in allogeneic hematopoietic stem cell transplantation. © 2010 John Wiley & Sons A/S.

Impaired Endothelial Progenitor Cell Mobilization and Dysfunctional Bone Marrow Stroma in Diabetes Mellitus

PubMed Central

Rafii, Shahin; Jaspers, Janneke E.; White, Ian A.; Hooper, Andrea T.; Doevendans, Pieter A.; Verhaar, Marianne C.

2013-01-01

Background Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired –at least partly– due to dysfunction of the bone marrow stromal compartment. Methods Diabetes was induced in mice by streptozotocin injection. Circulating Sca-1+Flk-1+ EPC were characterized and quantified by flow cytometry at baseline and after mobilization with G-CSF/SCF injections. In vivo hemangiogenic recovery was tested by 5-FU challenge. Interaction within the bone marrow environment between CD34+ hematopoietic progenitor cells (HPC) and supporting stroma was assessed by co-cultures. To study progenitor cell–endothelial cell interaction under normoglycemic and hyperglycemic conditions, a co-culture model using E4Orf1-transfected human endothelial cells was employed. Results In diabetic mice, bone marrow EPC levels were unaffected. However, circulating EPC levels in blood were lower at baseline and mobilization was attenuated. Diabetic mice failed to recover and repopulate from 5-FU injection. In vitro, primary cultured bone marrow stroma from diabetic mice was impaired in its capacity to support human CFU-forming HPC. Finally, hyperglycemia hampered the HPC supportive function of endothelial cells in vitro. Conclusion EPC mobilization is impaired under experimental diabetic conditions and our data suggest that diabetes induces alterations in the progenitor cell supportive capacity of the bone marrow stroma, which could be partially responsible for the attenuated EPC mobilization and reduced EPC levels observed in diabetic patients. PMID:23555959

Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus.

PubMed

Westerweel, Peter E; Teraa, Martin; Rafii, Shahin; Jaspers, Janneke E; White, Ian A; Hooper, Andrea T; Doevendans, Pieter A; Verhaar, Marianne C

2013-01-01

Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired -at least partly- due to dysfunction of the bone marrow stromal compartment. Diabetes was induced in mice by streptozotocin injection. Circulating Sca-1(+)Flk-1(+) EPC were characterized and quantified by flow cytometry at baseline and after mobilization with G-CSF/SCF injections. In vivo hemangiogenic recovery was tested by 5-FU challenge. Interaction within the bone marrow environment between CD34(+) hematopoietic progenitor cells (HPC) and supporting stroma was assessed by co-cultures. To study progenitor cell-endothelial cell interaction under normoglycemic and hyperglycemic conditions, a co-culture model using E4Orf1-transfected human endothelial cells was employed. In diabetic mice, bone marrow EPC levels were unaffected. However, circulating EPC levels in blood were lower at baseline and mobilization was attenuated. Diabetic mice failed to recover and repopulate from 5-FU injection. In vitro, primary cultured bone marrow stroma from diabetic mice was impaired in its capacity to support human CFU-forming HPC. Finally, hyperglycemia hampered the HPC supportive function of endothelial cells in vitro. EPC mobilization is impaired under experimental diabetic conditions and our data suggest that diabetes induces alterations in the progenitor cell supportive capacity of the bone marrow stroma, which could be partially responsible for the attenuated EPC mobilization and reduced EPC levels observed in diabetic patients.

Development of Short Term Immunotoxicological Assays for Prediction of Chronic Toxicological Responses Induced by Environmental Chemicals

DTIC Science & Technology

1986-11-25

Time 16 El E 4. IUdR Incorporation into Sp*,een Cells as .Function of Preincubationr :ime.II....... ... ...... ........ I...... I........ I...trichloroethylene B) Bone marrow parameters 1) Bone marrow cell number 3) Bone marrow stem cell number (CFU-GM) Y . ,.= z , 0 .2 Cc-C 02 @13 .~ LL 0 CL uj 0...lipopolysac- • .4 -C.- * 50 Figure 21 S pleen Cell Number In Cultures 8- Exposed to S3. Mixes .............. 6 2. 0 60 180 Exposure Time (Minutes) El No S9

[Recent research advance on bone marrow microenvironment-mediated leukemia drug resistant mechanism].

PubMed

Fu, Bing; Ling, Yan-Juan

2011-06-01

The bone marrow microenvironment consists of bone marrow stromal cells, osteoblasts and osteoclasts which facilities the survival, differentiation and proliferation of hematopoietic cells through secreting soluble factors and extracellular matrix proteins that mediate these functions. This environment not only supports the growth of normal and malignant hematopoietic cells, but also protects them against the damage from chemotherapeutic agents through the secretion of soluble cytokines, cell adhesion, up-regulation of resistant genes and changes of cell cycle. In this review, the research advances on drug-resistance mechanisms mediated by bone marrow microenvironment are summarized briefly, including soluble factors mediating drug resistance, intercellular adhesion inducing drug resistance, up-regulation of some drug resistance genes, regulation in metabolism of leukemic cells, changes in cell cycles of tumor cells and so on.

Skeletal stem cell isolation: A review on the state-of-the-art microfluidic label-free sorting techniques.

PubMed

Xavier, Miguel; Oreffo, Richard O C; Morgan, Hywel

2016-01-01

Skeletal stem cells (SSC) are a sub-population of bone marrow stromal cells that reside in postnatal bone marrow with osteogenic, chondrogenic and adipogenic differentiation potential. SSCs reside only in the bone marrow and have organisational and regulatory functions in the bone marrow microenvironment and give rise to the haematopoiesis-supportive stroma. Their differentiation capacity is restricted to skeletal lineages and therefore the term SSC should be clearly distinguished from mesenchymal stem cells which are reported to exist in extra-skeletal tissues and, critically, do not contribute to skeletal development. SSCs are responsible for the unique regeneration capacity of bone and offer unlimited potential for application in bone regenerative therapies. A current unmet challenge is the isolation of homogeneous populations of SSCs, in vitro, with homogeneous regeneration and differentiation capacities. Challenges that limit SSC isolation include a) the scarcity of SSCs in bone marrow aspirates, estimated at between 1 in 10-100,000 mononuclear cells; b) the absence of specific markers and thus the phenotypic ambiguity of the SSC and c) the complexity of bone marrow tissue. Microfluidics provides innovative approaches for cell separation based on bio-physical features of single cells. Here we review the physical principles underlying label-free microfluidic sorting techniques and review their capacity for stem cell selection/sorting from complex (heterogeneous) samples. Copyright © 2016 Elsevier Inc. All rights reserved.

Characterization of Fatty Acid Composition in Bone Marrow Fluid From Postmenopausal Women: Modification After Hip Fracture.

PubMed

Miranda, Melissa; Pino, Ana María; Fuenzalida, Karen; Rosen, Clifford J; Seitz, Germán; Rodríguez, J Pablo

2016-10-01

Bone marrow adipose tissue (BMAT) is associated with low bone mass, although the functional consequences for skeletal maintenance of increased BMAT are currently unclear. BMAT might have a role in systemic energy metabolism, and could be an energy source as well as an endocrine organ for neighboring bone cells, releasing cytokines, adipokines and free fatty acids into the bone marrow microenvironment. The aim of the present report was to compare the fatty acid composition in the bone marrow supernatant fluid (BMSF) and blood plasma of postmenopausal women women (65-80 years old). BMSF was obtained after spinning the aspirated bone marrow samples; donors were classified as control, osteopenic or osteoporotic after dual-energy X-ray absorptiometry. Total lipids from human bone marrow fluid and plasma were extracted, converted to the corresponding methyl esters, and finally analyzed by a gas chromatographer coupled with a mass spectrometer. Results showed that fatty acid composition in BMSF was dynamic and distinct from blood plasma, implying significance in the locally produced lipids. The fatty acid composition in the BMSF was enriched in saturated fatty acid and decreased in unsaturated fatty acids as compared to blood plasma, but this relationship switched in women who suffered a hip fracture. On the other hand, there was no relationship between BMSF and bone mineral density. In conclusion, lipid composition of BMSF is distinct from the circulatory compartment, most likely reflecting the energy needs of the marrow compartment. J. Cell. Biochem. 117: 2370-2376, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Exposure to hyperoxia in the neonatal period alters bone marrow function

USDA-ARS?s Scientific Manuscript database

Oxygen is often life saving in preterm infants, however, excessive exposure may lead to blood vessel and tissue injury in the lung and retina. Oxygen-treated neonates often exhibit bone marrow (BM) suppression requiring blood product transfusions. However, we do not know whether oxygen is directly t...

Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition.

PubMed

Perrotta, Silverio; Nobili, Bruno; Rossi, Francesca; Criscuolo, Maria; Iolascon, Achille; Di Pinto, Daniela; Passaro, Irene; Cennamo, Lucia; Oliva, Adriana; Della Ragione, Fulvio

2002-03-15

Vitamin A is a pivotal biochemical factor required for normal proliferation and differentiation as well as for specialized functions, such as vision. The dietary intake of 1500 IU/day is recommended in the first year of life. Here, we report the case of an infant who had been given 62 000 IU/day for 80 days. The infant showed several clinical signs of retinol intoxication, including severe anemia and thrombocytopenia. Bone marrow showed a remarkably reduced number of erythroid and megakaryocytic cells. The interruption of vitamin A treatment was immediately followed by clinical and biochemical recovery. To clarify whether the effects of retinol are due to a direct action on bone marrow cell proliferation, we investigated the activity of retinol (both the drug and the pure molecule) on the growth of K-562, a multipotent hematopoietic cell line, and on bone marrow mesenchymal stem cells. We observed that vitamin A strongly inhibited the proliferation of the cells at concentrations similar to those reached in vivo. Subsequent biochemical analyses of the cell cycle suggested that the effect was mediated by the up-regulation of cyclin-dependent kinase inhibitors, p21(Cip1) and p27(Kip1). These are the first findings to demonstrate that infant hypervitaminosis A causes a severe anemia and thrombocytopenia and that this is probably due to the direct effect of the molecule on the growth of all bone marrow cellular components. Our data also suggest potential bone marrow functional alterations after excessive vitamin A intake because of emerging social habits.

Abrogation of Cbl-PI3K interaction increases bone formation and osteoblast proliferation.

PubMed

Brennan, Tracy; Adapala, Naga Suresh; Barbe, Mary F; Yingling, Vanessa; Sanjay, Archana

2011-11-01

Cbl is an adaptor protein and E3 ligase that plays both positive and negative roles in several signaling pathways that affect various cellular functions. Tyrosine 737 is unique to Cbl and phosphorylated by Src family kinases. Phosphorylated CblY737 creates a binding site for the p85 regulatory subunit of phosphatidylinositol 3 kinase (PI3K) that also plays an important role in the regulation of bone homeostasis. To investigate the role of Cbl-PI3K interaction in bone homeostasis, we examined knock-in mice in which the PI3K binding site on Cbl was ablated due to the substitution of tyrosine 737 to phenylalanine (Cbl(YF/YF), YF mice). We previously reported that bone volume in these mice is increased due to decreased osteoclast function (Adapala et al., J Biol Chem 285:36745-36758, 19). Here, we report that YF mice also have increased bone formation and osteoblast numbers. In ex vivo cultures bone marrow-derived YF osteoblasts showed increased Col1A expression and their proliferation was also significantly augmented. Moreover, proliferation of MC3T3-E1 cells was increased after treatment with conditioned medium generated by culturing YF bone marrow stromal cells. Expression of stromal derived factor-1 (SDF-1) was increased in YF bone marrow stromal cells compared to wild type. Increased immunostaining of SDF-1 and CXCR4 was observed in YF bone marrow stromal cells compared to wild type. Treatment of YF condition medium with neutralizing anti-SDF-1 and anti-CXCR4 antibodies attenuated MC3T3-E1 cell proliferation. Cumulatively, these results show that abrogation of Cbl-PI3K interaction perturbs bone homeostasis, affecting both osteoclast function and osteoblast proliferation.

Response functions for computing absorbed dose to skeletal tissues from photon irradiation--an update.

PubMed

Johnson, Perry B; Bahadori, Amir A; Eckerman, Keith F; Lee, Choonsik; Bolch, Wesley E

2011-04-21

A comprehensive set of photon fluence-to-dose response functions (DRFs) is presented for two radiosensitive skeletal tissues-active and total shallow marrow-within 15 and 32 bone sites, respectively, of the ICRP reference adult male. The functions were developed using fractional skeletal masses and associated electron-absorbed fractions as reported for the UF hybrid adult male phantom, which in turn is based upon micro-CT images of trabecular spongiosa taken from a 40 year male cadaver. The new DRFs expand upon both the original set of seven functions produced in 1985, and a 2007 update calculated under the assumption of secondary electron escape from spongiosa. In this study, it is assumed that photon irradiation of the skeleton will yield charged particle equilibrium across all spongiosa regions at energies exceeding 200 keV. Kerma coefficients for active marrow, inactive marrow, trabecular bone and spongiosa at higher energies are calculated using the DRF algorithm setting the electron-absorbed fraction for self-irradiation to unity. By comparing kerma coefficients and DRF functions, dose enhancement factors and mass energy-absorption coefficient (MEAC) ratios for active marrow to spongiosa were derived. These MEAC ratios compared well with those provided by the NIST Physical Reference Data Library (mean difference of 0.8%), and the dose enhancement factors for active marrow compared favorably with values calculated in the well-known study published by King and Spiers (1985 Br. J. Radiol. 58 345-56) (mean absolute difference of 1.9 percentage points). Additionally, dose enhancement factors for active marrow were shown to correlate well with the shallow marrow volume fraction (R(2) = 0.91). Dose enhancement factors for the total shallow marrow were also calculated for 32 bone sites representing the first such derivation for this target tissue.

RESPONSE FUNCTIONS FOR COMPUTING ABSORBED DOSE TO SKELETAL TISSUES FROM PHOTON IRRADIATION – AN UPDATE

PubMed Central

Johnson, Perry; Bahadori, Amir; Eckerman, Keith; Lee, Choonsik; Bolch, Wesley E.

2014-01-01

A comprehensive set of photon fluence-to-dose response functions (DRFs) are presented for two radiosensitive skeletal tissues – active and total shallow marrow – within 15 and 32 bones sites, respectively, of the ICRP reference adult male. The functions were developed using fractional skeletal masses and associated electron absorbed fractions as reported for the UF hybrid adult male phantom, which in turn is based upon microCT images of trabecular spongiosa taken from a 40-year male cadaver. The new DRFs expand upon both the original set of seven functions produced in 1985, as well as a 2007 update calculated under the assumption of secondary electron escape from spongiosa. In the present study, it is assumed that photon irradiation of the skeleton will yield charged particle equilibrium across all spongiosa regions at energies exceeding 200 keV. Kerma factors for active marrow, inactive marrow, trabecular bone, and spongiosa at higher energies are calculated using the DRF algorithm setting the electron absorbed fraction for self-irradiation to unity. By comparing kerma factors and DRF functions, dose enhancement factors and mass energy-absorption coefficient (MEAC) ratios for active marrow to spongiosa were derived. These MEAC ratios compared well with those provided by the NIST Physical Reference Data Library (mean difference of 0.8%), and the dose enhancement factors for active marrow compared favorably with values calculated in the well-known study published by King and Spiers (1985) (mean absolute difference of 1.9 percentage points). Additionally, dose enhancement factors for active marrow were shown to correlate well with the shallow marrow volume fraction (R2 = 0.91). Dose enhancement factors for the total shallow marrow were also calculated for 32 bone sites PMID:21427484

Long-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in human bone marrow.

PubMed Central

Fairbairn, L J; Lashford, L S; Spooncer, E; McDermott, R H; Lebens, G; Arrand, J E; Arrand, J R; Bellantuono, I; Holt, R; Hatton, C E; Cooper, A; Besley, G T; Wraith, J E; Anson, D S; Hopwood, J J; Dexter, T M

1996-01-01

Allogeneic bone marrow transplantation is the most effective treatment for Hurler syndrome but, since this therapy is not available to all patients, we have considered an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full-length cDNA for alpha-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder. Various gene-transfer protocols have been assessed including the effect of intensive schedules of exposure of bone marrow to viral supernatant and the influence of growth factors. With these protocols, we have demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. Also, by using long-term bone marrow cultures, we have demonstrated high levels of enzyme expression sustained for several months. The efficiency of gene transfer has been assessed by PCR analysis of hemopoietic colonies as 25-56%. No advantage has been demonstrated for the addition of growth factors or intensive viral exposure schedules. The enzyme is secreted into the medium and functional localization has been demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. This work suggests that retroviral gene transfer into human bone marrow may offer the prospect for gene therapy of Hurler syndrome in young patients without a matched sibling donor. Images Fig. 2 Fig. 4 Fig. 7 Fig. 8 PMID:8700879

Periodontal regeneration with stem cells-seeded collagen-hydroxyapatite scaffold.

PubMed

Liu, Zeping; Yin, Xing; Ye, Qingsong; He, Wulin; Ge, Mengke; Zhou, Xiaofu; Hu, Jing; Zou, Shujuan

2016-07-01

Re-establishing compromised periodontium to its original structure, properties and function is demanding, but also challenging, for successful orthodontic treatment. In this study, the periodontal regeneration capability of collagen-hydroxyapatite scaffolds, seeded with bone marrow stem cells, was investigated in a canine labial alveolar bone defect model. Bone marrow stem cells were isolated, expanded and characterized. Porous collagen-hydroxyapatite scaffold and cross-linked collagen-hydroxyapatite scaffold were prepared. Attachment, migration, proliferation and morphology of bone marrow stem cells, co-cultured with porous collagen-hydroxyapatite or cross-linked collagen-hydroxyapatite, were evaluated in vitro. The periodontal regeneration capability of collagen-hydroxyapatite scaffold with or without bone marrow stem cells was tested in six beagle dogs, with each dog carrying one sham-operated site as healthy control, and three labial alveolar bone defects untreated to allow natural healing, treated with bone marrow stem cells - collagen-hydroxyapatite scaffold implant or collagen-hydroxyapatite scaffold implant, respectively. Animals were euthanized at 3 and 6 months (3 animals per group) after implantation and the resected maxillary and mandibular segments were examined using micro-computed tomography scan, H&E staining, Masson's staining and histometric evaluation. Bone marrow stem cells were successfully isolated and demonstrated self-renewal and multi-potency in vitro. The porous collagen-hydroxyapatite and cross-linked collagen-hydroxyapatite had average pore sizes of 415 ± 20 µm and 203 ± 18 µm and porosity of 69 ± 0.5% and 50 ± 0.2%, respectively. The attachment, proliferation and migration of bone marrow stem cells were satisfactory on both porous collagen-hydroxyapatite and cross-linked collagen-hydroxyapatite scaffolds. Implantation of bone marrow stem cells - collagen-hydroxyapatite or collagen-hydroxyapatite scaffold in beagle dogs with experimental periodontal defects resulted in significantly enhanced periodontal regeneration characterized by formation of new bone, periodontal ligament and cementum, compared with the untreated defects, as evidenced by histological and micro-computed tomography examinations. The prepared collagen-hydroxyapatite scaffolds possess favorable bio-compatibility. The bone marrow stem cells - collagen-hydroxyapatite and collagen-hydroxyapatite scaffold - induced periodontal regeneration, with no aberrant events complicating the regenerative process. Further research is necessary to improve the bone marrow stem cells behavior in collagen-hydroxyapatite scaffolds after implantation. © The Author(s) 2016.

Identification of CD22 Ligands on Bone Marrow Sinusoidal Endothelium Implicated in CD22-dependent Homing of Recirculating B Cells

PubMed Central

Nitschke, Lars; Floyd, Helen; Ferguson, David J.P.; Crocker, Paul R.

1999-01-01

CD22 is a B cell–specific transmembrane protein known to function as a negative regulator of B cell signaling. It has also been implicated in cell adhesion through recognition of α2,6-linked sialic acids on glycans of target cells. Previous studies showed that CD22-deficient mice had a strongly reduced population of mature recirculating B cells in the bone marrow despite normal B cell development. Using a soluble recombinant form of the receptor (CD22-Fc), we demonstrate here that sialylated ligands for CD22 are expressed on sinusoidal endothelial cells of murine bone marrow but not on endothelial cells in other tissues examined. Injection of CD22-Fc revealed that the CD22 ligands in the bone marrow were accessible to the circulation. Treatment of mice with either CD22-Fc or affinity-purified anti-CD22 antibody led to an ∼50% reduction in mature recirculating B cells in the bone marrow without affecting numbers in the spleen. Finally, consistent with the notion that CD22 is a homing receptor, we show that compared with wild-type mice, CD22-deficient animals have a lower number of immunoglobulin M–secreting plasma cells in the bone marrow. PMID:10224292

INF-γ encoding plasmid administration triggers bone loss and disrupts bone marrow microenvironment.

PubMed

Agas, Dimitrios; Gusmão Silva, Guilherme; Laus, Fulvio; Marchegiani, Andrea; Capitani, Melania; Vullo, Cecilia; Catone, Giuseppe; Lacava, Giovanna; Concetti, Antonio; Marchetti, Luigi; Sabbieti, Maria Giovanna

2017-02-01

IFN-γ is a pleotropic cytokine produced in the bone microenvironment. Although IFN-γ is known to play a critical role on bone remodeling, its function is not fully elucidated. Consistently, outcomes on the effects of IFN-γ recombinant protein on bone loss are contradictory among reports. In our work we explored, for the first time, the role of IFN-γ encoding plasmid (pIFN-γ) in a mouse model of osteopenia induced by ovariectomy and in the sham-operated counterpart to estimate its effects in skeletal homeostasis. Ovariectomy produced a dramatic decrease of bone mineral density (BMD). pINF-γ injected mice showed a pathologic bone and bone marrow phenotype; the disrupted cortical and trabecular bone microarchitecture was accompanied by an increased release of pro-inflammatory cytokine by bone marrow cells. Moreover, mesenchymal stem cells' (MSCs) commitment to osteoblast was found impaired, as evidenced by the decline of osterix-positive (Osx + ) cells within the mid-diaphyseal area of femurs. For instance, a reduction and redistribution of CXCL12 cells have been found, in accordance with bone marrow morphological alterations. As similar effects were observed both in sham-operated and in ovariectomized mice, our studies proved that an increased IFN-γ synthesis in bone marrow might be sufficient to induce inflammatory and catabolic responses even in the absence of pathologic predisposing substrates. In addition, the obtained data might raise questions about pIFN-γ's safety when it is used as vaccine adjuvant. © 2017 Society for Endocrinology.

USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells.

PubMed

Higuchi, Masaya; Kawamura, Hiroki; Matsuki, Hideaki; Hara, Toshifumi; Takahashi, Masahiko; Saito, Suguru; Saito, Kousuke; Jiang, Shuying; Naito, Makoto; Kiyonari, Hiroshi; Fujii, Masahiro

2016-12-13

Self-renewal, replication, and differentiation of hematopoietic stem cells (HSCs) are regulated by cytokines produced by niche cells in fetal liver and bone marrow. HSCs must overcome stresses induced by cytokine deprivation during normal development. In this study, we found that ubiquitin-specific peptidase 10 (USP10) is a crucial deubiquitinase for mouse hematopoiesis. All USP10 knockout (KO) mice died within 1 year because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of long-term HSCs (LT-HSCs) in bone marrow and fetal liver. Such USP10-KO fetal liver exhibited enhanced apoptosis of hematopoietic stem/progenitor cells (HSPCs) including LT-HSCs but not of lineage-committed progenitor cells. Transplantation of USP10-competent bone marrow cells into USP10-KO mice reconstituted multilineage hematopoiesis. These results suggest that USP10 is an essential deubiquitinase in hematopoiesis and functions by inhibiting apoptosis of HSPCs including LT-HSCs. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Experiment K-6-23. Effect of spaceflight on levels and function of immune cells

NASA Technical Reports Server (NTRS)

Mandel, A. D.; Sonnenfeld, G.; Berry, W.; Taylor, G.; Wellhausen, S. R.; Konstantinova, I.; Lesnyak, A.; Fuchs, B.

1990-01-01

Two different immunology experiments were performed on samples received from rats flown on Cosmos 1887. In the first experiment, rat bone marrow cells were examined in Moscow for their response to colony stimulating factor-M. In the second experiment, rat spleen and bone marrow cells were stained in Moscow with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and shipped to the United States where they were subjected to analysis on a flow cytometer. The results of the studies indicate that bone marrow cells from flown rats showed a decreased response to colony stimulating factor than did bone marrow cells from control rats. There was a higher percentage of spleen cells from flown rats staining positively for pan-T-cell, suppressor-T-cell and innate interleukin-2 receptor antigens than from control animals. In addition, a higher percentage of cells that appeared to be part of the myelogenous population of bone marrow cells from flown rats stained positively for surface immunoglobulin than did equivalent cells from control rats.

What Is a Bone Marrow Transplant?

MedlinePlus

... Print this page My Cart What is a bone marrow transplant? A bone marrow transplant is a ... blood.” – Edmund Waller, MD, PHD What is a bone marrow transplant? A bone marrow transplant is a ...

Reciprocal regulation of adipocyte and osteoblast differentiation of mesenchymal stem cells by Eupatorium japonicum prevents bone loss and adiposity increase in osteoporotic rats.

PubMed

Kim, Min-Ji; Jang, Woo-Seok; Lee, In-Kyoung; Kim, Jong-Keun; Seong, Ki-Seung; Seo, Cho-Rong; Song, No-Joon; Bang, Min-Hyuk; Lee, Young Min; Kim, Haeng Ran; Park, Ki-Moon; Park, Kye Won

2014-07-01

Pathological increases in adipogenic potential with decreases in osteogenic differentiation occur in osteoporotic bone marrow cells. Previous studies have shown that bioactive materials isolated from natural products can reciprocally regulate adipogenic and osteogenic fates of bone marrow cells. In this study, we showed that Eupatorium japonicum stem extracts (EJE) suppressed lipid accumulation and inhibited the expression of adipocyte markers in multipotent C3H10T1/2 and primary bone marrow cells. Conversely, EJE stimulated alkaline phosphatase activity and induced the expression of osteoblast markers in C3H10T1/2 and primary bone marrow cells. Daily oral administration of 50 mg/kg of EJE for 6 weeks to ovariectomized rats prevented body weight increase and bone mineral density decrease. Finally, activity-guided fractionation led to the identification of coumaric acid and coumaric acid methyl ester as bioactive anti-adipogenic and pro-osteogenic components in EJE. Taken together, our data indicate a promising possibility of E. japonicum as a functional food and as a therapeutic intervention for preventing osteoporosis and bone fractures.

The effects of the CXCR2 antagonist, MK-7123, on bone marrow functions in healthy subjects.

PubMed

Hastrup, Nina; Khalilieh, Sauzanne; Dale, David C; Hanson, Lars G; Magnusson, Peter; Tzontcheva, Anjela; Tseng, Jack; Huyck, Susan; Rosenberg, Elizabeth; Krogsgaard, Kim

2015-04-01

The CXCR2 antagonist MK-7123 causes dose-dependent reductions in absolute neutrophil counts (ANC) and decreases neutrophil tissue responses, but its effects on bone marrow functions are not yet known. We conducted a double-blind, randomized study in 18 healthy subjects comparing the effects of either MK-7123 (30mg, po, daily for 28days) or placebo on peripheral blood counts and bone marrow myeloid cell populations. MK-7123 caused a reversible decrease (approximately 50%) in the ANC as demonstrated on days 1 and 28, the first and last days of the treatment period. Bone marrow aspirate smears and biopsy imprints did not differ in the proportion of mature neutrophils in pretreatment, day 28, day 56 or placebo samples. There were no treatment effects on biopsy or aspirate clot cellularity, myeloid to erythroid or myeloid post-mitotic to mitotic ratios; flow-cytometric analyses of aspirate cells; or bone marrow fat to cell balance as assessed by MRI. MK-7123 was generally well tolerated with neutropenia being the most common adverse event; however, there were no clinical symptoms associated with decreased ANCs. These findings indicate that the CXCR2 antagonist MK-7123 causes rapidly reversible decrease in the ANC without measurable myelosuppressive effects. The results support the development of CXCR2 antagonists as potentially useful anti-inflammatory agents, primarily interrupting neutrophil trafficking. Copyright © 2015. Published by Elsevier Ltd.

Bone Marrow Transplantation in Mice as a Tool to Generate Genetically Modified Animals

NASA Astrophysics Data System (ADS)

Rőszer, Tamás; Pintye, Éva; Benkő, Ilona

2008-12-01

Transgenic mice can be used either as models of known inherited human diseases or can be applied to perform phenotypic tests of genes with unknown function. In some special applications of gene modification we have to create a tissue specific mutation of a given gene. In some cases however the gene modification can be lethal in the intrauterine life, therefore we should engraft the mutated cells in the postnatal life period. After total body irradiation transplantation of bone marrow cells can be a solution to introduce mutant hematopoietic stem cells into a mature animal. Bone marrow transplantation is a useful and novel tool to study the role of hematopoietic cells in the pathogenesis of inflammation, autoimmune syndromes and many metabolic alterations coupled recently to leukocyte functions.

Gametocytes of the Malaria Parasite Plasmodium falciparum Interact With and Stimulate Bone Marrow Mesenchymal Cells to Secrete Angiogenetic Factors

PubMed Central

Messina, Valeria; Valtieri, Mauro; Rubio, Mercedes; Falchi, Mario; Mancini, Francesca; Mayor, Alfredo; Alano, Pietro; Silvestrini, Francesco

2018-01-01

The gametocytes of Plasmodium falciparum, responsible for the transmission of this malaria parasite from humans to mosquitoes, accumulate and mature preferentially in the human bone marrow. In the 10 day long sexual development of P. falciparum, the immature gametocytes reach and localize in the extravascular compartment of this organ, in contact with several bone marrow stroma cell types, prior to traversing the endothelial lining and re-entering in circulation at maturity. To investigate the host parasite interplay underlying this still obscure process, we developed an in vitro tridimensional co-culture system in a Matrigel scaffold with P. falciparum gametocytes and self-assembling spheroids of human bone marrow mesenchymal cells (hBM-MSCs). Here we show that this co-culture system sustains the full maturation of the gametocytes and that the immature, but not the mature, gametocytes adhere to hBM-MSCs via trypsin-sensitive parasite ligands exposed on the erythrocyte surface. Analysis of a time course of gametocytogenesis in the co-culture system revealed that gametocyte maturation is accompanied by the parasite induced stimulation of hBM-MSCs to secrete a panel of 14 cytokines and growth factors, 13 of which have been described to play a role in angiogenesis. Functional in vitro assays on human bone marrow endothelial cells showed that supernatants from the gametocyte mesenchymal cell co-culture system enhance ability of endothelial cells to form vascular tubes. These results altogether suggest that the interplay between immature gametocytes and hBM-MSCs may induce functional and structural alterations in the endothelial lining of the human bone marrow hosting the P. falciparum transmission stages. PMID:29546035

RESPONSE FUNCTIONS FOR COMPUTING ABSORBED DOSE TO SKELETAL TISSUES FROM NEUTRON IRRADIATION

PubMed Central

Bahadori, Amir A.; Johnson, Perry; Jokisch, Derek W.; Eckerman, Keith F.; Bolch, Wesley E.

2016-01-01

Spongiosa in the adult human skeleton consists of three tissues - active marrow (AM), inactive marrow (IM), and trabecularized mineral bone (TB). Active marrow is considered to be the target tissue for assessment of both long-term leukemia risk and acute marrow toxicity following radiation exposure. The total shallow marrow (TM50), defined as all tissues laying within the first 50 μm the bone surfaces, is considered to be the radiation target tissue of relevance for radiogenic bone cancer induction. For irradiation by sources external to the body, kerma to homogeneous spongiosa has been used as a surrogate for absorbed dose to both of these tissues, as direct dose calculations are not possible using computational phantoms with homogenized spongiosa. Recent microCT imaging of a 40-year-old male cadaver has allowed for the accurate modeling of the fine microscopic structure of spongiosa in many regions of the adult skeleton [Hough et al PMB (2011)]. This microstructure, along with associated masses and tissue compositions, was used to compute specific absorbed fractions (SAF) values for protons originating in axial and appendicular bone sites [Jokisch et al PMB (submitted)]. These proton SAFs, bone masses, tissue compositions, and proton production cross-sections, were subsequently used to construct neutron dose response functions (DRFs) for both AM and TM50 targets in each bone of the reference adult male. Kerma conditions were assumed for other resultant charged particles. For comparison, active marrow, total shallow marrow, and spongiosa kerma coefficients were also calculated. At low incident neutron energies, AM kerma coefficients for neutrons correlate well with values of the AM DRF, while total marrow (TM) kerma coefficients correlate well with values of the TM50 DRF. At high incident neutron energies, all kerma coefficients and DRFs tend to converge as charged particle equilibrium (CPE) is established across the bone site. In the range of 10 eV to 100 MeV, substantial differences are observed among the kerma coefficients and DRF. As a result, it is recommended that the AM kerma coefficient be used to estimate the AM DRF, and that the TM kerma coefficient be used to estimate the TM50 DRF below 10 eV. Between 10 eV and 100 MeV, the appropriate DRF should be used as presented in this study. Above 100 MeV, spongiosa kerma coefficients apply well for estimating skeletal tissue doses. DRF values for each bone site as a function of energy are provided in an electronic annex to this article. PMID:21983525

Comparison of transplantation of bone marrow stromal cells (BMSC) and stem cell mobilization by granulocyte colony stimulating factor after traumatic brain injury in rat.

PubMed

Bakhtiary, Mehrdad; Marzban, Mohsen; Mehdizadeh, Mehdi; Joghataei, Mohammad Taghi; Khoei, Samideh; Pirhajati Mahabadi, Vahid; Laribi, Bahareh; Tondar, Mahdi; Moshkforoush, Arash

2010-10-01

Recent clinical studies of treating traumatic brain injury (TBI) with autologous adult stem cells led us to compare effect of intravenous injection of bone marrow mesenchymal stem cells (BMSC) and bone marrow hematopoietic stem cell mobilization, induced by granulocyte colony stimulating factor (G-CSF), in rats with a cortical compact device. Forty adult male Wistar rats were injured with controlled cortical impact device and divided randomly into four groups. The treatment groups were injected with 2 × 106 intravenous bone marrow stromal stem cell (n = 10) and also with subcutaneous G-CSF (n = 10) and sham-operation group (n = 10) received PBS and "bromodeoxyuridine (Brdu)" alone, i.p. All injections were performed 1 day after injury into the tail veins of rats. All cells were labeled with Brdu before injection into the tail veins of rats. Functional neurological evaluation of animals was performed before and after injury using modified neurological severity scores (mNSS). Animals were sacrificed 42 days after TBI and brain sections were stained by Brdu immunohistochemistry. Statistically, significant improvement in functional outcome was observed in treatment groups compared with control group (P<0.01). mNSS showed no significant difference between the BMSC and G-CSF-treated groups during the study period (end of the trial). Histological analyses showed that Brdu-labeled (MSC) were present in the lesion boundary zone at 42nd day in all injected animals. In our study, we found that administration of a bone marrow-stimulating factor (G-CSF) and BMSC in a TBI model provides functional benefits.

Treatment of active unicameral bone cysts with percutaneous injection of demineralized bone matrix and autogenous bone marrow.

PubMed

Rougraff, Bruce T; Kling, Thomas J

2002-06-01

The treatment of unicameral bone cysts varies from open bone-grafting procedures to percutaneous injection of corticosteroids or bone marrow. The purpose of this study was to evaluate the feasibility and effectiveness of percutaneous injection of a mixture of demineralized bone matrix and autogenous bone marrow for the treatment of simple bone cysts. Twenty-three patients with an active unicameral bone cyst were treated with trephination and injection of allogeneic demineralized bone matrix and autogenous bone marrow. The patients were followed for an average of fifty months (range, thirty to eighty-one months), at which time pain, function, and radiographic signs of resolution of the cyst were assessed. The average time until the patients had pain relief was five weeks, and the average time until the patients returned to full, unrestricted activities was six weeks. Bone-healing at the site of the injection was first seen radiographically at three to six months. No patient had a pathologic fracture during this early bone-healing stage. Cortical remodeling was seen radiographically by six to nine months, and after one year the response was usually complete, changing very little from then on. Five patients required a second injection because of recurrence of the cyst, and all five had a clinically and radiographically quiescent cyst after an average of thirty-six additional months of follow-up. Seven of the twenty-three patients had incomplete healing manifested by small, persistent radiolucent areas within the original cyst. None of these cysts increased in size or resulted in pain or fracture. Percutaneous injection of allogeneic demineralized bone matrix and autogenous bone marrow is an effective treatment for unicameral bone cysts.

An Animal Model of Chronic Aplastic Bone Marrow Failure Following Pesticide Exposure in Mice

PubMed Central

Chatterjee, Sumanta; Chaklader, Malay; Basak, Pratima; Das, Prosun; Das, Madhurima; Pereira, Jacintha Archana; Dutta, Ranjan Kumar; Chaudhuri, Samaresh; Law, Sujata

2010-01-01

The wide use of pesticides for agriculture, domestic and industrial purposes and evaluation of their subsequent effect is of major concern for public health. Human exposure to these contaminants especially bone marrow with its rapidly renewing cell population is one of the most sensitive tissues to these toxic agents represents a risk for the immune system leading to the onset of different pathologies. In this experimental protocol we have developed a mouse model of pesticide(s) induced hypoplastic/aplastic marrow failure to study quantitative changes in the bone marrow hematopoietic stem cell (BMHSC) population through flowcytometric analysis, defects in the stromal microenvironment through short term adherent cell colony (STACC) forming assay and immune functional capacity of the bone marrow derived cells through cell mediated immune (CMI) parameter study. A time course dependent analysis for consecutive 90 days were performed to monitor the associated changes in the marrow’s physiology after 30th, 60th and 90th days of chronic pesticide exposure. The peripheral blood showed maximum lowering of the blood cell count after 90 days which actually reflected the bone marrow scenario. Severe depression of BMHSC population, immune profile of the bone marrow derived cells and reduction of adherent cell colonies pointed towards an essentially empty and hypoplastic marrow condition that resembled the disease aplastic anemia. The changes were accompanied by splenomegaly and splenic erythroid hyperplasia. In conclusion, this animal model allowed us a better understanding of clinico-biological findings of the disease aplastic anemia following toxic exposure to the pesticide(s) used for agricultural and industrial purposes. PMID:24855541

Bone Marrow Adipocyte Developmental Origin and Biology.

PubMed

Bukowska, Joanna; Frazier, Trivia; Smith, Stanley; Brown, Theodore; Bender, Robert; McCarthy, Michelle; Wu, Xiying; Bunnell, Bruce A; Gimble, Jeffrey M

2018-06-01

This review explores how the relationships between bone marrow adipose tissue (BMAT) adipogenesis with advancing age, obesity, and/or bone diseases (osteopenia or osteoporosis) contribute to mechanisms underlying musculoskeletal pathophysiology. Recent studies have re-defined adipose tissue as a dynamic, vital organ with functions extending beyond its historic identity restricted solely to that of an energy reservoir or sink. "State of the art" methodologies provide novel insights into the developmental origin, physiology, and function of different adipose tissue depots. These include genetic tracking of adipose progenitors, viral vectors application, and sophisticated non-invasive imaging modalities. While constricted within the rigid bone cavity, BMAT vigorously contributes to local and systemic metabolic processes including hematopoiesis, osteogenesis, and energy metabolism and undergoes dynamic changes as a function of age, diet, bone topography, or sex. These insights will impact future research and therapies relating to osteoporosis.

Response functions for computing absorbed dose to skeletal tissues from photon irradiation—an update

NASA Astrophysics Data System (ADS)

Johnson, Perry B.; Bahadori, Amir A.; Eckerman, Keith F.; Lee, Choonsik; Bolch, Wesley E.

2011-04-01

A comprehensive set of photon fluence-to-dose response functions (DRFs) is presented for two radiosensitive skeletal tissues—active and total shallow marrow—within 15 and 32 bone sites, respectively, of the ICRP reference adult male. The functions were developed using fractional skeletal masses and associated electron-absorbed fractions as reported for the UF hybrid adult male phantom, which in turn is based upon micro-CT images of trabecular spongiosa taken from a 40 year male cadaver. The new DRFs expand upon both the original set of seven functions produced in 1985, and a 2007 update calculated under the assumption of secondary electron escape from spongiosa. In this study, it is assumed that photon irradiation of the skeleton will yield charged particle equilibrium across all spongiosa regions at energies exceeding 200 keV. Kerma coefficients for active marrow, inactive marrow, trabecular bone and spongiosa at higher energies are calculated using the DRF algorithm setting the electron-absorbed fraction for self-irradiation to unity. By comparing kerma coefficients and DRF functions, dose enhancement factors and mass energy-absorption coefficient (MEAC) ratios for active marrow to spongiosa were derived. These MEAC ratios compared well with those provided by the NIST Physical Reference Data Library (mean difference of 0.8%), and the dose enhancement factors for active marrow compared favorably with values calculated in the well-known study published by King and Spiers (1985 Br. J. Radiol. 58 345-56) (mean absolute difference of 1.9 percentage points). Additionally, dose enhancement factors for active marrow were shown to correlate well with the shallow marrow volume fraction (R2 = 0.91). Dose enhancement factors for the total shallow marrow were also calculated for 32 bone sites representing the first such derivation for this target tissue.

Effects of bioactive factors of the pineal gland on thymus function and cell composition of the bone marrow and spleen in mice of different age.

PubMed

Labunets, I F; Butenko, G M; Khavinson, V Kh

2004-05-01

The effects of factors from the pineal gland on the titer of thymic serum factor in the supernatant of 3-h thymus stroma cultures, number of stromal precursor fibroblasts and CD4+ cells in the bone marrow, and CD8+ cells in the spleens of adult and old CBA mice were studied in vitro. Epithalamin, Epithalon, and melatonin appreciably increased the titer of thymic serum factor in the supernatant of thymus stroma cultures from mice of different age and increased the percentage of CD4+ cells in the bone marrow suspension from old animals in vitro. The percentage of CD8+ lymphocytes decreased after incubation of splenic cells from old mice with melatonin. The percentage of bone marrow fibroblast precursor cells from adult and old mice did not appreciably change after incubation with the preparations.

Protective effects of deferasirox and N-acetyl-L-cysteine on iron overload-injured bone marrow.

PubMed

Shen, J C; Zhang, Y C; Zhao, M F

2017-10-19

Using an iron overload mouse model, we explored the protective effect of deferasirox (DFX) and N-acetyl-L-cysteine (NAC) on injured bone marrow hematopoietic stem/progenitor cells (HSPC) induced by iron overload. Mice were intraperitoneally injected with 25 mg iron dextran every 3 days for 4 weeks to establish an iron overload (Fe) model. DFX or NAC were co-administered with iron dextran in two groups of mice (Fe+DFX and Fe+NAC), and the function of HSPCs was then examined. Iron overload markedly decreased the number of murine HSPCs in bone marrow. Subsequent colony-forming cell assays showed that iron overload also decreased the colony forming capacity of HSPCs, the effect of which could be reversed by DFX and NAC. The bone marrow hematopoiesis damage caused by iron overload could be alleviated by DFX and NAC.

Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice

PubMed Central

Erlandsson, M C; Jonsson, C A; Islander, U; Ohlsson, C; Carlsten, H

2003-01-01

Oestrogen treatment down-regulates B lymphopoiesis in the bone marrow of mice. Meanwhile it up-regulates immunoglobulin production. To understand better the oestrogen action on bone marrow male mice lacking oestrogen receptor α (ERα; ERKO mice), lacking ERβ (BERKO mice), lacking both receptors (DERKO mice) or wild-type (wt) littermates were castrated and treated for 2·5 weeks with 30 μg/kg 17β-oestradiol (E2) or vehicle oil as controls. The B lymphopoiesis in the bone marrow was examined by flow cytometry and mature B-cell function was studied using an ELISPOT assay enumerating the B cells in bone marrow and spleen that were actively producing immunoglobulins. In wt mice the frequency of B-lymphopoietic (B220+) cells in the bone marrow decreased from 15% to 5% upon E2 treatment. In ERKO and BERKO mice significant reduction was seen but not of the same magnitude. In DERKO mice no reduction of B lymphopoiesis was seen. In addition, our results show that E2 mediated reduction of different steps in B lymphopoiesis require only ERα or both receptors. In wt and BERKO mice E2 treatment resulted in significantly increased levels of B cells actively producing immunoglobulin, while in ERKO and DERKO mice no such change was seen. Similar results were found in both bone marrow and spleen. In conclusion our results clearly show that both ERα and ERβ are required for complete down-regulation of B lymphopoiesis while only ERα is needed to up-regulate immunoglobulin production in both bone marrow and spleen. PMID:12603601

Isolation, Culture, and Differentiation of Bone Marrow Stromal Cells and Osteoclast Progenitors from Mice.

PubMed

Maridas, David E; Rendina-Ruedy, Elizabeth; Le, Phuong T; Rosen, Clifford J

2018-01-06

Bone marrow stromal cells (BMSCs) constitute a cell population routinely used as a representation of mesenchymal stem cells in vitro. They reside within the bone marrow cavity alongside hematopoietic stem cells (HSCs), which can give rise to red blood cells, immune progenitors, and osteoclasts. Thus, extractions of cell populations from the bone marrow results in a very heterogeneous mix of various cell populations, which can present challenges in experimental design and confound data interpretation. Several isolation and culture techniques have been developed in laboratories in order to obtain more or less homogeneous populations of BMSCs and HSCs invitro. Here, we present two methods for isolation of BMSCs and HSCs from mouse long bones: one method that yields a mixed population of BMSCs and HSCs and one method that attempts to separate the two cell populations based on adherence. Both methods provide cells suitable for osteogenic and adipogenic differentiation experiments as well as functional assays.

Bone marrow transplant

MedlinePlus

Transplant - bone marrow; Stem cell transplant; Hematopoietic stem cell transplant; Reduced intensity nonmyeloablative transplant; Mini transplant; Allogenic bone marrow transplant; Autologous bone marrow transplant; Umbilical ...

Isolation and hepatocyte differentiation of mesenchymal stem cells from porcine bone marrow--"surgical waste" as a novel MSC source.

PubMed

Brückner, S; Tautenhahn, H-M; Winkler, S; Stock, P; Jonas, S; Dollinger, M; Christ, B

2013-06-01

Mesenchymal stem cells (MSC) isolated from bone marrow and differentiated into hepatocyte-like cells have increasingly gained attention for clinical cell therapy of liver diseases because of their high regenerative capacity. They are available from bone marrow aspirates of the os coxae after puncture of the crista iliaca or from bone marrow "surgical waste" gained from amputations or knee and hip operations. Thus, the aim of the study was to demonstrate whether these pBM-MSC (porcine bone marrow-derived mesenchymal stem cells) displayed mesenchymal features and hepatocyte differentiation potential. MSC were isolated either from crista iliaca punctures or after sampling and collagenase digestion of bone marrow from the os femoris. Mesenchymal features were assessed by flow cytometry for specific surface antigens and their ability to differentiate into at least 3 lineages. Functional properties, such as urea or glycogen synthesis and cytochrome P450 activity, as well as the cell morphology were examined during hepatocyte differentiation. pBM-MSC from both sources lacked the hematopoietic markers CD14 and CD45 but expressed the typical mesenchymal markers CD44, CD29, CD90, and CD105. Both cell types could differentiate into adipocyte, osteocyte, and hepatocyte lineages. After hepatocyte differentiation, CD105 expression decreased significantly and cells changed morphology from fibroblastoid into polygonal, displaying significantly increased glycogen storage, urea synthesis, and cytochrome activity. pBM-MSC from various sources were identical in respect to their mesenchymal features and their hepatocyte differentiation potential. Hence, long bones might be a particularly useful resource to isolate bone marrow mesenchymal stem cells for transplantation. Copyright © 2013 Elsevier Inc. All rights reserved.

Management of an invasive and metastatic Sertoli cell tumor with associated myelotoxicosis in a dog

PubMed Central

Withers, Sita S.; Lawson, Corinne M.; Burton, Andrew G.; Rebhun, Robert B.; Steffey, Michele A.

2016-01-01

We describe the surgical and post-operative management of a large, invasive, and metastatic functional Sertoli cell tumor in a 9-year-old cryptorchid male Labrador retriever dog. Despite residual disease after surgery, bone marrow recovery occurred without administration of bone marrow stimulants and serum estradiol accurately predicted tumor recurrence. PMID:26933269

Survival of irradiated recipient mice after transplantation of bone marrow from young, old and "early aging" mice.

PubMed

Guest, Ian; Ilic, Zoran; Scrable, Heidi; Sell, Stewart

2015-12-01

Bone marrow transplantation is used to examine survival, hematopoietic stem cell function and pathology in recipients of young and old wild type bone marrow derived stem cells (BMDSCs) as well as cells from p53-based models of premature aging. There is no difference in the long term survival of recipients of 8 week-old p53+/m donor cells compared to recipients of 8 week-old wild-type (WT) donor cells (70 weeks) or of recipients of 16-18 weeks-old donor cells from either p53+/m or WT mice. There is shorter survival in recipients of older versus younger WT donor bone marrow, but the difference is only significant when comparing 8 and 18 week-old donors. In the p44-based model, short term survival/engraftment is significantly reduced in recipients of 11 month-old p44 donor cells compared to 4 week-old p44 or wild type donor cells of either age; mid-life survival at 40 weeks is also significantly less in recipients of p44 cells. BMDSCs are readily detectable within recipient bone marrow, lymph node, intestinal villi and liver sinusoids, but not in epithelial derived cells. These results indicate that recipients of young BMDSCs may survive longer than recipients of old bone marrow, but the difference is marginal at best.

Survival of irradiated recipient mice after transplantation of bone marrow from young, old and “early aging” mice

PubMed Central

Guest, Ian; Ilic, Zoran; Sell, Stewart

2015-01-01

Bone marrow transplantation is used to examine survival, hematopoietic stem cell function and pathology in recipients of young and old wild type bone marrow derived stem cells (BMDSCs) as well as cells from p53-based models of premature aging. There is no difference in the long term survival of recipients of 8 week-old p53+/m donor cells compared to recipients of 8 week-old wild-type (WT) donor cells (70 weeks) or of recipients of 16–18 weeks-old donor cells from either p53+/m or WT mice. There is shorter survival in recipients of older versus younger WT donor bone marrow, but the difference is only significant when comparing 8 and 18 week-old donors. In the p44-based model, short term survival/engraftment is significantly reduced in recipients of 11 month-old p44 donor cells compared to 4 week-old p44 or wild type donor cells of either age; mid-life survival at 40 weeks is also significantly less in recipients of p44 cells. BMDSCs are readily detectable within recipient bone marrow, lymph node, intestinal villi and liver sinusoids, but not in epithelial derived cells. These results indicate that recipients of young BMDSCs may survive longer than recipients of old bone marrow, but the difference is marginal at best. PMID:26796640

A prospective study on MRI findings and prognostic factors in athletes with MTSS.

PubMed

Moen, M H; Schmikli, S L; Weir, A; Steeneken, V; Stapper, G; de Slegte, R; Tol, J L; Backx, F J G

2014-02-01

In medial tibial stress syndrome (MTSS) bone marrow and periosteal edema of the tibia on the magnetic resonance imaging (MRI) is frequently reported. The relationship between these MRI findings and recovery has not been previously studied. This prospective study describes MRI findings of 52 athletes with MTSS. Baseline characteristics were recorded and recovery was related to these parameters and MRI findings to examine for prognostic factors. Results showed that 43.5% of the symptomatic legs showed bone marrow or periosteal edema. Absence of periosteal and bone marrow edema on MRI was associated with longer recovery (P = 0.033 and P = 0.013). A clinical scoring system for sports activity (SARS score) was significantly higher in the presence of bone marrow edema (P = 0.027). When clinical scoring systems (SARS score and the Lower Extremity Functional Scale) were combined in a model, time to recovery could be predicted substantially (explaining 54% of variance, P = 0.006). In conclusion, in athletes with MTSS, bone marrow or periosteal edema is seen on MRI in 43,5% of the symptomatic legs. Furthermore, periosteal and bone marrow edema on MRI and clinical scoring systems are prognostic factors. Future studies should focus on MRI findings in symptomatic MTSS and compare these with a matched control group. © 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment.

PubMed

Snyder, Robert

2014-03-01

Detection, treatment, and prevention of bone marrow diseases have long been the aims of experimental and clinical hematologists and mechanistically oriented toxicologists. Among these diseases is aplastic anemia, which manifests as the cessation of normal blood cell production; the leukemias, in contrast, feature the production of excessive hematologic cancer cells. Both diseases are associated with exposure to either industrial chemicals or cancer chemotherapeutic agents. Studies of hematopoietic bone marrow cells in culture have shown that the generation of circulating blood cells requires the interaction of hematopoietic stem cells (HSCs) with supporting marrow stromal cells; yet, isolation of HSCs from bone destroys the unique morphology of the marrow stroma in which the HSCs reside. Imaging techniques and related studies have made it possible to examine specific niches where HSCs may either initiate differentiation toward mature blood cells or reside in a dormant state awaiting a signal to begin differentiation. HSCs and related cells may be highly vulnerable to the mutagenic or toxic effects of drugs or other chemicals early in these processes. Additional studies are required to determine the mechanisms by which drug or chemical exposure may affect these cells and lead to either depression of bone marrow function or to leukemia. © 2014 New York Academy of Sciences.

Sphingosine 1-Phosphate- and C-C Chemokine Receptor 2-Dependent Activation of CD4+ Plasmacytoid Dendritic Cells in the Bone Marrow Contributes to Signs of Sepsis-Induced Immunosuppression

PubMed Central

Smirnov, Anna; Pohlmann, Stephanie; Nehring, Melanie; Ali, Shafaqat; Mann-Nüttel, Ritu; Scheu, Stefanie; Antoni, Anne-Charlotte; Hansen, Wiebke; Büettner, Manuela; Gardiasch, Miriam J.; Westendorf, Astrid M.; Wirsdörfer, Florian; Pastille, Eva; Dudda, Marcel; Flohé, Stefanie B.

2017-01-01

Sepsis is the dysregulated response of the host to systemic, mostly bacterial infection, and is associated with an enhanced susceptibility to life-threatening opportunistic infections. During polymicrobial sepsis, dendritic cells (DCs) secrete enhanced levels of interleukin (IL) 10 due to an altered differentiation in the bone marrow and contribute to the development of immunosuppression. We investigated the origin of the altered DC differentiation using murine cecal ligation and puncture (CLP), a model for human polymicrobial sepsis. Bone marrow cells (BMC) were isolated after sham or CLP operation, the cellular composition was analyzed, and bone marrow-derived DCs (BMDCs) were generated in vitro. From 24 h on after CLP, BMC gave rise to BMDC that released enhanced levels of IL-10. In parallel, a population of CD11chiMHCII+CD4+ DCs expanded in the bone marrow in a MyD88-dependent manner. Prior depletion of the CD11chiMHCII+CD4+ DCs from BMC in vitro reversed the increased IL-10 secretion of subsequently differentiating BMDC. The expansion of the CD11chiMHCII+CD4+ DC population in the bone marrow after CLP required the function of sphingosine 1-phosphate receptors and C-C chemokine receptor (CCR) 2, the receptor for C-C chemokine ligand (CCL) 2, but was not associated with monocyte mobilization. CD11chiMHCII+CD4+ DCs were identified as plasmacytoid DCs (pDCs) that had acquired an activated phenotype according to their increased expression of MHC class II and CD86. A redistribution of CD4+ pDCs from MHC class II− to MHC class II+ cells concomitant with enhanced expression of CD11c finally led to the rise in the number of CD11chiMHCII+CD4+ DCs. Enhanced levels of CCL2 were found in the bone marrow of septic mice and the inhibition of CCR2 dampened the expression of CD86 on CD4+ pDCs after CLP in vitro. Depletion of pDCs reversed the bias of splenic DCs toward increased IL-10 synthesis after CLP in vivo. Thus, during polymicrobial sepsis, CD4+ pDCs are activated in the bone marrow and induce functional reprogramming of differentiating BMDC toward an immunosuppressive phenotype. PMID:29218051

Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis.

PubMed

Jafari, Abbas; Qanie, Diyako; Andersen, Thomas L; Zhang, Yuxi; Chen, Li; Postert, Benno; Parsons, Stuart; Ditzel, Nicholas; Khosla, Sundeep; Johansen, Harald Thidemann; Kjærsgaard-Andersen, Per; Delaisse, Jean-Marie; Abdallah, Basem M; Hesselson, Daniel; Solberg, Rigmor; Kassem, Moustapha

2017-02-14

Secreted factors are a key component of stem cell niche and their dysregulation compromises stem cell function. Legumain is a secreted cysteine protease involved in diverse biological processes. Here, we demonstrate that legumain regulates lineage commitment of human bone marrow stromal cells and that its expression level and cellular localization are altered in postmenopausal osteoporotic patients. As shown by genetic and pharmacological manipulation, legumain inhibited osteoblast (OB) differentiation and in vivo bone formation through degradation of the bone matrix protein fibronectin. In addition, genetic ablation or pharmacological inhibition of legumain activity led to precocious OB differentiation and increased vertebral mineralization in zebrafish. Finally, we show that localized increased expression of legumain in bone marrow adipocytes was inversely correlated with adjacent trabecular bone mass in a cohort of patients with postmenopausal osteoporosis. Our data suggest that altered proteolytic activity of legumain in the bone microenvironment contributes to decreased bone mass in postmenopausal osteoporosis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Biofabricated Structures Reconstruct Functional Urinary Bladders in Radiation-injured Rat Bladders.

PubMed

Imamura, Tetsuya; Shimamura, Mitsuru; Ogawa, Teruyuki; Minagawa, Tomonori; Nagai, Takashi; Silwal Gautam, Sudha; Ishizuka, Osamu

2018-05-08

The ability to repair damaged urinary bladders through the application of bone marrow-derived cells is in the earliest stages of development. We investigated the application of bone marrow-derived cells to repair radiation-injured bladders. We used a three-dimensional (3D) bioprinting robot system to biofabricate bone marrow-derived cell structures. We then determined if the biofabricated structures could restore the tissues and functions of radiation-injured bladders. The bladders of female 10-week-old Sprague-Dawley (SD) rats were irradiated with 2-Gy once a week for 5 weeks. Adherent and proliferating bone marrow-derived cells harvested from the femurs of male 17-week-old green fluorescence protein-transfected Tg-SD rats were cultured in collagen-coated flasks. Bone marrow-derived cell spheroids were formed in 96-well plates. Three layers of spheroids were assembled by the bioprinter onto a 9x9 microneedle array. The assembled spheroids were perfusion cultured for 7 days, and then the microneedle array was removed. Two weeks after the last radiation treatment, the biofabricated structures were transplanted into an incision on the anterior wall of the bladders (n=10). Control rats received the same surgery but without the biofabricated structures (sham-structure, n=12). At 2 and 4 weeks after surgery, the sham-structure control bladder tissues exhibited disorganized smooth muscle layers, decreased nerve cells, and significant fibrosis with increased presence of fibrosis-marker P4HB-positive cells and hypoxia-marker HIF1α-positive cells. The transplanted structures survived within the recipient tissues, and blood vessels extended within them from the recipient tissues. The bone marrow-derived cells in the structures differentiated into smooth muscle cells and formed smooth muscle clusters. The recipient tissues near the transplanted structures had distinct smooth muscle layers and reconstructed nerve cells, and only minimal fibrosis with decreased presence of P4HB- and HIF1α-positive cells. At 4 weeks after surgery, the sham-structure control rats exhibited significant urinary frequency symptoms with irregular and short voiding intervals, and low micturition volumes. In contrast, the structure-transplanted rats had regular micturition with longer voiding intervals and higher micturition volumes compared to the control rats. Further, the residual volume of the structure-transplanted rats was lower than for the controls. Therefore, transplantation of biofabricated bone marrow-derived cell structures reconstructed functional bladders.

Class I and class II major histocompatibility molecules play a role in bone marrow-derived macrophage development

NASA Technical Reports Server (NTRS)

Armstrong, J. W.; Simske, S. J.; Beharka, A. A.; Balch, S.; Luttges, M. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1994-01-01

Class I and class II major histocompatibility complex (MHC) molecules play significant roles in T cell development and immune function. We show that MHCI- and MHCII-deficient mice have low numbers of macrophage precursors and circulating monocytes, as well as abnormal bone marrow cell colony-stimulating factor type 1 secretion and bone composition. We suggest that MHCI and MHCII molecules play a significant role in macrophage development.

Characterization of insulin-producing cells derived from PDX-1-transfected neural stem cells.

PubMed

Wang, Hailan; Jiang, Zesheng; Li, Aihui; Gao, Yi

2012-12-01

Islet cell transplantation is a promising treatment strategy for type-1 diabetes. However, functional islet cells are hard to obtain for transplantation and are in short supply. Directing the differentiation of stem cells into insulin‑producing cells, which serve as islet cells, would overcome this shortage. Bone marrow contains hematopoietic stem cells and mesenchymal stem cells. The present study used bone marrow cells isolated from rats and neural stem cells (NSCs) that were derived from bone marrow cells in culture. Strong nestin staining was detected in NSCs, but not in bone marrow stromal cells (BMSCs). In vitro transfection of the pancreatic duodenal homeobox-1 (PDX-1) gene into NSCs generated insulin‑producing cells. Reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analysis confirmed that PDX-1-transfected NSCs expressed insulin mRNA and released insulin protein. However, insulin release from PDX-1-transfected NSCs did not respond to the challenge of glucose and glucagon-like peptide-1. These results support the use of bone marrow-derived NSCs as a renewable source of insulin-producing cells for autologous transplantation to treat type-1 diabetes.

Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration.

PubMed

Inoue, Yuji; Iriyama, Aya; Ueno, Shuji; Takahashi, Hidenori; Kondo, Mineo; Tamaki, Yasuhiro; Araie, Makoto; Yanagi, Yasuo

2007-08-01

Because there is no effective treatment for this retinal degeneration, potential application of cell-based therapy has attracted considerable attention. Several investigations support that bone marrow mesenchymal stem cells (MSCs) can be used for a broad spectrum of indications. Bone marrow MSCs exert their therapeutic effect in part by secreting trophic factors to promote cell survival. The current study investigates whether bone marrow MSCs secrete factor(s) to promote photoreceptor cell survival and whether subretinal transplantation of bone marrow MSCs promotes photoreceptor survival in a retinal degeneration model using Royal College of Surgeons (RCS) rats. In vitro, using mouse retinal cell culture, it was demonstrated that the conditioned medium of the MSCs delays photoreceptor cell apoptosis, suggesting that the secreted factor(s) from the MSCs promote photoreceptor cell survival. In vivo, the MSCs were injected into the subretinal space of the RCS rats and histological analysis, real-time RT-PCR and electrophysiological analysis demonstrated that the subretinal transplantation of MSCs delays retinal degeneration and preserves retinal function in the RCS rats. These results suggest that MSC is a useful cell source for cell-replacement therapy for some forms of retinal degeneration.

Bone marrow blood vessel ossification and "microvascular dead space" in rat and human long bone.

PubMed

Prisby, Rhonda D

2014-07-01

Severe calcification of the bone microvascular network was observed in rats, whereby the bone marrow blood vessels appeared ossified. This study sought to characterize the magnitude of ossification in relation to patent blood vessels and adipocyte content in femoral diaphyses. Additionally, this study confirmed the presence of ossified vessels in patients with arteriosclerotic vascular disease and peripheral vascular disease and cellulitis. Young (4-6 month; n=8) and old (22-24 month; n=8) male Fischer-344 rats were perfused with barium sulfate to visualize patent bone marrow blood vessels. Femoral shafts were processed for bone histomorphometry to quantify ossified (Goldner's Trichrome) and calcified (Alizarin Red) vessels. Adipocyte content was also determined. Additional femora (n=5/age group) were scanned via μCT to quantify microvascular ossification. Bone marrow blood vessels from the rats and the human patients were also isolated and examined via microscopy. Ossified vessels (rats and humans) had osteocyte lacunae on the vessel surfaces and "normal" vessels were transitioning into bone. The volume of ossified vessels was 4800% higher (p<0.05) in the old vs. young rats. Calcified and ossified vessel volumes per tissue volume and calcified vessel volume per patent vessel volume were augmented (p<0.05) 262%, 375% and 263%, respectively, in the old vs. young rats. Ossified and patent vessel number was higher (171%) and lower (40%), respectively, in the old vs. young rats. Finally, adipocyte volume per patent vessel volume was higher (86%) with age. This study is the first to report ossification of bone marrow blood vessels in rats and humans. Ossification presumably results in "microvascular dead space" in regard to loss of patency and vasomotor function as opposed to necrosis. Progression of bone microvascular ossification may provide the common link associated with age-related changes in bone and bone marrow. The clinical implications may be evident in the difficulties treating bone disease in the elderly. Copyright © 2014 Elsevier Inc. All rights reserved.

Bone Marrow Blood Vessel Ossification and “Microvascular Dead Space” in Rat and Human Long Bone

PubMed Central

Prisby, Rhonda D.

2014-01-01

Severe calcification of the bone microvascular network was observed in rats, whereby the bone marrow blood vessels appeared ossified. This study sought to characterize the magnitude of ossification in relation to patent blood vessels and adipocyte content in femoral diaphyses. Additionally, this study confirmed the presence of ossified vessels in patients with arteriosclerotic vascular disease and peripheral vascular disease and cellulitis. Young (4–6 mon; n=8) and old (22–24 mon; n=8) male Fischer-344 rats were perfused with barium sulfate to visualize patent bone marrow blood vessels. Femoral shafts were processed for bone histomorphometry to quantify ossified (Goldner’s Trichrome) and calcified (Alizarin Red) vessels. Adipocyte content was also determined. Additional femora (n=5/age group) were scanned via µCT to quantify microvascular ossification. Bone marrow blood vessels from rats and the human patients were also isolated and examined via microscopy. Ossified vessels (rats and humans) had osteocyte lacunae on the vessel surfaces and “normal” vessels were transitioning into bone. The volume of ossified vessels was 4800% higher (p <0.05) in old vs. young rats. Calcified and ossified vessel volumes per tissue volume and calcified vessel volume per patent vessel volume were augmented (p <0.05) 262%, 375% and 263%, respectively, in old vs. young rats. Ossified and patent vessel number was higher (171%) and lower (40%), respectively, in old vs. young rats. Finally, adipocyte volume per patent vessel volume was higher (86%) with age. This study is the first to report ossification of bone marrow blood vessels in rats and humans. Ossification presumably results in “microvascular dead space” in regards to loss of patency and vasomotor function as opposed to necrosis. The progression of bone microvascular ossification may provide the common link associated with age-related changes in bone and bone marrow. The clinical implications may be evident in the difficulties treating bone disease in the elderly. PMID:24680721

Genetic response and morphologic characterization of chicken bone-marrow derived dendritic cells during infection with high and low pathogenic avian influenza viruses

USDA-ARS?s Scientific Manuscript database

Dendritic cells (DC) are professional antigen-presenting cells of the immune system that function to initiate primary immune responses. Progenitors of DCs are derived from haematopoietic stem cells in the bone marrow (BM) that migrate in non-lymphoid tissues to develop into immature DCs. Here, they ...

Cellular Sites of Immunologic Unresponsiveness*

PubMed Central

Chiller, Jacques M.; Habicht, Gail S.; Weigle, William O.

1970-01-01

The reconstitution of the immune response of lethally irradiated mice to human γ-globulin is dependent on the synergistic action of bone marrow with thymus cells. Immunologic unresponsiveness appears to involve a functional defect at each of these cellular levels, inasmuch as neither bone marrow nor thymus cells from unresponsive donors are capable of demonstrating synergism in combination with their normal counterpart. PMID:4192271

Low Connexin Channel-Dependent Intercellular Communication in Human Adult Hematopoietic Progenitor/Stem Cells: Probing Mechanisms of Autologous Stem Cell Therapy

PubMed Central

Yang, Jian; Darley, Richard L; Hallett, Maurice; Evans, W Howard

2009-01-01

Human bone marrow is a clinical source of autologous progenitor stem cells showing promise for cardiac repair following ischemic insult. Functional improvements following delivery of adult bone marrow CD34+ cells into heart tissue may require metabolic/electrical communication between participating cells. Since connexin43 (Cx43) channels are implicated in cardiogenesis and provide intercellular connectivity in the heart, the authors analyzed the expression of 20 connexins (Cx) in CD34+ cells and in monocytes and granulocytes in bone marrow and spinal cord. Reverse transcriptase-polymerase chain reaction (RT-PCR) detected only low expression of Cx43 and Cx37. Very low level dye coupling was detected by flow cytometry between CD34+ cells and other Cx43 expressing cells, including HL-1 cardiac cells, and was not inhibited by specific gap junction inhibitors. The results indicate that CD34+ cells are unlikely to communicate via gap junctions and the authors conclude that use of CD34+ cells to repair damaged hearts is unlikely to involve gap junctions. The results concur with the hypothesis that bone marrow cells elicit improved cardiac function through release of undefined paracrine mediators. PMID:20298144

Stromal and Hematopoietic Progenitors from C57/BI/6N Murine Bone Marrow After 30-Day "BION-M1" Spaceflight.

PubMed

Markina, Elena; Andreeva, Elena; Andrianova, Irina; Sotnezova, Elena; Buravkova, Ludmila

2018-05-02

Elucidation of the spaceflight (SF) effects on the adult stem and progenitor cells is an important goal in space biology and medicine. A unique opportunity for this was provided by project "BION-M1". The purpose of this study was to evaluate the effects of 30-day SF on biosatellite, 7-day recovery (SFR), and subsequent ground control (GC) experiment on the mononuclear cells (MNCs) from C57/BI/6N murine tibia bone marrow. Also, hematopoietic and stromal precursor functions were characterized ex vivo. There was no significant difference in the total MNC number between experimental groups. After SF, immunophenotyping revealed an increase of large-sized CD45 + MNCs corresponded to committed hematopoietic progenitors. The total hematopoietic colony-forming unit (CFU) number decreased after SF and did not restore after 7 day of recovery due to predominant reduction of bi- and multipotent CFUs and primitive burst-forming units in favor of unipotent CFUs. Functional activity of stromal precursors in vitro was only slightly altered. SF cells displayed the enhanced expression of alkaline phosphatase. The data of the GC experiment demonstrated the preservation of the functional activity of progenitor cells from mice bone marrow. The activation of erythropoiesis in expense of burst-forming units of erythrocytes elevation was detected. After 7 days of recovery, the number of colony-forming units of fibroblast (CFUs-f) was similar to the vivarium control, while the proliferative activity of bone marrow stromal precursors decreased. The present study demonstrated that certain hematopoietic progenitors are susceptible to SF factors, while the stromal precursors displayed a certain degree of resistance. These data indicate mild and reversible alterations of bone marrow progenitors after SF.

Assessment of bone marrow plasma cell infiltrates in multiple myeloma: the added value of CD138 immunohistochemistry

PubMed Central

Al-Quran, Samer Z.; Yang, Lijun; Magill, James M.; Braylan, Raul C.; Douglas-Nikitin, Vonda K.

2012-01-01

Summary Assessment of bone marrow involvement by malignant plasma cells is an important element in the diagnosis and follow-up of patients with multiple myeloma and other plasma cell dyscrasias. Microscope-based differential counts of bone marrow aspirates are used as the primary method to evaluate bone marrow plasma cell percentages. However, multiple myeloma is often a focal process, a fact that impacts the accuracy and reliability of the results of bone marrow plasma cell percentages obtained by differential counts of bone marrow aspirate smears. Moreover, the interobserver and intraobserver reproducibility of counting bone marrow plasma cells microscopically has not been adequately tested. CD138 allows excellent assessment of plasma cell numbers and distribution in bone marrow biopsies. We compared estimates of plasma cell percentages in bone marrow aspirates and in hematoxylin-eosin– and CD138-stained bone marrow biopsy sections (CD138 sections) in 79 bone marrows from patients with multiple myeloma. There was a notable discrepancy in bone marrow plasma cell percentages using the different methods of observation. In particular, there was a relatively poor concordance of plasma cell percentage estimation between aspirate smears and CD138 sections. Estimates of plasma cell percentage using CD138 sections demonstrated the highest interobserver concordance. This observation was supported by computer-assisted image analysis. In addition, CD138 expression highlighted patterns of plasma cell infiltration indicative of neoplasia even in the absence of plasmacytosis. We conclude that examination of CD138 sections should be considered for routine use in the estimation of plasma cell load in the bone marrow. PMID:17714757

Crosstalk between bone marrow-derived mesenchymal stem cells and regulatory T cells through a glucocorticoid-induced leucine zipper/developmental endothelial locus-1-dependent mechanism.

PubMed

Yang, Nianlan; Baban, Babak; Isales, Carlos M; Shi, Xing-Ming

2015-09-01

Bone marrow is a reservoir for regulatory T (T(reg)) cells, but how T(reg) cells are regulated in that environment remains poorly understood. We show that expression of glucocorticoid (GC)-induced leucine zipper (GILZ) in bone marrow mesenchymal lineage cells or bone marrow-derived mesenchymal stem cells (BMSCs) increases the production of T(reg) cells via a mechanism involving the up-regulation of developmental endothelial locus-1 (Del-1), an endogenous leukocyte-endothelial adhesion inhibitor. We found that the expression of Del-1 is increased ∼4-fold in the bone tissues of GILZ transgenic (Tg) mice, and this increase is coupled with a significant increase in the production of IL-10 (2.80 vs. 0.83) and decrease in the production of IL-6 (0.80 vs. 2.33) and IL-12 (0.25 vs. 1.67). We also show that GILZ-expressing BMSCs present antigen in a way that favors T(reg) cells. These results indicate that GILZ plays a critical role mediating the crosstalk between BMSCs and T(reg) in the bone marrow microenvironment. These data, together with our previous findings that overexpression of GILZ in BMSCs antagonizes TNF-α-elicited inflammatory responses, suggest that GILZ plays important roles in bone-immune cell communication and BMSC immune suppressive functions. © FASEB.

Ginsenoside Rg1 improves bone marrow haematopoietic activity via extramedullary haematopoiesis of the spleen

PubMed Central

Liu, Hua-Hsing; Chen, Fei-Peng; Liu, Rong-Kai; Lin, Chun-Lin; Chang, Ko-Tung

2015-01-01

Cyclophosphamide (CY) is a chemotherapeutic agent used for cancer and immunological diseases. It induces cytotoxicity of bone marrow and causes myelosuppression and extramedullary haematopoiesis (EMH) in treated patients. EMH is characterized with the emergence of multipotent haematopoietic progenitors most likely in the spleen and liver. Previous studies indicated that a Chinese medicine, ginsenoside Rg1, confers a significant effect to elevate the number of lineage (Lin−) Sca-1+ c-Kit+ haematopoietic stem and progenitor cells (HSPCs) and restore the function of bone marrow in CY-treated myelosuppressed mice. However, whether the amelioration of bone marrow by Rg1 accompanies an alleviation of EMH in the spleen was still unknown. In our study, the cellularity and weight of the spleen were significantly reduced after Rg1 treatment in CY-treated mice. Moreover, the number of c-Kit+ HSPCs was significantly decreased but not as a result of apoptosis, indicating that Rg1 alleviated EMH of the spleen induced by CY. Unexpectedly, the proliferation activity of c-Kit+ HSPCs was only up-regulated in the spleen, but not in the bone marrow, after Rg1 treatment in CY-treated mice. We also found that a fraction of c-Kit+/CD45+ HSPCs was simultaneously increased in the circulation after Rg1 treatment. Interestingly, the effects of Rg1 on the elevation of HSPCs in bone marrow and in the peripheral blood were suppressed in CY-treated splenectomized mice. These results demonstrated that Rg1 improves myelosuppression induced by CY through its action on the proliferation of HSPCs in EMH of the spleen and migration of HSPCs from the spleen to the bone marrow. PMID:26153045

Ginsenoside Rg1 improves bone marrow haematopoietic activity via extramedullary haematopoiesis of the spleen.

PubMed

Liu, Hua-Hsing; Chen, Fei-Peng; Liu, Rong-Kai; Lin, Chun-Lin; Chang, Ko-Tung

2015-11-01

Cyclophosphamide (CY) is a chemotherapeutic agent used for cancer and immunological diseases. It induces cytotoxicity of bone marrow and causes myelosuppression and extramedullary haematopoiesis (EMH) in treated patients. EMH is characterized with the emergence of multipotent haematopoietic progenitors most likely in the spleen and liver. Previous studies indicated that a Chinese medicine, ginsenoside Rg1, confers a significant effect to elevate the number of lineage (Lin(-) ) Sca-1(+) c-Kit(+) haematopoietic stem and progenitor cells (HSPCs) and restore the function of bone marrow in CY-treated myelosuppressed mice. However, whether the amelioration of bone marrow by Rg1 accompanies an alleviation of EMH in the spleen was still unknown. In our study, the cellularity and weight of the spleen were significantly reduced after Rg1 treatment in CY-treated mice. Moreover, the number of c-Kit(+) HSPCs was significantly decreased but not as a result of apoptosis, indicating that Rg1 alleviated EMH of the spleen induced by CY. Unexpectedly, the proliferation activity of c-Kit(+) HSPCs was only up-regulated in the spleen, but not in the bone marrow, after Rg1 treatment in CY-treated mice. We also found that a fraction of c-Kit(+) /CD45(+) HSPCs was simultaneously increased in the circulation after Rg1 treatment. Interestingly, the effects of Rg1 on the elevation of HSPCs in bone marrow and in the peripheral blood were suppressed in CY-treated splenectomized mice. These results demonstrated that Rg1 improves myelosuppression induced by CY through its action on the proliferation of HSPCs in EMH of the spleen and migration of HSPCs from the spleen to the bone marrow. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Human regulatory T cells do not suppress the antitumor immunity in the bone marrow: a role for bone marrow stromal cells in neutralizing regulatory T cells.

PubMed

Guichelaar, Teun; Emmelot, Maarten E; Rozemuller, Henk; Martini, Bianka; Groen, Richard W J; Storm, Gert; Lokhorst, Henk M; Martens, Anton C; Mutis, Tuna

2013-03-15

Regulatory T cells (Tregs) are potent tools to prevent graft-versus-host disease (GVHD) induced after allogeneic stem cell transplantation or donor lymphocyte infusions. Toward clinical application of Tregs for GVHD treatment, we investigated the impact of Tregs on the therapeutic graft-versus-tumor (GVT) effect against human multiple myeloma tumors with various immunogenicities, progression rates, and localizations in a humanized murine model. Immunodeficient Rag2(-/-)γc(-/-) mice, bearing various human multiple myeloma tumors, were treated with human peripheral blood mononuclear cell (PBMC) alone or together with autologous ex vivo cultured Tregs. Mice were analyzed for the in vivo engraftment, homing of T-cell subsets, development of GVHD and GVT. In additional in vitro assays, Tregs that were cultured together with bone marrow stromal cells were analyzed for phenotype and functions. Treatment with PBMC alone induced variable degrees of antitumor response, depending on the immunogenicity and the growth rate of the tumor. Coinfusion of Tregs did not impair the antitumor response against tumors residing within the bone marrow, irrespective of their immunogenicity or growth rates. In contrast, Tregs readily inhibited the antitumor effect against tumors growing outside the bone marrow. Exploring this remarkable phenomenon, we discovered that bone marrow stroma neutralizes the suppressive activity of Tregs in part via production of interleukin (IL)-1β/IL-6. We furthermore found in vitro and in vivo evidence of conversion of Tregs into IL-17-producing T cells in the bone marrow environment. These results provide new insights into the Treg immunobiology and indicate the conditional benefits of future Treg-based therapies.

Consequences of irradiation on bone and marrow phenotypes, and its relation to disruption of hematopoietic precursors

PubMed Central

Green, Danielle E.; Rubin, Clinton T.

2014-01-01

The rising levels of radiation exposure, specifically for medical treatments and accidental exposures, have added great concern for the long term risks of bone fractures. Both the bone marrow and bone architecture are devastated following radiation exposure. Even sub-lethal doses cause a deficit to the bone marrow microenvironment, including a decline in hematopoietic cells, and this deficit occurs in a dose dependent fashion. Certain cell phenotypes though are more susceptible to radiation damage, with mesenchymal stem cells being more resilient than the hematopoietic stem cells. The decline in total bone marrow hematopoietic cells is accompanied with elevated adipocytes into the marrow cavity, thereby inhibiting hematopoiesis and recovery of the bone marrow microenvironment. Poor bone marrow is also associated with a decline in bone architectural quality. Therefore, the ability to maintain the bone marrow microenvironment would hinder much of the trabecular bone loss caused by radiation exposure, ultimately decreasing some comorbidities in patients exposed to radiation. PMID:24607941

In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism

PubMed Central

Shih, Yu-Ru; Kang, Heemin; Rao, Vikram; Chiu, Yu-Jui; Kwon, Seong Keun; Varghese, Shyni

2017-01-01

Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures. Our results show that these matrices incorporated with BM cells or BM flush transplanted into recipient mice matured into functional bone displaying the cardinal features of both skeletal and hematopoietic compartments similar to native bone tissue. The hematopoietic function of bone tissues was demonstrated by its support for a higher percentage of mixed chimerism compared with i.v. injection and donor hematopoietic cell mobilization in the circulation of nonirradiated recipients. Furthermore, hematopoietic cells sorted from the engineered bone tissues reconstituted the hematopoietic system when transplanted into lethally irradiated secondary recipients. Such engineered bone tissues could potentially be used as ectopic BM surrogates for treatment of nonmalignant BM diseases and as a tool to study hematopoiesis, donor–host cell dynamics, tumor tropism, and hematopoietic cell transplantation. PMID:28484009

In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism.

PubMed

Shih, Yu-Ru; Kang, Heemin; Rao, Vikram; Chiu, Yu-Jui; Kwon, Seong Keun; Varghese, Shyni

2017-05-23

Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures. Our results show that these matrices incorporated with BM cells or BM flush transplanted into recipient mice matured into functional bone displaying the cardinal features of both skeletal and hematopoietic compartments similar to native bone tissue. The hematopoietic function of bone tissues was demonstrated by its support for a higher percentage of mixed chimerism compared with i.v. injection and donor hematopoietic cell mobilization in the circulation of nonirradiated recipients. Furthermore, hematopoietic cells sorted from the engineered bone tissues reconstituted the hematopoietic system when transplanted into lethally irradiated secondary recipients. Such engineered bone tissues could potentially be used as ectopic BM surrogates for treatment of nonmalignant BM diseases and as a tool to study hematopoiesis, donor-host cell dynamics, tumor tropism, and hematopoietic cell transplantation.

MR-Based Assessment of Bone Marrow Fat in Osteoporosis, Diabetes, and Obesity

PubMed Central

Cordes, Christian; Baum, Thomas; Dieckmeyer, Michael; Ruschke, Stefan; Diefenbach, Maximilian N.; Hauner, Hans; Kirschke, Jan S.; Karampinos, Dimitrios C.

2016-01-01

Bone consists of the mineralized component (i.e., cortex and trabeculae) and the non-mineralized component (i.e., bone marrow). Most of the routine clinical bone imaging uses X-ray-based techniques and focuses on the mineralized component. However, bone marrow adiposity has been also shown to have a strong linkage with bone health. Specifically, multiple previous studies have demonstrated a negative association between bone marrow fat fraction (BMFF) and bone mineral density. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) are ideal imaging techniques for non-invasively investigating the properties of bone marrow fat. In the present work, we first review the most important MRI and MRS methods for assessing properties of bone marrow fat, including methodologies for measuring BMFF and bone marrow fatty acid composition parameters. Previous MRI and MRS studies measuring BMFF and fat unsaturation in the context of osteoporosis are then reviewed. Finally, previous studies investigating the relationship between bone marrow fat, other fat depots, and bone health in patients with obesity and type 2 diabetes are presented. In summary, MRI and MRS are powerful non-invasive techniques for measuring properties of bone marrow fat in osteoporosis, obesity, and type 2 diabetes and can assist in future studies investigating the pathophysiology of bone changes in the above clinical scenarios. PMID:27445977

Assessment of functional liver reserve: old and new in 99mTc-sulfur colloid scintigraphy.

PubMed

Matesan, Manuela M; Bowen, Stephen R; Chapman, Tobias R; Miyaoka, Robert S; Velez, James W; Wanner, Michele F; Nyflot, Matthew J; Apisarnthanarax, Smith; Vesselle, Hubert J

2017-07-01

A semiquantitative assessment of hepatic reticuloendothelial system function using colloidal particles scintigraphy has been proposed previously as a surrogate for liver function evaluation. In this article, we present an updated method for the overall assessment of technetium-99m (Tc)-sulfur colloid (SC) biodistribution that combines information from planar and attenuation-corrected Tc-SC single-photon emission computed tomography (SPECT) images. The imaging protocol described here was developed as an easy-to-implement method to assess overall and regional liver function changes associated with chronic liver disease. Thirty patients with chronic liver disease and primary liver cancers underwent Tc-SC whole-body planar imaging and upper-abdomen SPECT/computed tomography (CT) imaging before external beam radiation therapy. Liver plus spleen and bone marrow counts as a fraction of whole-body total counts were calculated from SC planar imaging. Attenuation correction Tc-SC images were rigidly coregistered with treatment planning CT images that contained liver and spleen regions-of-interest. Ratios of total liver counts to total spleen counts were obtained from the aligned Tc-SC SPECT and CT images, and were subsequently used to separate liver plus spleen counts obtained on the planar images. This hybrid SPECT/CT and planar scintigraphy approach yielded an updated estimation of whole-body SC distribution. These biodistribution estimates were compared with historical data for reference. Statistical associations of Tc-SC biodistribution to liver function parameters and liver disease scoring systems (Child-Pugh) were evaluated by Spearman rank correlation. Percentages of Tc-SC uptake ranged from 19.3 to 77.3% for the liver; 3.4 to 40.7% for the spleen; and 19.0 to 56.7% for the bone marrow. Spearman's correlation coefficient showed a significant statistical association between Child-Pugh score and bone marrow uptake at 0.55 (P≤0.05), liver uptake at 0.71 (P≤0.001), spleen uptake at 0.56 (P≤0.05), and spleen plus bone marrow uptake at 0.71 (P≤0.001). There was also a good correlation of SC uptake percentages with individual quantitative liver function components such as albumin and total bilirubin, and qualitative liver function components (varices, portal hypertension, ascites). For albumin: r=0.64 (P<0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P<0.001) compared with splenic uptake percentage, and r=0.45 (P≤0.05) compared with bone marrow uptake percentage. We describe a novel liver function quantitative assessment method that combines whole-body planar images and SPECT/CT attenuation-corrected images of Tc-SC distribution. Attenuation-corrected SC images provide valuable regional liver function information, which is a unique feature compared with other imaging methods available. The results of our study indicate that the Tc-SC uptake by the liver, spleen, and bone marrow correlates with liver function parameters in patients with diffuse liver disease and the correlation with liver disease severity is slightly better for liver uptake percentages than for individual values of bone marrow and spleen uptake percentages.

Blood and Bone Marrow Donation

MedlinePlus

... who's waiting for a stem cell transplant. Risks Bone marrow donation The most serious risk associated with ... or her health insurance. What you can expect Bone marrow donation Collecting stem cells from bone marrow ...

Meeting report of the 2016 bone marrow adiposity meeting.

PubMed

van der Eerden, Bram; van Wijnen, André

2017-10-02

There is considerable interest in the physiology and pathology, as well as the cellular and molecular biology, of bone marrow adipose tissue (BMAT). Because bone marrow adiposity is linked not only to systemic energy metabolism, but also to both bone marrow and musculoskeletal disorders, this biologic compartment has become of major interest to investigators from diverse disciplines. Bone marrow adiposity represents a virtual multi-tissue endocrine organ, which encompasses cells from multiple developmental lineages (e.g., mesenchymal, myeloid, lymphoid) and occupies all the non-osseous and non-cartilaginous space within long bones. A number of research groups are now focusing on bone marrow adiposity to understand a range of clinical afflictions associated with bone marrow disorders and to consider mechanisms-based strategies for future therapies.

The ability of multipotent mesenchymal stromal cells from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells.

PubMed

Sorokina, Tamara; Shipounova, Irina; Bigildeev, Alexey; Petinati, Nataliya; Drize, Nina; Turkina, Anna; Chelysheva, Ekaterina; Shukhov, Oleg; Kuzmina, Larisa; Parovichnikova, Elena; Savchenko, Valery

2016-09-01

The development of leukemia impairs normal hematopoiesis and marrow stromal microenvironment. The aim of the investigation was to study the ability of multipotent mesenchymal stromal cells (MSCs) derived from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells. MSCs were obtained from the bone marrow of 14 patients with acute lymphoblastic (ALL), 25 with myeloid (AML), and 15 with chronic myeloid (CML) leukemia. As a control, MSCs from 22 healthy donors were used. The incidence of cobblestone area forming cells (CAFC 7-8 d) in the bone marrow of healthy donor cultivated on the supportive layer of patients MSCs was measured. The ability of MSCs from AML and ALL patients at the moment of diagnosis to maintain normal CAFC was significantly decreased when compared to donors. After chemotherapy, the restoration of ALL patients' MSCs functions was slower than that of AML. CML MSCs maintained CAFC better than donors' at the moment of diagnosis and this ability increased with treatment. The ability of patients' MSCs to maintain normal hematopoietic progenitor cells was shown to change in comparison with MSCs from healthy donors and depended on nosology. During treatment, the functional capacity of patients' MSCs had been partially restored. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Bone marrow with diffuse tumor infiltration in patients with lymphoproliferative diseases: dynamic gadolinium-enhanced MR imaging.

PubMed

Rahmouni, Alain; Montazel, Jean-Luc; Divine, Marine; Lepage, Eric; Belhadj, Karim; Gaulard, Philippe; Bouanane, Mohamed; Golli, Mondher; Kobeiter, Hicham

2003-12-01

To evaluate gadolinium enhancement of bone marrow in patients with lymphoproliferative diseases and diffuse bone marrow involvement. Dynamic contrast material-enhanced magnetic resonance (MR) imaging of the thoracolumbar spine was performed in 42 patients with histologically proved diffuse bone marrow involvement and newly diagnosed myeloma (n = 31), non-Hodgkin lymphoma (n = 8), or Hodgkin disease (n = 3). The maximum percentage of enhancement (Emax), enhancement slope, and enhancement washout were determined from enhancement time curves (ETCs). A three-grade system for scoring bone marrow involvement was based on the percentage of neoplastic cells in bone marrow samples. Quantitative ETC values for the 42 patients were compared with ETC values for healthy subjects and with grades of bone marrow involvement by using mean t test comparisons. Receiver operating characteristic (ROC) analysis was conducted by comparing Emax values between patients with and those without bone marrow involvement. Baseline and follow-up MR imaging findings were compared in nine patients. Significant differences in Emax (P <.001), slope (P <.001), and washout (P =.005) were found between subjects with normal bone marrow and patients with diffuse bone marrow involvement. ROC analysis results showed Emax values to have a diagnostic accuracy of 99%. Emax, slope, and washout values increased with increasing bone marrow involvement grade. The mean Emax increased from 339% to 737%. Contrast enhancement decreased after treatment in all six patients who responded to treatment but not in two of three patients who did not respond to treatment. Dynamic contrast-enhanced MR images can demonstrate increased bone marrow enhancement in patients with lymphoproliferative diseases and marrow involvement.

Investigating the Abscopal Effects of Radioablation on Shielded Bone Marrow in Rodent Models Using Multimodality Imaging.

PubMed

Afshar, Solmaz F; Zawaski, Janice A; Inoue, Taeko; Rendon, David A; Zieske, Arthur W; Punia, Jyotinder N; Sabek, Omaima M; Gaber, M Waleed

2017-07-01

The abscopal effect is the response to radiation at sites that are distant from the irradiated site of an organism, and it is thought to play a role in bone marrow (BM) recovery by initiating responses in the unirradiated bone marrow. Understanding the mechanism of this effect has applications in treating BM failure (BMF) and BM transplantation (BMT), and improving survival of nuclear disaster victims. Here, we investigated the use of multimodality imaging as a translational tool to longitudinally assess bone marrow recovery. We used positron emission tomography/computed tomography (PET/CT), magnetic resonance imaging (MRI) and optical imaging to quantify bone marrow activity, vascular response and marrow repopulation in fully and partially irradiated rodent models. We further measured the effects of radiation on serum cytokine levels, hematopoietic cell counts and histology. PET/CT imaging revealed a radiation-induced increase in proliferation in the shielded bone marrow (SBM) compared to exposed bone marrow (EBM) and sham controls. T 2 -weighted MRI showed radiation-induced hemorrhaging in the EBM and unirradiated SBM. In the EBM and SBM groups, we found alterations in serum cytokine and hormone levels and in hematopoietic cell population proportions, and histological evidence of osteoblast activation at the bone marrow interface. Importantly, we generated a BMT mouse model using fluorescent-labeled bone marrow donor cells and performed fluorescent imaging to reveal the migration of bone marrow cells from shielded to radioablated sites. Our study validates the use of multimodality imaging to monitor bone marrow recovery and provides evidence for the abscopal response in promoting bone marrow recovery after irradiation.

Aging and Bone

PubMed Central

Boskey, A.L.; Coleman, R.

2010-01-01

Bones provide mechanical and protective function, while also serving as housing for marrow and a site for regulation of calcium ion homeostasis. The properties of bones do not remain constant with age; rather, they change throughout life, in some cases improving in function, but in others, function deteriorates. Here we review the modifications in the mechanical function and shape of bones, the bone cells, the matrix they produce, and the mineral that is deposited on this matrix, while presenting recent theories about the factors leading to these changes. PMID:20924069

Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Magome, Taiki; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Radiology, The University of Tokyo Hospital, Tokyo

Purpose: To develop an imaging method to characterize and map marrow composition in the entire skeletal system, and to simulate differential targeted marrow irradiation based on marrow composition. Methods and Materials: Whole-body dual energy computed tomography (DECT) images of cadavers and leukemia patients were acquired, segmented to separate bone marrow components, namely, bone, red marrow (RM), and yellow marrow (YM). DECT-derived marrow fat fraction was validated using histology of lumbar vertebrae obtained from cadavers. The fractions of RM (RMF = RM/total marrow) and YMF were calculated in each skeletal region to assess the correlation of marrow composition with sites and ages. Treatmentmore » planning was simulated to target irradiation differentially at a higher dose (18 Gy) to either RM or YM and a lower dose (12 Gy) to the rest of the skeleton. Results: A significant correlation between fat fractions obtained from DECT and cadaver histology samples was observed (r=0.861, P<.0001, Pearson). The RMF decreased in the head, neck, and chest was significantly inversely correlated with age but did not show any significant age-related changes in the abdomen and pelvis regions. Conformity of radiation to targets (RM, YM) was significantly dependent on skeletal sites. The radiation exposure was significantly reduced (P<.05, t test) to organs at risk (OARs) in RM and YM irradiation compared with standard total marrow irradiation (TMI). Conclusions: Whole-body DECT offers a new imaging technique to visualize and measure skeletal-wide marrow composition. The DECT-based treatment planning offers volumetric and site-specific precise radiation dosimetry of RM and YM, which varies with aging. Our proposed method could be used as a functional compartment of TMI for further targeted radiation to specific bone marrow environment, dose escalation, reduction of doses to OARs, or a combination of these factors.« less

Bone Marrow Test: MedlinePlus Lab Test Information

MedlinePlus

... this page: https://medlineplus.gov/labtests/bonemarrowtest.html Bone Marrow Test To use the sharing features on this page, please enable JavaScript. What Are Bone Marrow Tests? Bone marrow is a soft, spongy ...

CD146/MCAM defines functionality of human bone marrow stromal stem cell populations.

PubMed

Harkness, Linda; Zaher, Walid; Ditzel, Nicholas; Isa, Adiba; Kassem, Moustapha

2016-01-11

Identification of surface markers for prospective isolation of functionally homogenous populations of human skeletal (stromal, mesenchymal) stem cells (hMSCs) is highly relevant for cell therapy protocols. Thus, we examined the possible use of CD146 to subtype a heterogeneous hMSC population. Using flow cytometry and cell sorting, we isolated two distinct hMSC-CD146(+) and hMSC-CD146(-) cell populations from the telomerized human bone marrow-derived stromal cell line (hMSC-TERT). Cells were examined for differences in their size, shape and texture by using high-content analysis and additionally for their ability to differentiate toward osteogenesis in vitro and form bone in vivo, and their migrational ability in vivo and in vitro was investigated. In vitro, the two cell populations exhibited similar growth rate and differentiation capacity to osteoblasts and adipocytes on the basis of gene expression and protein production of lineage-specific markers. In vivo, hMSC-CD146(+) and hMSC-CD146(-) cells formed bone and bone marrow organ when implanted subcutaneously in immune-deficient mice. Bone was enriched in hMSC-CD146(-) cells (12.6 % versus 8.1 %) and bone marrow elements enriched in implants containing hMSC-CD146(+) cells (0.5 % versus 0.05 %). hMSC-CD146(+) cells exhibited greater chemotactic attraction in a transwell migration assay and, when injected intravenously into immune-deficient mice following closed femoral fracture, exhibited wider tissue distribution and significantly increased migration ability as demonstrated by bioluminescence imaging. Our studies demonstrate that CD146 defines a subpopulation of hMSCs capable of bone formation and in vivo trans-endothelial migration and thus represents a population of hMSCs suitable for use in clinical protocols of bone tissue regeneration.

The effect of space and parabolic flight on macrophage hematopoiesis and function

NASA Technical Reports Server (NTRS)

Armstrong, J. W.; Gerren, R. A.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1995-01-01

We used weak electric fields to monitor macrophage spreading in microgravity. Using this technique, we demonstrated that bone marrow-derived macrophages responded to microgravity within 8 s. We also showed that microgravity differentially altered two processes associated with bone marrow-derived macrophage development. Spaceflight enhanced cellular proliferation and inhibited differentiation. These data indicate that the space/microgravity environment significantly affects macrophages.

T2 vertebral bone marrow changes after space flight

NASA Technical Reports Server (NTRS)

LeBlanc, A.; Lin, C.; Evans, H.; Shackelford, L.; Martin, C.; Hedrick, T.

1999-01-01

Bone biopsies indicate that during immobilization bone marrow adipose tissue increases while the functional cellular fraction decreases. One objective of our Spacelab flight experiment was to determine, using in vivo volume-localized magnetic resonance spectroscopy (VLMRS), whether bone marrow composition was altered by space flight. Four crew members of a 17 day Spacelab mission participated in the experiment. The apparent cellular fraction and transverse relaxation time (T2) were determined twice before launch and at several times after flight. Immediately after flight, no significant change in the cellular fraction was found. However, the T2 of the cellular, but not the fat component increased following flight, although to a variable extent, in all crew members with a time course for return to baseline lasting several months. The T2 of seven control subjects showed no significant change. Although these observations may have several explanations, it is speculated that the observed T2 changes might reflect increased marrow osteoblastic activity during recovery from space flight.

Meeting report of the 2016 bone marrow adiposity meeting

PubMed Central

van der Eerden, Bram; van Wijnen, André

2017-01-01

Abstract There is considerable interest in the physiology and pathology, as well as the cellular and molecular biology, of bone marrow adipose tissue (BMAT). Because bone marrow adiposity is linked not only to systemic energy metabolism, but also to both bone marrow and musculoskeletal disorders, this biologic compartment has become of major interest to investigators from diverse disciplines. Bone marrow adiposity represents a virtual multi-tissue endocrine organ, which encompasses cells from multiple developmental lineages (e.g., mesenchymal, myeloid, lymphoid) and occupies all the non-osseous and non-cartilaginous space within long bones. A number of research groups are now focusing on bone marrow adiposity to understand a range of clinical afflictions associated with bone marrow disorders and to consider mechanisms-based strategies for future therapies. PMID:28410005

The role of bone marrow-derived cells during the bone healing process in the GFP mouse bone marrow transplantation model.

PubMed

Tsujigiwa, Hidetsugu; Hirata, Yasuhisa; Katase, Naoki; Buery, Rosario Rivera; Tamamura, Ryo; Ito, Satoshi; Takagi, Shin; Iida, Seiji; Nagatsuka, Hitoshi

2013-03-01

Bone healing is a complex and multistep process in which the origin of the cells participating in bone repair is still unknown. The involvement of bone marrow-derived cells in tissue repair has been the subject of recent studies. In the present study, bone marrow-derived cells in bone healing were traced using the GFP bone marrow transplantation model. Bone marrow cells from C57BL/6-Tg (CAG-EGFP) were transplanted into C57BL/6 J wild mice. After transplantation, bone injury was created using a 1.0-mm drill. Bone healing was histologically assessed at 3, 7, 14, and 28 postoperative days. Immunohistochemistry for GFP; double-fluorescent immunohistochemistry for GFP-F4/80, GFP-CD34, and GFP-osteocalcin; and double-staining for GFP and tartrate-resistant acid phosphatase were performed. Bone marrow transplantation successfully replaced the hematopoietic cells into GFP-positive donor cells. Immunohistochemical analyses revealed that osteoblasts or osteocytes in the repair stage were GFP-negative, whereas osteoclasts in the repair and remodeling stages and hematopoietic cells were GFP-positive. The results indicated that bone marrow-derived cells might not differentiate into osteoblasts. The role of bone marrow-derived cells might be limited to adjustment of the microenvironment by differentiating into inflammatory cells, osteoclasts, or endothelial cells in immature blood vessels.

Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets

NASA Astrophysics Data System (ADS)

Dant, James T.; Richardson, Richard B.; Nie, Linda H.

2013-05-01

Alpha (α) particles and low-energy beta (β) particles present minimal risk for external exposure. While these particles can induce leukemia and bone cancer due to internal exposure, they can also be beneficial for targeted radiation therapies. In this paper, a trabecular bone model is presented to investigate the radiation dose from bone- and marrow-seeking α and β emitters to different critical compartments (targets) of trabecular bone for different age groups. Two main issues are addressed with Monte Carlo simulations. The first is the absorption fractions (AFs) from bone and marrow to critical targets within the bone for different age groups. The other issue is the application of 223Ra for the radiotherapy treatment of bone metastases. Both a static model and a simulated bone remodeling process are established for trabecular bone. The results show significantly lower AFs from radionuclide sources in the bone volume to the peripheral marrow and the haematopoietic marrow for adults than for newborns and children. The AFs from sources on the bone surface and in the bone marrow to peripheral marrow and haematopoietic marrow also varies for adults and children depending on the energy of the particles. Regarding the use of 223Ra as a radionuclide for the radiotherapy of bone metastases, the simulations show a significantly higher dose from 223Ra and its progeny in forming bone to the target compartment of bone metastases than that from two other more commonly used β-emitting radiopharmaceuticals, 153Sm and 89Sr. There is also a slightly lower dose from 223Ra in forming bone to haematopoietic marrow than that from 153Sm and 89Sr. These results indicate a higher therapy efficiency and lower marrow toxicity from 223Ra and its progeny. In conclusion, age-related changes in bone dimension and cellularity seem to significantly affect the internal dose from α and β emitters in the bone and marrow to critical targets, and 223Ra may be a more efficient radiopharmaceutical for the treatment of bone metastases than 153Sm and 89Sr, if the diffusion of 219Rn to the bone marrow is insignificant.

Comparison of collagen matrix treatment impregnated with platelet rich plasma vs bone marrow.

PubMed

Minamimura, Ai; Ichioka, Shigeru; Sano, Hitomi; Sekiya, Naomi

2014-02-01

This study has reported the efficacy of an autologous bone marrow-impregnated collagen matrix experimentally and clinically. Then, it reflected that platelet rich plasma (PRP) was as good a source of growth factors as bone marrow and available in a less invasive procedure. This study aimed to compare the efficacy of a PRP-impregnated collagen matrix with that of a bone marrow-impregnated collagen matrix by quantifying wound size and capillary density using genetically diabetic db/db mice. Bone marrow cells were obtained from femurs of ddy mice. Then, a small amount of collagen matrix was immersed in bone marrow suspension. This is called a bone marrow-impregnated collagen matrix. PRP was obtained from healthy human blood and a small amount of collagen matrix was immersed in PRP. This is called a PRP-impregnated collagen matrix. A bone marrow-impregnated collagen matrix and PRP-impregnated collagen matrix were applied to excisional skin wounds on a genetically healing-impaired mouse (n = 6) and wounds were evaluated 6 days after the procedure. Wounds were divided into two groups: PRP (n = 6), in which a PRP-impregnated collagen matrix was applied; and bone marrow (n = 6), in which collagen immersed in a bone marrow suspension was applied. There was no significant difference between the PRP and bone-marrow groups in the rate of vascular density increase or wound size decrease. The present study suggested that the PRP-impregnated collagen matrix promotes repair processes at least as strongly as the bone marrow-impregnated collagen matrix. Given lower invasiveness, the PRP-impregnated collagen matrix would have advantages in clinical use.

Aspiration and Biopsy: Bone Marrow

MedlinePlus

... Print What It Is Bone marrow aspirations and biopsies are performed to examine bone marrow, the spongy liquid part of the bone where blood cells are ... you might also feel the pressure of the biopsy needle pushing in. Some ... sharp cramp as the liquid bone marrow is withdrawn for the aspiration or ...

Quantitative MRI and spectroscopy of bone marrow

PubMed Central

Ruschke, Stefan; Dieckmeyer, Michael; Diefenbach, Maximilian; Franz, Daniela; Gersing, Alexandra S.; Krug, Roland; Baum, Thomas

2017-01-01

Bone marrow is one of the largest organs in the human body, enclosing adipocytes, hematopoietic stem cells, which are responsible for blood cell production, and mesenchymal stem cells, which are responsible for the production of adipocytes and bone cells. Magnetic resonance imaging (MRI) is the ideal imaging modality to monitor bone marrow changes in healthy and pathological states, thanks to its inherent rich soft‐tissue contrast. Quantitative bone marrow MRI and magnetic resonance spectroscopy (MRS) techniques have been also developed in order to quantify changes in bone marrow water–fat composition, cellularity and perfusion in different pathologies, and to assist in understanding the role of bone marrow in the pathophysiology of systemic diseases (e.g. osteoporosis). The present review summarizes a large selection of studies published until March 2017 in proton‐based quantitative MRI and MRS of bone marrow. Some basic knowledge about bone marrow anatomy and physiology is first reviewed. The most important technical aspects of quantitative MR methods measuring bone marrow water–fat composition, fatty acid composition, perfusion, and diffusion are then described. Finally, previous MR studies are reviewed on the application of quantitative MR techniques in both healthy aging and diseased bone marrow affected by osteoporosis, fractures, metabolic diseases, multiple myeloma, and bone metastases. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:332–353. PMID:28570033

Bone marrow vascular endothelial growth factor level per platelet count might be a significant predictor for the treatment outcomes of patients with diffuse large B-cell lymphomas.

PubMed

Kim, Jung Sun; Gang, Ga Won; Lee, Se Ryun; Sung, Hwa Jung; Park, Young; Kim, Dae Sik; Choi, Chul Won; Kim, Byung Soo

2015-10-01

Developing a parameter to predict bone marrow invasion by non-Hodgkin's lymphoma is an important unmet medical need for treatment decisions. This study aimed to confirm the validity of the hypothesis that bone marrow plasma vascular endothelial growth factor level might be correlated with the risk of bone marrow involvement and the prognosis of patients with diffuse large B-cell non-Hodgkin's lymphoma. Forty-nine diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone regimen were enrolled. Vascular endothelial growth factor level was measured with enzyme-linked immunosorbent assay. The validity of bone marrow plasma vascular endothelial growth factor level and bone marrow vascular endothelial growth factor level per platelet count for predicting treatment response and survival after initial rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone combined chemotherapy was assessed. Bone marrow plasma vascular endothelial growth factor level per platelet count was significantly associated with old age (≥ 65 years), poor performance score (≥ 2), high International prognosis index (≥ 3) and bone marrow invasion. The patients with high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) showed a significantly lower complete response rate than the others. On Kaplan-Meier survival curves, the patients with high bone marrow plasma vascular endothelial growth factor levels (≥ 655 pg/ml) or high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) demonstrated a significantly shorter overall survival and progression-free survival than the others. In the patients without bone marrow involvement, bone marrow plasma vascular endothelial growth factor level per platelet count had a significant relationship with overall survival and progression-free survival. Multivariate analysis revealed that the patients without BM invasion showing high level of bone marrow plasma vascular endothelial growth factor per platelet count had significantly shorter progression-free survival and overall survival. Bone marrow plasma vascular endothelial growth factor level per platelet count might be associated with bone marrow invasion by diffuse large B-cell lymphoma and is correlated with clinical outcomes after treatment. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Can lung function measurements be used to predict which patients will be at risk of developing interstitial pneumonitis after bone marrow transplantation?

PubMed

Milburn, H J; Prentice, H G; du Bois, R M

1992-06-01

Lung function often deteriorates after bone marrow transplantation for haematological malignancies. Whether pulmonary function measurements are useful for monitoring patients' progress after transplantation and for alerting clinicians to the development of pneumonitis is uncertain. Serial pulmonary function measurements were made in 39 patients with a haematological malignancy, and the values from 18 recipients of T cell depleted allogeneic (n = 17) or autologous (n = 1) bone marrow transplants who developed interstitial pneumonitis were compared retrospectively with values from 21 recipients of allogeneic (n = 17) or autologous (n = 4) transplants who did not develop pneumonitis. Lung function was measured at the onset of a further 18 episodes of pneumonitis. Measurements made before transplantation showed no difference in forced expiratory volume in one second (FEV1), transfer factor for carbon monoxide (TLCO), or total lung capacity between the two groups, but the forced vital capacity (FVC) was slightly higher in those who developed pneumonitis (mean (SD)% predicted 104 (12)) than in those who did not (93 (17%)). Six weeks and three months after transplantation all pulmonary function measurements had fallen slightly in both groups but TLCO had fallen considerably more in those who later developed pneumonitis, being 71% (SD 11%) and 77% (7%) of pretransplant values in patients who later developed pneumonitis compared with 109% (38%) and 96% (26%) in those who did not. All lung function measurements were significantly lower at the onset of pneumonitis than three months after transplantation, even in patients with no abnormal signs and a normal chest radiograph. Serial measurements of gas transfer before and after bone marrow transplantation may be useful for predicting which patients will be at risk of developing pneumonitis and may help to diagnose pneumonitis in breathless patients with no abnormal signs.

Stem cells and bone diseases: new tools, new perspective

PubMed Central

Riminucci, Mara; Remoli, Cristina; Robey, Pamela G.; Bianco, Paolo

2017-01-01

Postnatal skeletal stem cells are a unique class of progenitors with biological properties that extend well beyond the limits of stemness as commonly defined. Skeletal stem cells sustain skeletal tissue homeostasis, organize and maintain the complex architectural structure of the bone marrow microenvironment and provide a niche for hematopoietic progenitor cells. The identification of stem cells in the human post-natal skeleton has profoundly changed our approach to the physiology and pathology of this system. Skeletal diseases have been long interpreted essentially in terms of defective function of differentiated cells and/or abnormal turnover of the matrix they produce. The notion of a skeletal stem cell has brought forth multiple, novel concepts in skeletal biology that provide potential alternative concepts. At the same time, the recognition of the complex functions played by skeletal progenitors, such as the structural and functional organization of the bone marrow, has provided an innovative, unifying perspective for understanding bone and bone marrow changes simultaneously occurring in many disorders. Finally, the possibility to isolate and highly enrich for skeletal progenitors, enables us to reproduce perfectly normal or pathological organ miniatures. These, in turn, provide suitable models to investigate and manipulate the pathogenetic mechanisms of many genetic and non-genetic skeletal diseases. PMID:25240458

Fractalkine (CX3CL1) is involved in the early activation of hypothalamic inflammation in experimental obesity.

PubMed

Morari, Joseane; Anhe, Gabriel F; Nascimento, Lucas F; de Moura, Rodrigo F; Razolli, Daniela; Solon, Carina; Guadagnini, Dioze; Souza, Gabriela; Mattos, Alexandre H; Tobar, Natalia; Ramos, Celso D; Pascoal, Vinicius D; Saad, Mario J; Lopes-Cendes, Iscia; Moraes, Juliana C; Velloso, Licio A

2014-11-01

Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow-derived cells or only in bone marrow-derived cells. We show that a functional TLR4 in bone marrow-derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow-derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Stem cells and bone diseases: new tools, new perspective.

PubMed

Riminucci, Mara; Remoli, Cristina; Robey, Pamela G; Bianco, Paolo

2015-01-01

Postnatal skeletal stem cells are a unique class of progenitors with biological properties that extend well beyond the limits of stemness as commonly defined. Skeletal stem cells sustain skeletal tissue homeostasis, organize and maintain the complex architectural structure of the bone marrow microenvironment and provide a niche for hematopoietic progenitor cells. The identification of stem cells in the human post-natal skeleton has profoundly changed our approach to the physiology and pathology of this system. Skeletal diseases have been long interpreted essentially in terms of defective function of differentiated cells and/or abnormal turnover of the matrix that they produce. The notion of a skeletal stem cell has brought forth multiple, novel concepts in skeletal biology that provide potential alternative concepts. At the same time, the recognition of the complex functions played by skeletal progenitors, such as the structural and functional organization of the bone marrow, has provided an innovative, unifying perspective for understanding bone and bone marrow changes simultaneously occurring in many disorders. Finally, the possibility to isolate and highly enrich for skeletal progenitors, enables us to reproduce perfectly normal or pathological organ miniatures. These, in turn, provide suitable models to investigate and manipulate the pathogenetic mechanisms of many genetic and non-genetic skeletal diseases. This article is part of a Special Issue entitled Stem cells and Bone. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

A fat option for the pig: Hepatocytic differentiated mesenchymal stem cells for translational research

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de; Tautenhahn, Hans-Michael, E-mail: hans-michael.tautenhahn@medizin.uni-leipzig.de; TRM, Translational Centre for Regenerative Medicine, Philipp-Rosenthal-Str. 55, Leipzig D-04103

Study background: Extended liver resection is the only curative treatment option of liver cancer. Yet, the residual liver may not accomplish the high metabolic and regenerative capacity needed, which frequently leads to acute liver failure. Because of their anti-inflammatory and -apoptotic as well as pro-proliferative features, mesenchymal stem cells differentiated into hepatocyte-like cells might provide functional and regenerative compensation. Clinical translation of basic research requires pre-clinical approval in large animals. Therefore, we characterized porcine mesenchymal stem cells (MSC) from adipose tissue and bone marrow and their hepatocyte differentiation potential for future assessment of functional liver support after surgical intervention inmore » the pig model. Methods: Mesenchymal surface antigens and multi-lineage differentiation potential of porcine MSC isolated by collagenase digestion either from bone marrow or adipose tissue (subcutaneous/visceral) were assessed by flow cytometry. Morphology and functional properties (urea-, glycogen synthesis and cytochrome P450 activity) were determined during culture under differentiation conditions and compared with primary porcine hepatocytes. Results: MSC from porcine adipose tissue and from bone marrow express the typical mesenchymal markers CD44, CD29, CD90 and CD105 but not haematopoietic markers. MSC from both sources displayed differentiation into the osteogenic as well as adipogenic lineage. After hepatocyte differentiation, expression of CD105 decreased significantly and cells adopted the typical polygonal morphology of hepatocytes. Glycogen storage was comparable in adipose tissue- and bone marrow-derived cells. Urea synthesis was about 35% lower in visceral than in subcutaneous adipose tissue-derived MSC. Cytochrome P450 activity increased significantly during differentiation and was twice as high in hepatocyte-like cells generated from bone marrow as from adipose tissue. Conclusion: The hepatocyte differentiation of porcine adipose tissue-derived MSC was shown for the first time yielding hepatocyte-like cells with specific functions similar in bone marrow and subcutaneous adipose tissue-derived MSC. That makes them good pre-clinical candidates for supportive approaches after liver resection in the pig. - Highlights: • First time to show hepatocytic differentiation of porcine adipose tissue-derived MSC. • Hepatocytic-differentiated MSC display metabolic qualities of primary hepatocytes. • Metabolic potency varies between differentiated MSC from different tissues. • MSC are good candidates for pre-clinical evaluation of stem cell-based therapies.« less

Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking

PubMed Central

Taniguchi Ishikawa, E.; Chang, K.H.; Nayak, R.; Olsson, H.A; Ficker, A.; Dunn, S.K.; Madhu, M.; Sengupta, A.; Whitsett, J.A.; Grimes, H.L.; Cancelas, J.A.

2013-01-01

Kruppel-like factor 5 (Klf5) regulates pluripotent stem cell self-renewal but its role in somatic stem cells is unknown. Here we show that Klf5 deficient haematopoietic stem cells and progenitors (HSC/P) fail to engraft after transplantation. This HSC/P defect is associated with impaired bone marrow homing and lodging and decreased retention in bone marrow, and with decreased adhesion to fibronectin and expression of membrane-bound β1/β2-integrins. In vivo inducible gain-of-function of Klf5 in HSCs increases HSC/P adhesion. The expression of Rab5 family members, mediators of β1/β2-integrin recycling in the early endosome, is decreased in Klf5Δ/Δ HSC/Ps. Klf5 binds directly to the promoter of Rab5a/b and overexpression of Rab5b rescues the expression of activated β1/β2-integrins, adhesion and bone marrow homing of Klf5Δ/Δ HSC/Ps. Altogether, these data indicate that Klf5 is indispensable for adhesion, homing, lodging and retention of HSC/Ps in the bone marrow through Rab5-dependent post-translational regulation of β1/β2 integrins. PMID:23552075

Aplastic anemia as a feature of systemic lupus erythematosus: a case report and literature review.

PubMed

Chalayer, Émilie; Ffrench, Martine; Cathébras, Pascal

2015-06-01

Peripheral cytopenias are common in systemic lupus erythematosus, but bone marrow involvement is rarely reported. Aplastic anemia is the result of immune-mediated destruction of hematopoietic stem cells causing pancytopenia and characterized by an empty bone marrow. This rare but serious disease has been described as an unusual manifestation of systemic lupus erythematosus. We reviewed the 25 cases published in the English language literature and discuss the clinical presentation, outcome, treatment, and pathophysiology of aplastic anemia as a complication of systemic lupus erythematosus. We report here the first case of aplastic anemia associated with systemic lupus erythematosus treated with an allogeneic hematopoietic stem cell transplant. Over one half of patients received concomitantly the diagnoses of systemic lupus erythematosus and aplastic anemia. No clinical or histological features can distinguish primary aplastic anemia from aplastic anemia occurring in systemic lupus erythematosus patients. The overall mortality is about 15% and corticosteroid-based therapy alone or in combination with other immunomodulatory drugs can restore bone marrow function. Systemic lupus erythematosus may be complicated by bone marrow involvement. The diagnosis of peripheral cytopenias should be confirmed by bone marrow aspiration. All these patients should receive cortisone as a first treatment. Plasma exchanges seem to have some efficacy. Other different immunomodulatory therapies were used with variable results.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Degowin, R.L.; Lass, S.L.

Our studies show that the induction of a chronic inflammatory lesion in the left hind legs of mice by administration of 5000 rad produced distinct abnormalities of the hematopoietic system. A peripheral neutrophilia accompanied reduced numbers of total nucleated cells, stem cells, stromal cells, erythroblasts, and lymphocytes in the unirradiated femoral marrow, and the spleen was enlarged. Mice with these hematopoietic abnormalities promptly succumbed with bone marrow failure to a sublethal dose of total body irradiation (600 rad TB). Acute inflammation associated with a sterile abscess also impaired survival after 600 rad TB. Hematopoietic abnormalities resembling those in mice withmore » inflammation had been reported in mice bearing a solid extramedullary tumor of sarcoma-180. Concomitant studies showed that bone marrow failure and impaired survival after 600 rad TB administered to mice bearing sarcoma-180 occurred at the same time as that in mice with chronic inflammation. We concluded that chronic inflammation or tumor produced similar abnormalities in the bone marrow and spleen that led to markedly impaired survival and death from bone marrow failure after a sublethal dose of total body irradiation. Although the extramedullary hematopoiesis in the enlarged spleen indicated that its microenvironment supported hematopoiesis, whereas that in marrow was reduced, it was insufficient to compensate for a total body deficit of functional stem cells.« less

Identification of resident and inflammatory bone marrow derived cells in the sclera by bone marrow and haematopoietic stem cell transplantation

PubMed Central

Hisatomi, Toshio; Sonoda, Koh‐hei; Ishikawa, Fumihiko; Qiao, Hong; Nakamura, Takahiro; Fukata, Mitsuhiro; Nakazawa, Toru; Noda, Kousuke; Miyahara, Shinsuke; Harada, Mine; Kinoshita, Shigeru; Hafezi‐Moghadam, Ali; Ishibashi, Tatsuro; Miller, Joan W

2007-01-01

Aims To characterise bone marrow derived cells in the sclera under normal and inflammatory conditions, we examined their differentiation after transplantation from two different sources, bone marrow and haematopoietic stem cells (HSC). Methods Bone marrow and HSC from green fluorescent protein (GFP) transgenic mice were transplanted into irradiated wild‐type mice. At 1 month after transplantation, mice were sacrificed and their sclera examined by histology, immunohistochemistry (CD11b, CD11c, CD45), and transmission and scanning electron microscopy. To investigate bone marrow derived cell recruitment under inflammatory conditions, experimental autoimmune uveitis (EAU) was induced in transplanted mice. Results GFP positive cells were distributed in the entire sclera and comprised 22.4 (2.8)% (bone marrow) and 28.4 (10.9)% (HSC) of the total cells in the limbal zone and 18.1 (6.7)% (bone marrow) and 26.3 (3.4)% (HSC) in the peripapillary zone. Immunohistochemistry showed that GFP (+) CD11c (+), GFP (+) CD11b (+) cells migrated in the sclera after bone marrow and HSC transplantation. Transmission and scanning electron microscopy revealed antigen presenting cells among the scleral fibroblasts. In EAU mice, vast infiltration of GFP (+) cells developed into the sclera. Conclusion We have provided direct and novel evidence for the migration of bone marrow and HSC cells into the sclera differentiating into macrophages and dendritic cells. Vast infiltration of bone marrow and HSC cells was found to be part of the inflammatory process in EAU. PMID:17035278

Concentration of adipogenic and proinflammatory cytokines in the bone marrow supernatant fluid of osteoporotic women.

PubMed

Pino, Ana María; Ríos, Susana; Astudillo, Pablo; Fernández, Mireya; Figueroa, Paula; Seitz, Germán; Rodríguez, J Pablo

2010-03-01

Osteoporosis is characterized by low bone mass, microarchitectural deterioration of bone tissue leading to increased bone fragility, and a resulting susceptibility to fractures. Distinctive environmental bone marrow conditions appear to support the development and maintenance of the unbalance between bone resorption and bone formation; these complex bone marrow circumstances would be reflected in the fluid surrounding bone marrow cells. The content of regulatory molecules in the extracellular fluid from the human bone marrow is practically unknown. Since the content of cytokines such as adiponectin, leptin, osteoprogeterin (OPG), soluble receptor activator of nuclear factor kappaB ligand (s-RANKL), tumor necrosis factor alpha, and interleukin 6 (IL-6) may elicit conditions promoting or sustaining osteoporosis, in this work we compared the concentrations of the above-mentioned cytokines and also the level of the soluble receptors for both IL-6 and leptin in the extracellular fluid from the bone marrow of nonosteoporotic and osteoporotic human donors. A supernatant fluid (bone marrow supernatant fluid [BMSF]) was obtained after spinning the aspirated bone marrow samples; donors were classified as nonosteoporotic or osteoporotic after dual-energy X-ray absorptiometry (DXA) measuring. Specific commercially available kits were used for all measurements. The cytokines' concentration in BMSF showed differently among nonosteoporotic and osteoporotic women; this last group was characterized by higher content of proinflammatory and adipogenic cytokines. Also, osteoporotic BMSF differentiated by decreased leptin bioavailability, suggesting that insufficient leptin action may distinguish the osteoporotic bone marrow. Copyright 2010 American Society for Bone and Mineral Research.

[Morphofunctional properties of the peripheral blood and bone marrow cells of rats following a flight on board the Kosmos-936 biosatellite].

PubMed

Kozinets, G I; Korol'kov, V I; Britvan, I I; Bykova, I A; Spitsyna, N E

1983-01-01

Morphofunctional properties of peripheral blood cells of Cosmos-936 rats were examined, using morphological, interferometric and electron microscopic techniques. As follows from the morphological data, immediately after recovery the weightless rats showed symptoms of a stress reaction which disappeared by R+3. The centrifuged rats exhibited less expressed symptoms of this sort. The percentage of bone marrow cell distribution was shifted towards enhanced myelopoiesis and diminished erythropoiesis. By the end of the readaptation period the ratio of bone marrow cell composition returned to normal. Interferometric and electron microscopic examinations did not reveal any irreversible changes in the structure and function of cells that may be caused by zero-g.

Carbon nanotubes functionalized with fibroblast growth factor accelerate proliferation of bone marrow-derived stromal cells and bone formation

NASA Astrophysics Data System (ADS)

Hirata, Eri; Ménard-Moyon, Cécilia; Venturelli, Enrica; Takita, Hiroko; Watari, Fumio; Bianco, Alberto; Yokoyama, Atsuro

2013-11-01

Multi-walled carbon nanotubes (MWCNTs) were functionalized with fibroblast growth factor (FGF) and the advantages of their use as scaffolds for bone augmentation were evaluated in vitro and in vivo. The activity of FGF was assessed by measuring the effect on the proliferation of rat bone marrow stromal cells (RBMSCs). The presence of FGF enhanced the proliferation of RBMSCs and the FGF covalently conjugated to the nanotubes (FGF-CNT) showed the same effect as FGF alone. In addition, FGF-CNT coated sponges were implanted between the parietal bone and the periosteum of rats and the formation of new bone was investigated. At day 14 after implantation, a larger amount of newly formed bone was clearly observed in most pores of FGF-CNT coated sponges. These findings indicated that MWCNTs accelerated new bone formation in response to FGF, as well as the integration of particles into new bone during its formation. Scaffolds coated with FGF-CNT could be considered as promising novel substituting materials for bone regeneration in future tissue engineering applications.

Differentiation of mesenchymal stem cells into neuronal cells on fetal bovine acellular dermal matrix as a tissue engineered nerve scaffold

PubMed Central

Feng, Yuping; Wang, Jiao; Ling, Shixin; Li, Zhuo; Li, Mingsheng; Li, Qiongyi; Ma, Zongren; Yu, Sijiu

2014-01-01

The purpose of this study was to assess fetal bovine acellular dermal matrix as a scaffold for supporting the differentiation of bone marrow mesenchymal stem cells into neural cells following induction with neural differentiation medium. We performed long-term, continuous observation of cell morphology, growth, differentiation, and neuronal development using several microscopy techniques in conjunction with immunohistochemistry. We examined specific neuronal proteins and Nissl bodies involved in the differentiation process in order to determine the neuronal differentiation of bone marrow mesenchymal stem cells. The results show that bone marrow mesenchymal stem cells that differentiate on fetal bovine acellular dermal matrix display neuronal morphology with unipolar and bi/multipolar neurite elongations that express neuronal-specific proteins, including βIII tubulin. The bone marrow mesenchymal stem cells grown on fetal bovine acellular dermal matrix and induced for long periods of time with neural differentiation medium differentiated into a multilayered neural network-like structure with long nerve fibers that was composed of several parallel microfibers and neuronal cells, forming a complete neural circuit with dendrite-dendrite to axon-dendrite to dendrite-axon synapses. In addition, growth cones with filopodia were observed using scanning electron microscopy. Paraffin sectioning showed differentiated bone marrow mesenchymal stem cells with the typical features of neuronal phenotype, such as a large, round nucleus and a cytoplasm full of Nissl bodies. The data suggest that the biological scaffold fetal bovine acellular dermal matrix is capable of supporting human bone marrow mesenchymal stem cell differentiation into functional neurons and the subsequent formation of tissue engineered nerve. PMID:25598779

Erythropoietic bone marrow in the pigeon: Development of its distribution and volume during growth and pneumatization of bones

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schepelmann, K.

1990-01-01

During postnatal development of the pigeon, a large portion of the skeleton becomes pneumatized, displacing the hemopoietic bone marrow. The consequences of pneumatization on distribution and quantity of bone marrow as well as the availability of other sites for hemopoiesis have been investigated. Hemopoietic marrow of differently aged pigeons divided into five groups from 1 week posthatching (p.h.) up to 6 months p.h. was labeled with Fe-59 and examined by serial whole-body sections. Autoradiography and morphometry as well as scintillation counts of single bones and organs were also carried out. No sign of a reactivation of embryonic sites of erythropoiesismore » was found. Bone marrow weight and its proportion of whole-body weight increased during the first 4 weeks p.h. from 0.54% to 2.44% and decreased in the following months to about 1.0%. The developing bone marrow showed a progressive distribution during the first months of life, eventually being distributed proportionally over the entire skeleton, except for the skull. At the age of 6 months p.h. bone marrow had been displaced, its volume decreasing in correlation to increasing pneumaticity and conversion to fatty marrow. This generates the characteristic pattern of bone marrow distribution in adult pigeons, which shows hemopoietic bone marrow in ulna, radius, femur, tibiotarsus, scapula, furcula, and the caudal vertebrae.« less

The Application of Bone Marrow Transplantation to the Treatment of Genetic Diseases

NASA Astrophysics Data System (ADS)

Parkman, Robertson

1986-06-01

Genetic diseases can be treated by transplantation of either normal allogeneic bone marrow or, potentially, autologous bone marrow into which the normal gene has been inserted in vitro (gene therapy). Histocompatible allogeneic bone marrow transplantation is used for the treatment of genetic diseases whose clinical expression is restricted to lymphoid or hematopoietic cells. The therapeutic role of bone marrow transplantation in the treatment of generalized genetic diseases, especially those affecting the central nervous system, is under investigation. The response of a generalized genetic disease to allogeneic bone marrow transplantation may be predicted by experiments in vitro. Gene therapy can be used only when the gene responsible for the disease has been characterized. Success of gene therapy for a specific genetic disease may be predicted by its clinical response to allogeneic bone marrow transplantation.

Computational modelling of the mechanics of trabecular bone and marrow using fluid structure interaction techniques.

PubMed

Birmingham, E; Grogan, J A; Niebur, G L; McNamara, L M; McHugh, P E

2013-04-01

Bone marrow found within the porous structure of trabecular bone provides a specialized environment for numerous cell types, including mesenchymal stem cells (MSCs). Studies have sought to characterize the mechanical environment imposed on MSCs, however, a particular challenge is that marrow displays the characteristics of a fluid, while surrounded by bone that is subject to deformation, and previous experimental and computational studies have been unable to fully capture the resulting complex mechanical environment. The objective of this study was to develop a fluid structure interaction (FSI) model of trabecular bone and marrow to predict the mechanical environment of MSCs in vivo and to examine how this environment changes during osteoporosis. An idealized repeating unit was used to compare FSI techniques to a computational fluid dynamics only approach. These techniques were used to determine the effect of lower bone mass and different marrow viscosities, representative of osteoporosis, on the shear stress generated within bone marrow. Results report that shear stresses generated within bone marrow under physiological loading conditions are within the range known to stimulate a mechanobiological response in MSCs in vitro. Additionally, lower bone mass leads to an increase in the shear stress generated within the marrow, while a decrease in bone marrow viscosity reduces this generated shear stress.

Bone Marrow Diseases

MedlinePlus

Bone marrow is the spongy tissue inside some of your bones, such as your hip and thigh bones. It contains stem cells. The stem cells can ... the platelets that help with blood clotting. With bone marrow disease, there are problems with the stem ...

Bone Marrow Transplantation

MedlinePlus

Bone marrow is the spongy tissue inside some of your bones, such as your hip and thigh bones. It contains immature cells, called stem cells. The ... platelets, which help the blood to clot. A bone marrow transplant is a procedure that replaces a ...

Effects of extracellular matrix proteins on macrophage differentiation, growth, and function: comparison of liquid and agar culture systems

NASA Technical Reports Server (NTRS)

Armstrong, J. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1994-01-01

Both spaceflight and skeletal unloading suppress the haematopoietic differentiation of macrophages (Sonnenfeld et al., Aviat. Space Environ. Med., 61:648-653, 1990; Armstrong et al., J. Appl. Physiol., 75:2734-2739, 1993). The mechanism behind this reduction in haematopoiesis has yet to be elucidated. However, changes in bone marrow extracellular matrix (ECM) may be involved. To further understand the role of ECM products in macrophage differentiation, we have performed experiments evaluating the effects of fibronectin, laminin, collagen type I, and collagen type IV on macrophage development and function. Bone marrow-derived macrophages cultured on four different ECM substrates in liquid culture medium showed less growth than those cultured on plastic. Significant morphological differences were seen on each of the substrates used. Phenotypically and functionally, as measured by class II major histocompatibility molecule (MHCII) expression, MAC-2 expression, and the secretion of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), these macrophages were similar. In contrast, bone marrow-derived macrophages cultured in suspension, using agar, showed no difference in growth when exposed to ECM proteins. However, IL-6 and TNF-alpha secretion was affected by fibronectin, laminin, collagen type I, and collagen type IV in a concentration-dependent manner. We conclude that the ECM products fibronectin, laminin, collagen type I, and collagen type IV have profound effects on macrophage development and function. Additionally, we suggest that an ECM-supplemented agar culture system provides an environment more analogous to in vivo bone marrow than does a traditional liquid culture system.

Cell-specific paracrine actions of IL-6 family cytokines from bone, marrow and muscle that control bone formation and resorption.

PubMed

Sims, Natalie A

2016-10-01

Bone renews itself and changes shape throughout life to account for the changing needs of the body; this requires co-ordinated activities of bone resorbing cells (osteoclasts), bone forming cells (osteoblasts) and bone's internal cellular network (osteocytes). This review focuses on paracrine signaling by the IL-6 family of cytokines between bone cells, bone marrow, and skeletal muscle in normal physiology and in pathological states where their levels may be locally or systemically elevated. These functions include the support of osteoclast formation by osteoblast lineage cells in response to interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM) and cardiotrophin 1 (CT-1). In addition it will discuss how bone-resorbing osteoclasts promote osteoblast activity by secreting CT-1, which acts as a "coupling factor" on osteocytes, osteoblasts, and their precursors to promote bone formation. OSM, produced by osteoblast lineage cells and macrophages, stimulates bone formation via osteocytes. IL-6 family cytokines also mediate actions of other bone formation stimuli like parathyroid hormone (PTH) and mechanical loading. CT-1, OSM and LIF suppress marrow adipogenesis by shifting commitment of pluripotent precursors towards osteoblast differentiation. Ciliary neurotrophic factor (CNTF) is released as a myokine from skeletal muscle and suppresses osteoblast differentiation and bone formation on the periosteum (outer bone surface in apposition to muscle). Finally, IL-6 acts directly on marrow-derived osteoclasts to stimulate release of "osteotransmitters" that act through the cortical osteocyte network to stimulate bone formation on the periosteum. Each will be discussed as illustrations of how the extended family of IL-6 cytokines acts within the skeleton in physiology and may be altered in pathological conditions or by targeted therapies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Direct reprogramming of human bone marrow stromal cells into functional renal cells using cell-free extracts.

PubMed

Papadimou, Evangelia; Morigi, Marina; Iatropoulos, Paraskevas; Xinaris, Christodoulos; Tomasoni, Susanna; Benedetti, Valentina; Longaretti, Lorena; Rota, Cinzia; Todeschini, Marta; Rizzo, Paola; Introna, Martino; Grazia de Simoni, Maria; Remuzzi, Giuseppe; Goligorsky, Michael S; Benigni, Ariela

2015-04-14

The application of cell-based therapies in regenerative medicine is gaining recognition. Here, we show that human bone marrow stromal cells (BMSCs), also known as bone-marrow-derived mesenchymal cells, can be reprogrammed into renal proximal tubular-like epithelial cells using cell-free extracts. Streptolysin-O-permeabilized BMSCs exposed to HK2-cell extracts underwent morphological changes-formation of "domes" and tubule-like structures-and acquired epithelial functional properties such as transepithelial-resistance, albumin-binding, and uptake and specific markers E-cadherin and aquaporin-1. Transmission electron microscopy revealed the presence of brush border microvilli and tight intercellular contacts. RNA sequencing showed tubular epithelial transcript abundance and revealed the upregulation of components of the EGFR pathway. Reprogrammed BMSCs integrated into self-forming kidney tissue and formed tubular structures. Reprogrammed BMSCs infused in immunodeficient mice with cisplatin-induced acute kidney injury engrafted into proximal tubuli, reduced renal injury and improved function. Thus, reprogrammed BMSCs are a promising cell resource for future cell therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Programmable 3D silk bone marrow niche for platelet generation ex vivo and modeling of megakaryopoiesis pathologies

PubMed Central

Di Buduo, Christian A.; Wray, Lindsay S.; Tozzi, Lorenzo; Malara, Alessandro; Chen, Ying; Ghezzi, Chiara E.; Smoot, Daniel; Sfara, Carla; Antonelli, Antonella; Spedden, Elise; Bruni, Giovanna; Staii, Cristian; De Marco, Luigi; Magnani, Mauro; Kaplan, David L.

2015-01-01

We present a programmable bioengineered 3-dimensional silk-based bone marrow niche tissue system that successfully mimics the physiology of human bone marrow environment allowing us to manufacture functional human platelets ex vivo. Using stem/progenitor cells, megakaryocyte function and platelet generation were recorded in response to variations in extracellular matrix components, surface topography, stiffness, coculture with endothelial cells, and shear forces. Millions of human platelets were produced and showed to be functional based on multiple activation tests. Using adult hematopoietic progenitor cells our system demonstrated the ability to reproduce key steps of thrombopoiesis, including alterations observed in diseased states. A critical feature of the system is the use of natural silk protein biomaterial allowing us to leverage its biocompatibility, nonthrombogenic features, programmable mechanical properties, and surface binding of cytokines, extracellular matrix components, and endothelial-derived proteins. This in turn offers new opportunities for the study of blood component production ex vivo and provides a superior tissue system for the study of pathologic mechanisms of human platelet production. PMID:25575540

Cordyceps sinensis health supplement enhances recovery from taxol-induced leukopenia.

PubMed

Liu, Wei-Chung; Chuang, Wei-Ling; Tsai, Min-Lung; Hong, Ji-Hong; McBride, William H; Chiang, Chi-Shiun

2008-04-01

This study aimed to evaluate the ability of the health food supplement Cordyceps sinensis (CS) to ameliorate suppressive effects of chemotherapy on bone marrow function as a model for cancer treatment. Mice were treated with Taxol (17 mg/kg body wt) one day before oral administration of a hot-water extract of CS (50 mg/kg daily) that was given daily for 3 weeks. White blood cell counts in peripheral blood of mice receiving Taxol were at 50% of normal levels on day 28 but had recovered completely in mice treated with CS. In vitro assays showed that CS enhanced the colony-forming ability of both granulocyte macrophage colony forming unit (GM-CFU) and osteogenic cells from bone marrow preparations and promoted the differentiation of bone marrow mesenchymal stromal cells into adipocytes, alkaline phosphatase-positive osteoblasts, and bone tissue. This result could be attributed to enhanced expression of Cbfa1 (core binding factor a) and BMP-2 (bone morphogenetic protein) with concurrent suppression of ODF (osteoclast differentiation factor/RANK [receptor activator of NF-kappaB]) ligand. In summary, CS enhances recovery of mice from leukopenia caused by Taxol treatment. It appears to do so by protecting both hematopoietic progenitor cells directly and the bone marrow stem cell niche through its effects on osteoblast differentiation.

Effects of Iron Overload on the Bone Marrow Microenvironment in Mice

PubMed Central

Zhao, Mingfeng; Li, Deguan; Chai, Xiao; Cao, Xiaoli; Meng, Juanxia; Chen, Jie; Xiao, Xia; Li, Qing; Mu, Juan; Shen, Jichun; Meng, Aimin

2015-01-01

Objective Using a mouse model, Iron Overload (IO) induced bone marrow microenvironment injury was investigated, focusing on the involvement of reactive oxygen species (ROS). Methods Mice were intraperitoneally injected with iron dextran (12.5, 25, or 50mg) every three days for two, four, and six week durations. Deferasirox(DFX)125mg/ml and N-acetyl-L-cysteine (NAC) 40mM were co-administered. Then, bone marrow derived mesenchymal stem cells (BM-MSCs) were isolated and assessed for proliferation and differentiation ability, as well as related gene changes. Immunohistochemical analysis assessed the expression of haematopoietic chemokines. Supporting functions of BM-MSCs were studied by co-culture system. Results In IO condition (25mg/ml for 4 weeks), BM-MSCs exhibited proliferation deficiencies and unbalanced osteogenic/adipogenic differentiation. The IO BM-MSCs showed a longer double time (2.07±0.14 days) than control (1.03±0.07 days) (P<0.05). The immunohistochemical analysis demonstrated that chemokine stromal cell-derived factor-1, stem cell factor -1, and vascular endothelial growth factor-1 expression were decreased. The co-cultured system demonstrated that bone marrow mononuclear cells (BMMNCs) co-cultured with IO BM-MSCs had decreased colony forming unit (CFU) count (p<0.01), which indicates IO could lead to decreased hematopoietic supporting functions of BM-MSCs. This effect was associated with elevated phosphatidylinositol 3 kinase (PI3K) and reduced of Forkhead box protein O3 (FOXO3) mRNA expression, which could induce the generation of ROS. Results also demonstrated that NAC or DFX treatment could partially attenuate cell injury and inhibit signaling pathway striggered by IO. Conclusion These results demonstrated that IO can impair the bone marrow microenvironment, including the quantity and quality of BM-MSCs. PMID:25774923

Contralesional Axonal Remodeling of the Corticospinal System in Adult Rats After Stroke and Bone Marrow Stromal Cell Treatment

PubMed Central

Liu, Zhongwu; Li, Yi; Zhang, Xueguo; Savant-Bhonsale, Smita; Chopp, Michael

2008-01-01

Background and Purpose Motor recovery after stroke is associated with neuronal reorganization in bilateral hemispheres. We investigated contralesional corticospinal tract remodeling in the brain and spinal cord in rats after stroke and treatment of bone marrow stromal cells. Methods Adult male Wistar rats were subjected to permanent right middle cerebral artery occlusion. Phosphate-buffered saline or bone marrow stromal cells were injected into a tail vein 1 day postischemia. An adhesive removal test was performed weekly to monitor functional recovery. Threshold currents of intracortical microstimulation on the left motor cortex for evoking bilateral forelimb movements were measured 6 weeks after stroke. When intracortical microstimulation was completed, biotinylated dextran amine was injected into the left motor cortex to anterogradely label the corticospinal tract. At 4 days before euthanization, pseudorabies virus-152-EGFP and 614-mRFP were injected into left or right forelimb extensor muscles, respectively. All animals were euthanized 8 weeks after stroke. Results In normal rats (n=5), the corticospinal tract showed a unilateral innervation pattern. In middle cerebral artery occlusion rats (n=8), our data demonstrated that: 1) stroke reduced the stimulation threshold evoking ipsilateral forelimb movement; 2) EGFP-positive pyramidal neurons were increased in the left intact cortex, which were labeled from the left stroke-impaired forelimb; and 3) biotinylated dextran amine-labeled contralesional axons sprouted into the denervated spinal cord. Bone marrow stromal cells significantly enhanced all 3 responses (n=8, P<0.05). Conclusions Our data demonstrated that corticospinal tract fibers originating from the contralesional motor cortex sprout into the denervated spinal cord after stroke and bone marrow stromal cells treatment, which may contribute to functional recovery. PMID:18617661

[Hypoplastic acute promyelocytic leukemia with continuous hypocellular bone marrow after remission].

PubMed

Nakamura, Toshiki; Makiyama, Junya; Matsuura, Ayumi; Kurohama, Hirokazu; Kitanosono, Hideaki; Ito, Masahiro; Yoshida, Shinichiro; Miyazaki, Yasushi

2018-01-01

An 87-year old female presented with unsteady gait and occasional subcutaneous hematomas. Blood examination findings revealed pancytopenia and mild coagulopathy. Both the histopathological evaluation of bone marrow smears and bone marrow biopsy revealed a hypocellular bone marrow. However, APL cells were observed and PML-RARA fusion gene was detected. On the basis of these findings, the patient was diagnosed with hypoplastic acute promyelocytic leukemia. She received ATRA treatment and achieved complete remission (CR) 29 days from the commencement of therapy. After the first CR, she received two courses of ATO as a consolidation therapy. Following the latter treatments, she maintained CR, but a hypoplastic bone marrow was still observed. Hypoplastic AML is defined as AML with a low bone marrow cellularity. It is clinically important to distinguish it from aplastic anemia and hypoplastic MDS. It has been suggested that both cytogenetic and morphological diagnosis are imperative to the differential diagnosis of hypocellular bone marrow.

Three dimensional de novo micro bone marrow and its versatile application in drug screening and regenerative medicine.

PubMed

Li, Guanqun; Liu, Xujun; Du, Qian; Gao, Mei; An, Jing

2015-08-01

The finding that bone marrow hosts several types of multipotent stem cell has prompted extensive research aimed at regenerating organs and building models to elucidate the mechanisms of diseases. Conventional research depends on the use of two-dimensional (2D) bone marrow systems, which imposes several obstacles. The development of 3D bone marrow systems with appropriate molecules and materials however, is now showing promising results. In this review, we discuss the advantages of 3D bone marrow systems over 2D systems and then point out various factors that can enhance the 3D systems. The intensive research on 3D bone marrow systems has revealed multiple important clinical applications including disease modeling, drug screening, regenerative medicine, etc. We also discuss some possible future directions in the 3D bone marrow research field. © 2015 by the Society for Experimental Biology and Medicine.

Short communication: Effect of commercial or depurinized milk diet on plasma advanced oxidation protein products, cardiovascular markers, and bone marrow CD34+ stem cell potential in rat experimental hyperuricemia.

PubMed

Kocic, Gordana; Sokolovic, Dusan; Jevtovic, Tatjana; Cvetkovic, Tatjana; Veljkovic, Andrej; Kocic, Hristina; Stojanovic, Svetlana; Jovanovic, Aneta; Jovanovic, Jelena; Zivkovic, Petar

2014-11-01

Cardiovascular repair and myocardial contractility may be improved by migration of bone marrow stem cells (BMSC) and their delivery to the site of injury, a process known as BMSC homing. The aim of our study was to examine the dietary effect of a newly patented depurinized milk (DP) that is almost free of uric acid and purine and pyrimidine compounds compared with a standard commercial 1.5% fat UHT milk diet or allopurinol therapy in rat experimental hyperuricemia. Bone marrow stem cell potential (BMCD34(+), CD34-postive bone marrow cells), plasma oxidative stress parameters [advanced oxidation protein products, AOPP) and thiobarbituric acid reactive substances (TBARS)], myocardial damage markers [creatine phosphokinase (CPK), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)], plasma cholesterol, and high-density lipoprotein cholesterol were investigated. The DP milk diet significantly increased the number of BMCD34(+) stem cells compared with commercial UHT milk. Allopurinol given alone also increased the number of BMCD34(+). Hyperuricemia caused a significant increase in all plasma enzyme markers for myocardial damage (CPK, LDH, and AST). A cardioprotective effect was achieved with allopurinol but almost equally with DP milk and more than with commercial milk. Regarding plasma AOPP, TBARS, and cholesterol levels, the most effective treatment was DP milk. In conclusion, the protective role of a milk diet on cardiovascular function may be enhanced through the new depurinized milk diet, which may improve cardiovascular system function via increased bone marrow stem cell regenerative potential, decreased plasma oxidative stress parameters, and decreased levels of myocardial damage markers and cholesterol. New dairy technology strategies focused on eliminating harmful milk compounds should be completely nontoxic. Novel milk products should be tested for their ability to improve tissue repair and function. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats

PubMed Central

Zhang, Qing; Miller, Christopher; Bible, Jesse; Li, Jiliang; Xu, Xiaoqing; Mehta, Nozer; Gilligan, James; Vignery, Agnès; Scholz, Jodi A Carlson

2012-01-01

Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture. PMID:24710549

Use of various diagnostic methods in a patient with Gaucher disease type I.

PubMed

Farahati, J; Trenn, G; John-Mikolajewski, V; Zander, C; Pastores, G M; Sciuk, J; Reiners, C

1996-08-01

A series of plain radiographs, bone scans, bone marrow scans, and MRIs is reported in a patient with Gaucher disease type I, in whom two episodes of acute bone crisis developed during a 6-year period of follow-up. Acute bone crisis and global indolent bone marrow displacement could both be assessed by bone marrow scintigraphy, whereas MRI could better clarify the corti-comedullary alteration after bone infarction. Thus, MRI and bone marrow scintigraphy could be used as complementary imaging methods in the management of patients with Gaucher disease.

Generation and Identification of GM-CSF Derived Alveolar-like Macrophages and Dendritic Cells From Mouse Bone Marrow

PubMed Central

Dong, Yifei; Arif, Arif A.; Poon, Grace F. T.; Hardman, Blair; Dosanjh, Manisha; Johnson, Pauline

2016-01-01

Macrophages and dendritic cells (DCs) are innate immune cells found in tissues and lymphoid organs that play a key role in the defense against pathogens. However, they are difficult to isolate in sufficient numbers to study them in detail, therefore, in vitro models have been developed. In vitro cultures of bone marrow-derived macrophages and dendritic cells are well-established and valuable methods for immunological studies. Here, a method for culturing and identifying both DCs and macrophages from a single culture of primary mouse bone marrow cells using the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) is described. This protocol is based on the established procedure first developed by Lutz et al. in 1999 for bone marrow-derived DCs. The culture is heterogeneous, and MHCII and fluoresceinated hyaluronan (FL-HA) are used to distinguish macrophages from immature and mature DCs. These GM-CSF derived macrophages provide a convenient source of in vitro derived macrophages that closely resemble alveolar macrophages in both phenotype and function. PMID:27404290

Effects of hypergravity on immunologic function

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Koebel, D. A.; Davis, S.

1995-01-01

The purpose of this study was to compare the effects of hypergravity exposure (2g) with those of exposure to space flight in the Cosmos 2044 flight. To do so, rats were centrifuged continuously for 14 days. Two different experiments were carried out on tissue obtained from the centrifuged rats. In the first experiment, rat bone marrow cells were examined for their response to recombinant murine colony stimulating factor-granulocyte/monocyte (GM-CSF). In the second experiment, rat spleen and bone marrow cells were stained in with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and analyzed on a flow cytometer. The results of the studies indicated that bone marrow cells from centrifuged rats showed no significant change in response to GM-CSF as compared to bone marrow cells from control rats. Spleen cells from flown rats showed some statistically significant changes in leukocytes subset distribution, but no differences that appeared to be of biological significance. These results indicate that hypergravity did not greatly affect the same immunological parameters affected by space flight in the Cosmos 2044 mission.

Effects of hypergravity on immunologic function

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Koebel, D. A.; Davis, S.

1994-01-01

The purpose of this study was to compare the effects of hypergravity exposure (2g) with those of exposure to space flight in the Cosmos 2044 flight. To do so, rats were centrifuged continuously for 14 days. Two different experiments were carried out on tissue obtained from the centrifuged rats. In the first experiment, rat bone marrow cells were examined for their response to recombinant murine colony stimulating factor-granulocyte/monocyte (GM-CSF). In the second experiment, rate spleen and bone marrow cells were stained in with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and analyzed on a flow cytometer. The results of the studies indicated that bone marrow cells from centrifuged rats showed no significant change in response to GM-CSF as compared to bone marrow cells from control rats. Spleen cells from flown rats showed some statistically significant changes in leukocytes subset distribution, but no differences that appeared to be of biological significance. These results indicate that hypergravity did not greatly affect the same immunological parameters affected by space flight in the Cosmos 2044 mission.

Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation

USDA-ARS?s Scientific Manuscript database

A major problem in patients with multiple myeloma is chemotherapy resistance, which develops in myeloma cells upon interaction with bone marrow stromal cells. However, few studies have determined the role of bone marrow adipocytes, a major component of stromal cells in the bone marrow, in myeloma ch...

A method to generate enhanced GFP+ chimeric mice to study the role of bone marrow-derived cells in the eye.

PubMed

Singh, Vivek; Jaini, Ritika; Torricelli, André A M; Tuohy, Vincent K; Wilson, Steven E

2013-11-01

GFP-chimeric mice are important tools to study the role of bone marrow-derived cells in eye physiology. A method is described to generate GFP-chimeric mice using whole-body, sub-lethal radiation (600 rad) of wild-type C57BL/6 recipients followed by tail vein injection of bone marrow cells derived from GFP+ (GFP-transgenic C57/BL/6-Tg(UBC-GFP)30 Scha/J) mice. This method yields stable GFP+ chimeras with greater than 95% chimerism (range 95-99%), achieved within one month of bone marrow transfer confirmed by microscopy and fluorescence-assisted cell sorting (FACS) analysis, with lower mortality after irradiation than prior methods. To demonstrate the efficacy of GFP+ bone marrow chimeric mice, the role of circulating GFP+ bone marrow-derived cells in myofibroblast generation after irregular photo-therapeutic keratectomy (PTK) was analyzed. Many SMA+ myofibroblasts that were generated at one month after PTK were derived from GFP+ bone marrow-derived cells. The GFP+ bone marrow chimeric mouse provides an excellent model for studying the role of bone marrow-derived cells in corneal wound healing, glaucoma surgery, optic nerve head pathology and retinal pathophysiology and wound healing. Copyright © 2013 Elsevier Ltd. All rights reserved.

Role of whole bone marrow, whole bone marrow cultured cells, and mesenchymal stem cells in chronic wound healing.

PubMed

Rodriguez-Menocal, Luis; Shareef, Shahjahan; Salgado, Marcela; Shabbir, Arsalan; Van Badiavas, Evangelos

2015-03-13

Recent evidence has shown that bone marrow cells play critical roles during the inflammatory, proliferative and remodeling phases of cutaneous wound healing. Among the bone marrow cells delivered to wounds are stem cells, which can differentiate into multiple tissue-forming cell lineages to effect, healing. Gaining insight into which lineages are most important in accelerating wound healing would be quite valuable in designing therapeutic approaches for difficult to heal wounds. In this report we compared the effect of different bone marrow preparations on established in vitro wound healing assays. The preparations examined were whole bone marrow (WBM), whole bone marrow (long term initiating/hematopoietic based) cultured cells (BMC), and bone marrow derived mesenchymal stem cells (BM-MSC). We also applied these bone marrow preparations in two murine models of radiation induced delayed wound healing to determine which had a greater effect on healing. Angiogenesis assays demonstrated that tube formation was stimulated by both WBM and BMC, with WBM having the greatest effect. Scratch wound assays showed higher fibroblast migration at 24, 48, and 72 hours in presence of WBM as compared to BM-MSC. WBM also appeared to stimulate a greater healing response than BMC and BM-MSC in a radiation induced delayed wound healing animal model. These studies promise to help elucidate the role of stem cells during repair of chronic wounds and reveal which cells present in bone marrow might contribute most to the wound healing process.

Persistent injury-associated anemia: the role of the bone marrow microenvironment.

PubMed

Millar, Jessica K; Kannan, Kolenkode B; Loftus, Tyler J; Alamo, Ines G; Plazas, Jessica; Efron, Philip A; Mohr, Alicia M

2017-06-15

The regulation of erythropoiesis involves hematopoietic progenitor cells, bone marrow stroma, and the microenvironment. Following severe injury, a hypercatecholamine state develops that is associated with increased mobilization of hematopoietic progenitor cells to peripheral blood and decreased growth of bone marrow erythroid progenitor cells that manifests clinically as a persistent injury-associated anemia. Changes within the bone marrow microenvironment influence the development of erythroid progenitor cells. Therefore, we sought to determine the effects of lung contusion, hemorrhagic shock, and chronic stress on the hematopoietic cytokine response. Bone marrow was obtained from male Sprague-Dawley rats (n = 6/group) killed 7 d after lung contusion followed by hemorrhagic shock (LCHS) or LCHS followed by daily chronic restraint stress (LCHS/CS). End point polymerase chain reaction was performed for interleukin-1β, interleukin-10, stem cell factor, transforming growth factor-β, high-mobility group box-1 (HMGB-1), and B-cell lymphoma-extra large. Seven days following LCHS and LCHS/CS, bone marrow expression of prohematopoietic cytokines (interleukin-1β, interleukin-10, stem cell factor, and transforming growth factor-β) was significantly decreased, and bone marrow expression of HMGB-1 was significantly increased. B-cell lymphoma-extra large bone marrow expression was not affected by LCHS or LCHS/CS (naïve: 44 ± 12, LCHS: 44 ± 12, LCHS/CS: 37 ± 1, all P > 0.05). The bone marrow microenvironment was significantly altered following severe trauma in a rodent model. Prohematopoietic cytokines were downregulated, and the proinflammatory cytokine HMGB-1 had increased bone marrow expression. Modulation of the bone marrow microenvironment may represent a therapeutic strategy following severe trauma to alleviate persistent injury-associated anemia. Copyright © 2017 Elsevier Inc. All rights reserved.

SU-E-T-13: A Comparative Dosimetric Study On Radio-Dynamic Therapy for Pelvic Cancer Treatment: Strategies for Bone Marrow Dose and Volume Reduction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, C; Renmin Hospital of Wuhan University, Wuhan, Hubei Province; Wang, B

Purpose: Radio-dynamic therapy (RDT) is a potentially effective modality for local and systemic cancer treatment. Using RDT, the administration of a radio-sensitizer enhances the biological effect of high-energy photons. Although the sensitizer uptake ratio of tumor to normal tissue is normally high, one cannot simply neglect its effect on critical structures. In this study, we aim to explore planning strategies to improve bone marrow sparing without compromising the plan quality for RDT treatment of pelvic cancers. Methods: Ten cervical and ten prostate cancer patients who previously received radiotherapy at our institution were selected for this study. For each patient, ninemore » plans were created using the Varian Eclipse treatmentplanning-system (TPS) with 3D-CRT, IMRT, and VMAT delivery techniques containing various gantry angle combinations and optimization parameters (dose constraints to the bone marrow). To evaluate the plans for bone marrow sparing, the dose-volume parameters V5, V10, V15, V20, V30, and V40 for bone marrow were examined. Effective doseenhancement factors for the sensitizer were used to weigh the dose-volume histograms for various tissues from individual fractions. Results: The planning strategies had different impacts on bone marrow sparing for the cervical and prostate cases. For the cervical cases, provided the bone marrow constraints were properly set during optimization, the dose to bone marrow sparing was found to be comparable between different IMRT and VMAT plans regardless of the gantry angle selection. For the prostate cases, however, careful selection of gantry angles could dramatically improve the bone marrow sparing, although the dose distribution in bone marrow was clinically acceptable for all prostate plans that we created. Conclusion: For intensity-modulated RDT planning for cervical cancer, planners should set bone marrow constraints properly to avoid any adverse damage, while for prostate cancer one can carefully select gantry angles to improve bone marrow sparing when necessary.« less

[Study of migration and distribution of bone marrow cells transplanted animals with B16 melanoma ].

PubMed

Poveshchenko, A F; Solovieva, A O; Zubareva, K E; Strunkin, D N; Gricyk, O B; Poveshchenko, O V; Shurlygina, A V; Konenkov, V I

2017-01-01

Purpose. Reveal features migration and distribution of syngeneic bone marrow cells (BMC) and subpopulations (MSC) after transplantation into the recipient carrier B16 melanoma bodies. Methods. We used mouse male and female C57BL/6 mice. Induction of Tumor Growth: B16 melanoma cells implanted subcutaneously into right hind paw of female C57BL/6 mice at a dose of 2.5 x 105 cells / mouse. migration study in vivo distribution and BMC and MSC was performed using genetic markers - Y-chromosome specific sequence line male C57Bl/6 syngeneic intravenous transplantation in females using the polymerase chain reaction (PCR) in real time on Authorized Termal Cycler - Light Cycler 480 II / 96 (Roche). Introduction suspension of unseparated bone marrow cells, mesenchymal stem cells from donor to recipient male mice (syngeneic recipient female C57BL/6), followed by isolation of recipients of organs was performed at regular intervals, then of organ recipients isolated DNA. Results. It was shown that bone marrow cells positive for Y-chromosome in migrate lymphoid (lymph nodes, spleen, bone marrow) or in non-lymphoid organs (liver, heart, brain, skin) syngeneic recipients. In addition to the migration of cells from the bone marrow to other organs, there is a way back migration of cells from the circulation to the bone marrow. B16 melanoma stimulates the migration of transplanted MSCs and BMC in bone marrow. It is found that tumor growth enhanced migration of transplanted bone marrow cells, including populations of MSCs in the bone marrow. In the early stages of tumor formation MSC migration activity higher than the BMC. In the later stages of tumor formation undivided population of bone marrow cells migrate to the intense swelling compared with a population of MSCs. Conclusion. The possibility of using bone marrow MSCs for targeted therapy of tumor diseases, because migration of MSCs in tumor tissue can be used to effectively deliver anticancer drugs.

Expansion of Endothelial Progenitor Cells in High Density Dot Culture of Rat Bone Marrow Cells

PubMed Central

Wang, Ling; Kretlow, James D.; Zhou, Guangdong; Cao, Yilin; Liu, Wei; Zhang, Wen Jie

2014-01-01

In vitro expansion of endothelial progenitor cells (EPCs) remains a challenge in stem cell research and its application. We hypothesize that high density culture is able to expand EPCs from bone marrow by mimicking cell-cell interactions of the bone marrow niche. To test the hypothesis, rat bone marrow cells were either cultured in high density (2×105 cells/cm2) by seeding total 9×105 cells into six high density dots or cultured in regular density (1.6×104 cells/cm2) with the same total number of cells. Flow cytometric analyses of the cells cultured for 15 days showed that high density cells exhibited smaller cell size and higher levels of marker expression related to EPCs when compared to regular density cultured cells. Functionally, these cells exhibited strong angiogenic potentials with better tubal formation in vitro and potent rescue of mouse ischemic limbs in vivo with their integration into neo-capillary structure. Global gene chip and ELISA analyses revealed up-regulated gene expression of adhesion molecules and enhanced protein release of pro-angiogenic growth factors in high density cultured cells. In summary, high density cell culture promotes expansion of bone marrow contained EPCs that are able to enhance tissue angiogenesis via paracrine growth factors and direct differentiation into endothelial cells. PMID:25254487

Platelet bioreactor-on-a-chip

PubMed Central

Mazutis, Linas; Wu, Stephen; Sylman, Joanna L.; Ehrlicher, Allen; Machlus, Kellie R.; Feng, Qiang; Lu, Shijiang; Lanza, Robert; Neeves, Keith B.; Weitz, David A.; Italiano, Joseph E.

2014-01-01

Platelet transfusions total >2.17 million apheresis-equivalent units per year in the United States and are derived entirely from human donors, despite clinically significant immunogenicity, associated risk of sepsis, and inventory shortages due to high demand and 5-day shelf life. To take advantage of known physiological drivers of thrombopoiesis, we have developed a microfluidic human platelet bioreactor that recapitulates bone marrow stiffness, extracellular matrix composition, micro-channel size, hemodynamic vascular shear stress, and endothelial cell contacts, and it supports high-resolution live-cell microscopy and quantification of platelet production. Physiological shear stresses triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets. Modeling human bone marrow composition and hemodynamics in vitro obviates risks associated with platelet procurement and storage to help meet growing transfusion needs. PMID:25606631

Mycobacterium tuberculosis Contaminant Risk on Bone Marrow Aspiration Material from Iliac Bone Patients with Active Tuberculous Spondylitis.

PubMed

Rahyussalim, Ahmad Jabir; Kurniawati, Tri; Rukmana, Andriansjah

2016-01-01

There was a concern on Mycobacterium tuberculosis spreading to the bone marrow, when it was applied on tuberculous spine infection. This research aimed to study the probability of using autologous bone marrow as a source of mesenchymal stem cell for patients with tuberculous spondylitis. As many as nine patients with tuberculous spondylitis were used as samples. During the procedure, the vertebral lesion material and iliac bone marrow aspirates were obtained for acid fast staining, bacteria culture, and PCR (polymerase chain reaction) tests for Mycobacterium tuberculosis at the Clinical Microbiology Laboratory of Faculty of Medicine Universitas Indonesia. This research showed that there was a relationship between diagnostic confirmation of tuberculous spondylitis based on the PCR test and bacterial culture on the solid vertebral lesion material with the PCR test and bacterial culture from the bone marrow aspirates. If the diagnostic confirmation concluded positive results, then there was a higher probability that there would be a positive result for the bone marrow aspirates, so that it was not recommended to use autologous bone marrow as a source of mesenchymal stem cell for patients with tuberculous spondylitis unless the PCR and culture examination of the bone marrow showed a negative result.

Efficient natural defense mechanisms against Listeria monocytogenes in T and B cell-deficient allogeneic bone marrow radiation chimeras. Preactivated macrophages are the main effector cells in an early phase after bone marrow transfer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roesler, J.; Groettrup, E.B.; Baccarini, M.

1989-09-01

Radiation chimeras in the early phase after bone marrow transplantation are a good model to study the efficiency of the body's nonspecific defense system represented by macrophages (M phi), polymorphonuclear cells (PMN), and NK cells. These cell types are present in large numbers in spleen and liver at that time, whereas the specific immune system represented by T and B cells is functionally deficient. We previously reported enhanced activities in vitro of M phi (and PMN) from recipient animals in an early phase after allogeneic bone marrow transfer. We here demonstrate that these activities result in enhanced spontaneous resistance againstmore » Listeria monocytogenes in vivo: CFU of L. monocytogenes in spleen and liver 48 h after infection were about 1 or 2 to 4 log steps less than in untreated control mice of donor or host haplotype. This enhanced resistance decreased over the 4-mo period after marrow transfer. Preactivated M phi were identified as the most important effector cells. Isolated from spleen and peritoneal cavity, they performed enhanced killing of phagocytosed Listeria. Such preactivated M phi occurred in recipient animals after transfer of allogeneic but not of syngeneic bone marrow. The precise mechanism of M phi activation in the allogeneic radiation chimera in the complete absence of any detectable T cell function is not clear at present. However, these preactivated M phi display an important protective effect against L. monocytogenes: chimeras could eliminate Listeria without acquisition of positive delayed-type sensitivity when infected with 10(3) bacteria. An inoculum of 5 . 10(3) L. monocytogenes resulted either in prolonged survival compared with normal mice of the recipient haplotype or in definitive survival accompanied by a positive delayed-type sensitivity.« less

Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis.

PubMed

Marachelian, Araz; Villablanca, Judith G; Liu, Cathy W; Liu, Betty; Goodarzian, Fariba; Lai, Hollie A; Shimada, Hiroyuki; Tran, Hung C; Parra, Jaime A; Gallego, Richard; Bedrossian, Nora; Young, Sabrina; Czarnecki, Scarlett; Kennedy, Rebekah; Weiss, Brian D; Goldsmith, Kelly; Granger, Meaghan; Matthay, Katherine K; Groshen, Susan; Asgharzadeh, Shahab; Sposto, Richard; Seeger, Robert C

2017-09-15

Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma. Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, Δ C t , for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, 123 I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between Δ C t and progression-free survival (PFS). Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their Δ C t values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow C t was 7.9 ± 0.5 C t stronger than blood C t When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity ( P < 0.0001 and P = 0.007). Bone marrow and blood Δ C t values correlated with PFS ( P < 0.001; P = 0.001) even when bone marrow was morphologically negative ( P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood Δ C t values were associated with PFS independently of clinical disease and MYCN gene status ( P < 0.001; P = 0.055). Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374-83. ©2017 AACR . ©2017 American Association for Cancer Research.

Distribution Atlas of Proliferating Bone Marrow in Non-Small Cell Lung Cancer Patients Measured by FLT-PET/CT Imaging, With Potential Applicability in Radiation Therapy Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Campbell, Belinda A., E-mail: Belinda.Campbell@petermac.org; Callahan, Jason; Bressel, Mathias

Purpose: Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)–positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility. Methods and Materials: The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletalmore » FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status. Results: Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age. Conclusions: This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required.« less

Bone marrow transplant - discharge

MedlinePlus

Transplant - bone marrow - discharge; Stem cell transplant - discharge; Hematopoietic stem cell transplant - discharge; Reduced intensity; Non-myeloablative transplant - discharge; Mini transplant - discharge; Allogenic bone marrow transplant - discharge; ...

A patient with familial bone marrow failure and an inversion of chromosome 8.

PubMed

Buchbinder, David Kyle; Zadeh, Touran; Nugent, Diane

2011-12-01

Familial bone marrow failure has been associated with a variety of chromosomal aberrations. Chromosome 8 abnormalities have been described in association with neoplastic and hematologic disorders; however, to our knowledge, inversion of the long arm of chromosome 8 has not been described in the context of familial bone marrow failure. We describe a 9-year-old female with familial bone marrow failure and an inversion of chromosome 8 [inv (8) (q22, q24.3)]. Given the importance of considering the genetic determinants of familial bone marrow failure, the potential role of chromosome 8 abnormalities in the development of marrow failure is discussed.

Cocaine-contaminated allogeneic bone marrow transplantation.

PubMed

Keung, Y K; Morgan, D; Cobos, E

2001-01-01

Should a person with history of drug addiction be categorically denied as a bone marrow donor? The answer to the question is controversial. We report a case of allogeneic bone marrow transplantation for refractory acute myeloid leukemia preceded by essential thrombocythemia. The donor used cocaine and marijuana the night before the bone marrow harvest. Copyright 2001 S. Karger AG, Basel

Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.

PubMed

Mitsiades, Constantine S; Rouleau, Cecile; Echart, Cinara; Menon, Krishna; Teicher, Beverly; Distaso, Maria; Palumbo, Antonio; Boccadoro, Mario; Anderson, Kenneth C; Iacobelli, Massimo; Richardson, Paul G

2009-02-15

Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells. Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules. Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in combination with conventional and novel therapies to potentially improve patient outcome in multiple myeloma and other malignancies.

A study of 23 unicameral bone cysts of the calcaneus: open chip allogeneic bone graft versus percutaneous injection of bone powder with autogenous bone marrow.

PubMed

Park, Il-Hyung; Micic, Ivan Dragoljub; Jeon, In-Ho

2008-02-01

The treatment of unicameral bone cyst varies from percutaneous needle biopsy, aspiration and local injection of steroid, autologous bone marrow, or demineralized bone matrix to curettage and open bone-grafting. The purpose of this study was to compare the results of open chip allogeneic bone graft versus percutaneous injection of demineralized bone powder with autogenous bone marrow in management of calcaneal cysts. Twenty-three calcaneal unicameral cysts in 20 patients were treated. Lyophilized irradiated chip allogeneic bone (CAB) and autogenous bone marrow were used for treatment of 13 cysts in 11 patients, and 10 cysts in 9 patients were treated with percutaneous injection of irradiated allogeneic demineralized bone powder (DBP) and autogenous bone marrow. There were 11 males and 9 female patients with mean age of 17 years. The patients were followed for an average of 49.4 months. Complete healing was achieved in 9 cysts treated with chip allogeneic bone and in 5 cysts treated with powdered bone. Four cysts treated with CAB and 3 cysts treated with DBP healed with a defect. Two cysts treated with powdered bone and autogenous bone marrow were classified as persistent. No infections or pathological fractures were observed during the followup period. Percutaneous injection of a mixture of allogeneic bone powder with autogenous bone marrow is a minimal invasive method and could be an effective alternative in the treatment of unicameral calcaneal bone cysts. The postoperative morbidity was low, the hospital stay was brief, and patient's comfort for unrestricted activity was enhanced.

The role of bone marrow evaluation in the staging of patients with otherwise localized, low-risk neuroblastoma.

PubMed

Russell, Heidi V; Golding, Laurie A; Suell, Mary Nell; Nuchtern, Jed G; Strother, Douglas R

2005-12-01

Bone marrow aspirations and biopsies are standard staging procedures for neuroblastoma because the tumor frequently metastasizes to the bone marrow. The presence of bone marrow metastases indicates stage 4 or 4S neuroblastoma by International Neuroblastoma Staging System (INSS) criteria; these stages are also associated with other metastatic sites of disease. We questioned whether bone marrow studies changed the staging or treatment of children with localized, completely resected tumors if there was no other evidence of metastatic spread. If stage of disease rarely changed with bone marrow results, it might be possible to avoid this procedure in a subset of patients with neuroblastoma. The staging studies of patients with INSS stage 1 (n = 29), 4 (n = 60), and 4S (n = 13) neuroblastoma from two institutions were reviewed. There were no patients upstaged from stage 1 to 4 or 4S by bone marrow metastases alone. Fifty-nine of 60 stage 4 patients had other sites of metastases on imaging studies, the remaining patient had an unresectable primary tumor and marrow disease. All subjects with stage 4S disease had liver metastases. Bone marrow studies did not contribute data that changed the stage of patients who had surgically resectable tumors and no evidence of metastatic spread on imaging studies. When present, metastatic spread to the marrow was associated with advanced local tumors or other sites of metastatic disease. Given the relatively small size of our study population, further studies are warranted that investigate the utility of bone marrow studies for patients who otherwise have INSS stage 1 neuroblastoma. 2005 Wiley-Liss, Inc.

Daily propranolol administration reduces persistent injury-associated anemia following severe trauma and chronic stress

PubMed Central

Alamo, Ines G.; Kannan, Kolenkode B.; Bible, Letitia E.; Loftus, Tyler J.; Ramos, Harry; Efron, Philip A.; Mohr, Alicia M.

2017-01-01

Background Following severe trauma, patients develop a norepinephrine-mediated persistent, injury-associated anemia. This anemia is associated with suppression of bone marrow erythroid colony growth, along with decreased iron levels, and elevated erythropoietin (EPO) levels, which are insufficient to promote effective erythropoiesis. The impact of norepinephrine on iron regulators such as ferroportin, transferrin and transferrin receptor-1 (TFR-1) are unknown. Using a clinically relevant rodent model of lung contusion (LC), hemorrhagic shock (HS), and chronic stress (CS), we hypothesize that daily propranolol (BB), a non-selective beta-blocker, restores bone marrow function and improves iron homeostasis. Methods Male Sprague-Dawley rats were subjected to LCHS±BB and LCHS/CS±BB. BB was achieved with propranolol (10mg/kg) daily until the day of sacrifice. Hemoglobin (Hgb), plasma EPO, plasma hepcidin, bone marrow cellularity and bone marrow erythroid colony growth were assessed. RNA was isolated to measure transferrin, TFR-1 and ferroportin expression. Data is presented as mean±SD; *p<0.05 vs. untreated counterpart by t-test. Results The addition of CS to LCHS leads to persistent anemia on post-trauma day 7, while the addition of BB improved Hgb levels (LCHS/CS: 10.6±0.8 vs. LCHS/CS+BB: 13.9±0.4* g/dL). Daily BB use following LCHS/CS improved BM cellularity, CFU-GEMM, BFU-E and CFU-E colony growth. LCHS/CS+BB significantly reduced plasma EPO levels and increased plasma hepcidin levels on day 7. The addition of CS to LCHS resulted in decreased liver ferroportin expression as well as decreased bone marrow transferrin and TFR-1 expression, thus, blocking iron supply to erythroid cells. However, daily BB after LCHS/CS improved expression of all iron regulators. Conclusions Daily propranolol administration following LCHS/CS restored bone marrow function and improved anemia after severe trauma. In addition, iron regulators are significantly reduced following LCHS/CS, which may contribute to iron restriction after injury. However, daily propranolol administration after LCHS/CS improved iron homeostasis. Level of Evidence Level II, therapeutic study PMID:28099381

NOS2 deficiency has no influence on the radiosensitivity of the hematopoietic system.

PubMed

Li, Chengcheng; Luo, Yi; Shao, Lijian; Meng, Aimin; Zhou, Daohong

2018-01-01

Previous studies have shown that inhibition of inducible NO synthase (NOS2 or iNOS) with an inhibitor can selectively protect several normal tissues against radiation during radiotherapy. However, the role of NOS2 in ionizing radiation (IR)-induced bone marrow (BM) suppression is unknown and thus was investigated in the present study using NOS2 - / - and wild-type mice 14 days after they were exposed to a sublethal dose of total body irradiation (TBI). The effects of different doses of IR (1, 2 and 4 Gy) on the apoptosis and colony-forming ability of bone marrow cells from wild-type (WT) and NOS2 - / - mice were investigated in vitro. In addition, we exposed NOS2 - / - mice and WT mice to 6-Gy TBI or sham irradiation. They were euthanized 14 days after TBI for analysis of peripheral blood cell counts and bone marrow cellularity. Colony-forming unit-granulocyte and macrophage, burst-forming unit-erythroid and CFU-granulocyte, erythroid, macrophage in bone marrow cells from the mice were determined to evaluate the function of hematopoietic progenitor cells (HPCs), and the ability of hematopoietic stem cells (HSCs) to self-renew was analysed by the cobblestone area forming cell assay. The cell cycling of HPCs and HSCs were measured by flow cytometry. Exposure to 2 and 4 Gy IR induced bone marrow cell apoptosis and inhibited the proliferation of HPCs in vitro. However, there was no difference between the cells from WT mice and NOS2 - / - mice in response to IR exposure in vitro. Exposure of WT mice and NOS2 - / - mice to 6 Gy TBI decreased the white blood cell, red blood cell, and platelet counts in the peripheral blood and bone marrow mononuclear cells, and reduced the colony-forming ability of HPCs (P < 0.05), damaged the clonogenic function of HSCs. However, these changes were not significantly different in WT and NOS2 - / - mice. These data suggest that IR induces BM suppression in a NOS2-independent manner.

Hematoxylin Bodies in Pediatric Bone Marrow Aspirates and Their Utility in the Diagnosis of Systemic Lupus Erythematosus.

PubMed

Xu, Min; Chisholm, Karen M; Fan, Guang; Stevens, Anne M; Rutledge, Joe C

2017-01-01

In our recent case report, the finding of lupus erythematosus (LE) cells in a bone marrow aspirate led to the diagnosis of systemic lupus erythematosus (SLE) and appropriate treatment, although the patient was not clinically suspected to have SLE. To determine whether LE cells are present in the bone marrow aspirates of SLE patients, but overlooked in routine bone marrow morphology review, bone marrow aspirates from 30 pediatric patients (15 with SLE and 15 with other diagnoses) evaluated by rheumatologists were reviewed. LE cells were found in the bone marrow aspirates of only 1 SLE patient and none in non-SLE patients. However, hematoxylin bodies were identified in 53% (8/15) of SLE patients. Neither hematoxylin bodies nor LE cells were found in the aspirates from patients with other disorders. Three additional pediatric patients identified prospectively were found to have hematoxylin bodies in the bone marrow aspirates. Although the diagnosis was not initially suspected, 2 of the 3 patients were subsequently diagnosed with SLE. All patients with hematoxylin bodies and SLE had antinuclear antibody titers ≥1:640 with a homogeneous staining pattern. In addition, bone marrow aspirates of 9 adult patients were reviewed, and neither LE cells nor hematoxylin bodies were identified. In summary, hematoxylin bodies were present in the bone marrow aspirates of many pediatric SLE patients, while LE cells were rare. The finding of hematoxylin bodies in pediatric bone marrow aspirates is a helpful and specific diagnostic clue that may lead to the diagnosis of SLE when other clinical features are nonspecific.

Development and characterization of a lung-protective method of bone marrow transplantation in the mouse.

PubMed

Janssen, William J; Muldrow, Alaina; Kearns, Mark T; Barthel, Lea; Henson, Peter M

2010-05-31

Allogeneic bone marrow transplantation is a common method used to study the contribution of myeloid and lymphoid cell populations in murine models of disease. The method requires lethal doses of radiation to ablate the bone marrow. Unintended consequences of radiation include organ injury and inflammatory cell activation. The goal of our study was to determine the degree to which bone marrow transplantation alters lungs and to develop a system to protect the lungs during radiation. C57BL/6 mice were subjected to total body irradiation with 900cGy and then transplanted with bone marrow from green fluorescent protein (GFP) expressing mice. Resultant chimeras exhibited a significant decline in alveolar macrophage numbers within 72h, modest influx of neutrophils in the lungs at 14days, and repopulation of the lungs by alveolar macrophages of bone marrow origin by 28days. Neutrophil influx and alveolar macrophage turnover were prevented when 1cm thick lead shields were used to protect the lungs during radiation, such that 8weeks after transplantation less than 30% of alveolar macrophages were of donor origin. Lung-shielded mice achieved a high level of bone marrow engraftment with greater than 95% of circulating leukocytes expressing GFP. In addition, their response to intratracheal lipopolysaccharide was similar to non-transplanted mice. We describe a model whereby lead shields protect resident cell populations in the lungs from radiation during bone marrow transplantation but permit full bone marrow engraftment. This system may be applicable to other organ systems in which protection from radiation during bone marrow transplantation is desired.

Bone marrow analysis of immune cells and apoptosis in patients with systemic lupus erythematosus.

PubMed

Park, J W; Moon, S Y; Lee, J H; Park, J K; Lee, D S; Jung, K C; Song, Y W; Lee, E B

2014-09-01

To examine the immune cell profile in the bone marrow of systemic lupus erythematosus (SLE) patients and to assess its clinical relevance. Sixteen bone marrow samples from 14 SLE patients were compared with seven healthy control samples. The numbers of immune cells and apoptotic cells in the bone marrow were examined by immunohistochemistry. The association between immune cell subsets and clinical features was investigated. CD4+ T cells, macrophages and plasma cells were more common in the bone marrow of SLE patients than in healthy controls (p=0.001, p=0.004 and p<0.001, respectively). Greater numbers of CD4+ T cells and macrophages were associated with high-grade bone marrow damage. The percentage of apoptotic cells in bone marrow of SLE patients was significantly higher than that in controls (p<0.001) and was positively correlated with the number of plasmacytoid dendritic cells (p=0.013). Increased number of plasma cells along with high interleukin-6 expression was correlated with anti-double stranded DNA antibody levels and the SLE disease activity index (p=0.031 and 0.013, respectively). Bone marrow from SLE patients showed a distinct immune cell profile and increased apoptosis. This, coupled with a correlation with disease activity, suggests that the bone marrow may play a critical role in the pathogenesis of SLE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Comparison among T1-weighted magnetic resonance imaging, modified dixon method, and magnetic resonance spectroscopy in measuring bone marrow fat.

PubMed

Shen, Wei; Gong, Xiuqun; Weiss, Jessica; Jin, Ye

2013-01-01

An increasing number of studies are utilizing different magnetic resonance (MR) methods to quantify bone marrow fat due to its potential role in osteoporosis. Our aim is to compare the measurements of bone marrow fat among T1-weighted magnetic resonance imaging (MRI), modified Dixon method (also called fat fraction MRI (FFMRI)), and magnetic resonance spectroscopy (MRS). Contiguous MRI scans were acquired in 27 Caucasian postmenopausal women with a modified Dixon method (i.e., FFMRI). Bone marrow adipose tissue (BMAT) of T1-weighted MRI and bone marrow fat fraction of the L3 vertebra and femoral necks were quantified using SliceOmatic and Matlab. MRS was also acquired at the L3 vertebra. Correlation among the three MR methods measured bone marrow fat fraction and BMAT ranges from 0.78 to 0.88 (P < 0.001) in the L3 vertebra. Correlation between BMAT measured by T1-weighted MRI and bone marrow fat fraction measured by modified FFMRI is 0.86 (P < 0.001) in femoral necks. There are good correlations among T1-weighted MRI, FFMRI, and MRS for bone marrow fat quantification. The inhomogeneous distribution of bone marrow fat, the threshold segmentation of the T1-weighted MRI, and the ambiguity of the FFMRI may partially explain the difference among the three methods.

Comparison among T1-Weighted Magnetic Resonance Imaging, Modified Dixon Method, and Magnetic Resonance Spectroscopy in Measuring Bone Marrow Fat

PubMed Central

Shen, Wei; Gong, Xiuqun; Weiss, Jessica; Jin, Ye

2013-01-01

Introduction. An increasing number of studies are utilizing different magnetic resonance (MR) methods to quantify bone marrow fat due to its potential role in osteoporosis. Our aim is to compare the measurements of bone marrow fat among T1-weighted magnetic resonance imaging (MRI), modified Dixon method (also called fat fraction MRI (FFMRI)), and magnetic resonance spectroscopy (MRS). Methods. Contiguous MRI scans were acquired in 27 Caucasian postmenopausal women with a modified Dixon method (i.e., FFMRI). Bone marrow adipose tissue (BMAT) of T1-weighted MRI and bone marrow fat fraction of the L3 vertebra and femoral necks were quantified using SliceOmatic and Matlab. MRS was also acquired at the L3 vertebra. Results. Correlation among the three MR methods measured bone marrow fat fraction and BMAT ranges from 0.78 to 0.88 (P < 0.001) in the L3 vertebra. Correlation between BMAT measured by T1-weighted MRI and bone marrow fat fraction measured by modified FFMRI is 0.86 (P < 0.001) in femoral necks. Conclusion. There are good correlations among T1-weighted MRI, FFMRI, and MRS for bone marrow fat quantification. The inhomogeneous distribution of bone marrow fat, the threshold segmentation of the T1-weighted MRI, and the ambiguity of the FFMRI may partially explain the difference among the three methods. PMID:23606951

Marrow donor registry and cord blood bank in Taiwan.

PubMed

Lee, Tsung Dao

2002-08-01

Unrelated Bone marrow transplant was initiated thirty years ago. Though there are over millions of donors registered with the bone marrow registries worldwide, Asian patients rarely find a match with all these donors. Tzu Chi Marrow Donor Registry was established to meet this need. It has become the largest Asian marrow donor registry in the world. With the introduction of high technology to test the HLA of the donors and recipients, the success rate of bone marrow transplant is greatly improved among Asian countries. 50% of blood disease Asian patients who cannot find a bone marrow matched donor will be complemented by the establishment of cord blood banks in Taiwan.

An Association between BK Virus Replication in Bone Marrow and Cytopenia in Kidney-Transplant Recipients

PubMed Central

Pambrun, Emilie; Mengelle, Catherine; Fillola, Geneviève; Laharrague, Patrick; Esposito, Laure; Cardeau-Desangles, Isabelle; Del Bello, Arnaud; Izopet, Jacques; Rostaing, Lionel; Kamar, Nassim

2014-01-01

The human polyomavirus BK (BKV) is associated with severe complications, such as ureteric stenosis and polyomavirus-associated nephropathy (PVAN), which often occur in kidney-transplant patients. However, it is unknown if BKV can replicate within bone marrow. The aim of this study was to search for BKV replication within the bone marrow of kidney-transplant patients presenting with a hematological disorder. Seventy-two kidney-transplant patients underwent bone-marrow aspiration for cytopenia. At least one virus was detected in the bone marrow of 25/72 patients (35%), that is, parvovirus B19 alone (n = 8), parvovirus plus Epstein-Barr virus (EBV) (n = 3), cytomegalovirus (n = 4), EBV (n = 2), BKV alone (n = 7), and BKV plus EBV (n = 1). Three of the eight patients who had BKV replication within the bone marrow had no detectable BKV replication in the blood. Neutropenia was observed in all patients with BKV replication in the bone marrow, and blockade of granulocyte maturation was observed. Hematological disorders disappeared in all patients after doses of immunosuppressants were reduced. In conclusion, an association between BKV replication in bone marrow and hematological disorders, especially neutropenia, was observed. Further studies are needed to confirm these findings. PMID:24868448

Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells.

PubMed

Kemp, Kevin; Morse, Ruth; Sanders, Kelly; Hows, Jill; Donaldson, Craig

2011-07-01

The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well-known; however, the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterised. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high-dose chemotherapy (HDC) regimens, there is a lack of data comparing the short- or long-term effects these drugs have on patients post treatment. To help address these problems, the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in vitro. Within this study, the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore highlight potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC.

Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate.

PubMed

Fan, Yi; Hanai, Jun-Ichi; Le, Phuong T; Bi, Ruiye; Maridas, David; DeMambro, Victoria; Figueroa, Carolina A; Kir, Serkan; Zhou, Xuedong; Mannstadt, Michael; Baron, Roland; Bronson, Roderick T; Horowitz, Mark C; Wu, Joy Y; Bilezikian, John P; Dempster, David W; Rosen, Clifford J; Lanske, Beate

2017-03-07

Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption, and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1 + RANKL + marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotic patients. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH's therapeutic action through its ability to direct mesenchymal cell fate. Copyright © 2017 Elsevier Inc. All rights reserved.

Bone Marrow Adipose Tissue and Skeletal Health.

PubMed

Muruganandan, Shanmugam; Govindarajan, Rajgopal; Sinal, Christopher J

2018-05-31

To summarize and discuss recent progress and novel signaling mechanisms relevant to bone marrow adipocyte formation and its physiological/pathophysiological implications for bone remodeling. Skeletal remodeling is a coordinated process entailing removal of old bone and formation of new bone. Several bone loss disorders such as osteoporosis are commonly associated with increased bone marrow adipose tissue. Experimental and clinical evidence supports that a reduction in osteoblastogenesis from mesenchymal stem cells at the expense of adipogenesis, as well as the deleterious effects of adipocyte-derived signaling, contributes to the etiology of osteoporosis as well as bone loss associated with aging, diabetes mellitus, post-menopause, and chronic drug therapy. However, this view is challenged by findings indicating that, in some contexts, bone marrow adipose tissue may have a beneficial impact on skeletal health. Further research is needed to better define the role of marrow adipocytes in bone physiology/pathophysiology and to determine the therapeutic potential of manipulating mesenchymal stem cell differentiation.

Autologous bone marrow purging with LAK cells.

PubMed

Giuliodori, L; Moretti, L; Stramigioli, S; Luchetti, F; Annibali, G M; Baldi, A

1993-12-01

In this study we will demonstrate that LAK cells, in vitro, can lyse hematologic neoplastic cells with a minor toxicity of the staminal autologous marrow cells. In fact, after bone marrow and LAK co-culture at a ratio of 1/1 for 8 hours, the inhibition on the GEMM colonies resulted to be 20% less compared to the untreated marrow. These data made LAK an inviting agent for marrow purging in autologous bone marrow transplantation.

Evaluation of mRNA expression levels and electrophysiological function of neuron-like cells derived from canine bone marrow stromal cells.

PubMed

Nakano, Rei; Edamura, Kazuya; Sugiya, Hiroshi; Narita, Takanori; Okabayashi, Ken; Moritomo, Tadaaki; Teshima, Kenji; Asano, Kazushi; Nakayama, Tomohiro

2013-10-01

To investigate the in vitro differentiation of canine bone marrow stromal cells (BMSCs) into functional, mature neurons. Bone marrow from 6 adult dogs. BMSCs were isolated from bone marrow and chemically induced to develop into neurons. The morphology of the BMSCs during neuronal induction was monitored, and immunocytochemical analyses for neuron markers were performed after the induction. Real-time PCR methods were used to evaluate the mRNA expression levels of markers for neural stem or progenitor cells, neurons, and ion channels, and western blotting was used to assess the expression of neuronal proteins before and after neuronal induction. The electrophysiological properties of the neuron-like cells induced from canine BMSCs were evaluated with fluorescent dye to monitor Ca(2)+ influx. Canine BMSCs developed a neuron-like morphology after neuronal induction. Immunocytochemical analysis revealed that these neuron-like cells were positive for neuron markers. After induction, the cells' mRNA expression levels of almost all neuron and ion channel markers increased, and the protein expression levels of nestin and neurofilament-L increased significantly. However, the neuron-like cells derived from canine BMSCs did not have the Ca(2)+ influx characteristic of spiking neurons. Although canine BMSCs had neuron-like morphological and biochemical properties after induction, they did not develop the electrophysiological characteristics of neurons. Thus, these results have suggested that canine BMSCs could have the capacity to differentiate into a neuronal lineage, but the differentiation protocol used may have been insufficient to induce development into functional neurons.

Modeling Marrow Failure and MDS for Novel Therapeutics

DTIC Science & Technology

2017-03-01

predisposition syndrome Shwachman-Diamond syndrome (SDS) into which a deletion of the MDS-associated region of 7q has been genomically engineered . We...associated region of 7q has been genomically engineered . We will perform functional genomic screens to identify genes and molecular pathways with...disease arising from marrow failure. 2. Keywords Bone marrow failure, clonal evolution, induced pluripotent stem cells, genomic engineering 3

Graft-versus-host disease

MedlinePlus

GVHD; Bone marrow transplant - graft-versus-host disease; Stem cell transplant - graft-versus-host disease; Allogeneic transplant - ... GVHD may occur after a bone marrow, or stem cell, transplant in which someone receives bone marrow ...

Bone Marrow Failure Secondary to Cytokinesis Failure

DTIC Science & Technology

2015-12-01

SUPPLEMENTARY NOTES 14. ABSTRACT Fanconi anemia (FA) is a human genetic disease characterized by a progressive bone marrow failure and heightened...Fanconi anemia (FA) is the most commonly inherited bone marrow failure syndrome. FA patients develop bone marrow failure during the first decade of...experiments proposed in specific aims 1- 3 (Tasks 1-3). Task 1: To determine whether HSCs from Fanconi anemia mouse models have increased cytokinesis

Combination of BMP-2-releasing gelatin/β-TCP sponges with autologous bone marrow for bone regeneration of X-ray-irradiated rabbit ulnar defects.

PubMed

Yamamoto, Masaya; Hokugo, Akishige; Takahashi, Yoshitake; Nakano, Takayoshi; Hiraoka, Masahiro; Tabata, Yasuhiko

2015-07-01

The objective of this study is to evaluate the feasibility of gelatin sponges incorporating β-tricalcium phosphate (β-TCP) granules (gelatin/β-TCP sponges) to enhance bone regeneration at a segmental ulnar defect of rabbits with X-ray irradiation. After X-ray irradiation of the ulnar bone, segmental critical-sized defects of 20-mm length were created, and bone morphogenetic protein-2 (BMP-2)-releasing gelatin/β-TCP sponges with or without autologous bone marrow were applied to the defects to evaluate bone regeneration. Both gelatin/β-TCP sponges containing autologous bone marrow and BMP-2-releasing sponges enhanced bone regeneration at the ulna defect to a significantly greater extent than the empty sponges (control). However, in the X-ray-irradiated bone, the bone regeneration either by autologous bone marrow or BMP-2 was inhibited. When combined with autologous bone marrow, the BMP-2 exhibited significantly high osteoinductivity, irrespective of the X-ray irradiation. The bone mineral content at the ulna defect was similar to that of the intact bone. It is concluded that the combination of bone marrow with the BMP-2-releasing gelatin/β-TCP sponge is a promising technique to induce bone regeneration at segmental bone defects after X-ray irradiation. Copyright © 2015 Elsevier Ltd. All rights reserved.

[The effect of lithium carbonate on the leukocyte count following ionizing radiation. 4. The effect of lithium carbonate on the activation of granulocytes].

PubMed

Wolf, G; Müller, G M; Kehrberg, G

1989-01-01

From numerous investigations it is known that lithium carbonate promotes granulocytopoiesis by stimulation of CSF (colony stimulating factor) in bone marrow. To prove if no immature, in their functions restricted cells are delivered from bone marrow, the activity of granulocytes was tested in vitro in patients with lithium therapy. It could be seen that granulocytes of peripheral blood show an increased in-vitro-activation after lithium influence in vivo.

Unicameral bone cysts treated by injection of bone marrow or methylprednisolone.

PubMed

Chang, C H; Stanton, R P; Glutting, J

2002-04-01

In 79 consecutive patients with unicameral bone cysts we compared the results of aspiration and injection of bone marrow with those of aspiration and injection of steroid. All were treated by the same protocol. The only difference was the substance injected into the cysts. The mean radiological follow-up to detect activity in the cyst was 44 months (12 to 108). Of the 79 patients, 14 received a total of 27 injections of bone marrow and 65 a total of 99 injections of steroid. Repeated injections were required in 57% of patients after bone marrow had been used and in 49% after steroid. No complications were noted in either group. In this series no advantage could be shown for the use of autogenous injection of bone marrow compared with injection of steroid in the management of unicameral bone cysts.

Immune response

MedlinePlus Videos and Cool Tools

... These cells develop into two groups in the bone marrow. From the bone marrow, one group of lymphocytes migrates to a ... or B cells, mature and develop within the bone marrow itself. In that process, they achieve the ...

[Bone marrow stromal damage mediated by immune response activity].

PubMed

Vojinović, J; Kamenov, B; Najman, S; Branković, Lj; Dimitrijević, H

1994-01-01

The aim of this work was to estimate influence of activated immune response on hematopoiesis in vitro, using the experimental model of BCG immunized BALB/c mice and in patients with chronic immunoactivation: long-lasting infections, autoimmunity or malignancy. We correlated changes in long term bone marrow cultures (Dexter) and NBT reduction with appearance of anemia in patients and experimental model of immunization by BCG. Increased spontaneous NBT reduction pointed out role of macrophage activation in bone marrow stroma damage. Long-term bone marrow cultures showed reduced number of hematopoietic cells, with predomination of fibroblasts and loss of fat cells. This results correlated with anemia and leucocytosis with stimulated myelopoiesis in peripheral blood. Activation of immune response, or acting of any agent that directly changes extracellular matrix and cellularity of bone marrow, may result in microenviroment bone marrow damage that modify hematopoiesis.

Survival and endogenous colony formation in irradiated mice grafted with normal or infectious mononucleosis bone marrow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Louwagie, A. C.; Verwilghen, R. L.

1973-07-01

Mice were exposed to 850 or 975 rad of whole-body radiation; three hr later mice were given normal human bone marrow, infectious mononucleosis bone marrow, or cells from malignant blood diseases. The surviving mice were killed at day 9 and the spleen nodules were counted. Some mice were also given antihuman antilymphocytic serum (ALS). In mice exposed to 975 rad, the highest survival was observed in mice grafted with infectious mononucleosis bone marrow, while none of the animals grafted with cells from malignant blood diseases survived 9 days. In mice exposed to 850 rad, grafting of normal or infectious mononucleosismore » bone marrow markedly decreased the survival. Endogenous spleen colonies were induced in all animals grafted with normal or infectious mononucleosis bone marrow. (HLW)« less

Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity

PubMed Central

Zhang, Michael Y.; Keel, Siobán B.; Walsh, Tom; Lee, Ming K.; Gulsuner, Suleyman; Watts, Amanda C.; Pritchard, Colin C.; Salipante, Stephen J.; Jeng, Michael R.; Hofmann, Inga; Williams, David A.; Fleming, Mark D.; Abkowitz, Janis L.; King, Mary-Claire; Shimamura, Akiko

2015-01-01

Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in GATA2, RUNX1, DKC1, or LIG4. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes. PMID:25239263

Experiment K-7-23: Effect of Spaceflight on Level and Function of Immune Cells. Part 1; Immunology Studies

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Mandel, A.; Konstantinova, I. V.; Berry, W. D.; Taylor, G. R.; Lesnyak, A. T.; Fuchs, B. B.; Rakhmilevich, A. L.

1994-01-01

Two different experiments were carried out in this segment of the immunology protocol for samples received from rats flown on Cosmos 2044. Control groups included vivarium, synchronous and antiorthostatically suspended rats. In the first experiment, rat bone marrow cells were examined in Moscow for their response to recombinant murine colony stimulating factor-granulocyte / monocyte (CSF-GM). In the second experiment, rat spleen and bone marrow cells were stained in Moscow with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and shipped to the United States for analysis on a flow cytometer. The results of the studies indicated that bone marrow cells from flown and suspended rats showed a decreased response to CSF-GM as compared to bone marrow cells from control rats. Spleen cells from flown rats showed increased percentages of suppressor-cytotoxic-T and helper-T cells amongst the entire cell population. Bone marrow cells showed an increase in the percentage of helper-T cells in the myelogenous population and increased percentages of anti-asialo GM-1 bearing, interleukin-2 receptor bearing, pan-T and helper-T cells in the lymphocytic population. Cell populations from rats suspended antiorthostatically did not follow the same pattern of distribution of leukocytes as cell populations for flown rats. These results are similar, but not identical to, earlier results from Cosmos 1887, and confirm that space flight can have profound effects on immune system components and activities.

Hematologic effects of subcutaneous administration of recombinant human granulocyte colony-stimulating factor (filgrastim) in healthy alpacas.

PubMed

McKenzie, Erica C; Tornquist, Susan J; Gorman, M Elena; Cebra, Christopher K; Payton, Mark E

2008-06-01

To determine the effects of SC administration of filgrastim on cell counts in venous blood and bone marrow of healthy adult alpacas. 10 healthy alpacas. Alpacas were randomly assigned to receive treatment with filgrastim (5 microg/kg, SC; n=5) or an equivalent volume of physiologic saline (0.9% NaCl) solution (5) once a day for 3 days. Blood samples were obtained via jugular venipuncture 1 day prior to treatment and once a day for 5 days commencing 24 hours after the first dose was administered. Complete blood counts were performed for each blood sample. Bone marrow aspirates were obtained from the sternum of each alpaca 48 hours before the first treatment was administered and 72 hours after the third treatment was administered. Myeloid-to-erythroid cell (M:E) ratio was determined via cytologic evaluation of bone marrow aspirates. In filgrastim-treated alpacas, substantial increases in counts of WBCs and neutrophils were detected within 24 hours after the first dose was administered. Band cell count and percentage significantly increased 24 hours after the second dose. Counts of WBCs, neutrophils, and band cells remained high 48 hours after the third dose. Red blood cell counts and PCV were unaffected. The M:E ratio also increased significantly after treatment with filgrastim. Filgrastim induced rapid and substantial increases in numbers of circulating neutrophils and M:E ratios of bone marrow in healthy alpacas. Therefore, filgrastim may be useful in the treatment of camelids with impaired bone marrow function.

FoxO4 inhibits atherosclerosis through its function in bone marrow derived cells

PubMed Central

Zhu, Min; Zhang, Qing-Jun; Wang, Lin; Li, Hao; Liu, Zhi-Ping

2011-01-01

Objectives FoxO proteins are transcription factors involved in varieties of cellular processes, including immune cell homeostasis, cytokine production, anti-oxidative stress, and cell proliferation and differentiation. Although these processes are implicated in the development of atherosclerosis, very little is known about the role of FoxO proteins in the context of atherosclerosis. Our objectives were to determine whether and how inactivation of Foxo4, a member of the FoxO family, in vivo promotes atherosclerosis. Methods and Results Apolipoprotein E-deficient (apoE−/−) mice were crossbred with animals lacking Foxo4 (Foxo4−/−). After 10 weeks on a high fat diet (HFD), Foxo4−/−apoE−/− mice showed elevated atherosclerosis and increased amount of macrophages and T cells in the plaque compared to apoE−/− mice. Bone marrow transplantations of chimeric C57B/6 mice reconstituted with either wild-type or Foxo4−/− bone marrows indicate that Foxo4-deficiency in bone marrow derived cells sufficiently promoted atherosclerosis. Foxo4-null macrophages produced elevated inflammatory cytokine IL-6 and levels of reactive oxygen species (ROS) in response to lipopolysaccharides in vitro. Serum levels of IL-6 were upregulated in HFD-fed Foxo4−/−apoE−/− mice compared to those of apoE−/− mice. Conclusions FoxO4 inhibits atherosclerosis through bone marrow derived cells, possibly by inhibition of ROS and inflammatory cytokines that promote monocyte recruitment and/or retention. PMID:22005198

Spliced XBP1 promotes macrophage survival and autophagy by interacting with Beclin-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tian, Ping-Ge; Jiang, Zhi-Xin; Li, Jian-Hua

Macrophage autophagy plays an important role in the development of atherosclerosis, but the precise mechanism mediating this process is unclear. The potential role of the X-box binding protein 1 (XBP1), a crucial transduction factor that is involved in endoplasmic reticulum stress and the unfolded protein response, in bone marrow-derived macrophage autophagy is unknown. This study mainly explores the roles of XBP1 mRNA splicing in bone marrow-derived macrophage autophagy. The present study shows that the transient overexpression of spliced XBP1 via adenovirus-mediated gene transfer induces autophagy and promotes proliferation in bone marrow-derived macrophages via the down-regulation of Beclin-1, but that themore » sustained overexpression of spliced XBP1 leads to apoptosis. When XBP1 is down-regulated in bone marrow-derived macrophages using siRNA, rapamycin-induced autophagosome formation is ablated. Furthermore, we have detected the overexpression of XBP1 in areas of atherosclerotic plaques in the arteries of ApoE−/− mice. These results demonstrate that XBP1 mRNA splicing plays an important role in maintaining the function of bone marrow-derived macrophages and provide new insight into the study and treatment of atherosclerosis. - Highlights: • XBP1 was up-regulated in atherosclerotic plaques of ApoE−/− mice. • Transient spliced XBP1 overexpression induced macrophages autophagy via Beclin-1. • Sustained spliced XBP1 overexpression triggered macrophages apoptosis. • Spliced XBP1 plays a key role in maintaining the macrophages survival.« less

Bone marrow biopsy in monoclonal gammopathies: correlations between pathological findings and clinical data. The Cooperative Group for Study and Treatment of Multiple Myeloma.

PubMed Central

Riccardi, A; Ucci, G; Luoni, R; Castello, A; Coci, A; Magrini, U; Ascari, E

1990-01-01

Between January 1987 and October 1989, 561 consecutive untreated patients with monoclonal gammopathy of undetermined clinical importance (MGUS) (n = 295) or with multiple myeloma (n = 266) were evaluated in a multicentre trial. Both bone marrow biopsy and aspiration (performed at different anatomical sites) were required at presentation. Bone marrow biopsy data indicated that changes in bone marrow composition from MGUS to early multiple myeloma and to advanced multiple myeloma followed a precise pattern, including an increased percentage of bone marrow plasma cells (BMPC%), a shift from plasmocytic to plasmoblastic cytology, an increase in bone marrow cellularity and fibrosis, a change in bone marrow infiltration (becoming diffuse rather than interstitial), a decrease in residual haemopoiesis and an increase in osteoclasts. In multiple myeloma the BMPC% of biopsy specimens and aspirate were closely related, although in 5% of cases the difference between the two values was greater than 20%. Some histological features were remarkably associated with each other. For example, BMPC% was higher in cases with plasmoblastic cytology, heavy fibrosis, or reduced residual haemopoiesis. Anaemia was the clinical characteristic most influenced by bone marrow histology. The BMPC% was the only histological variable which affected the greatest number of clinical and laboratory characteristics, including, besides haemoglobin concentration, erythrocyte sedimentation rate, radiographic skeletal bone disease, and serum concentrations of monoclonal component, calcium, beta 2-microglobulin and thymidine kinase activity. These data indicate that comparative bone marrow histology in monoclonal gammopathies has clinical importance. Images PMID:2199532

Microarray profiling of diaphyseal bone of rats suffering from hypervitaminosis A.

PubMed

Lind, Thomas; Hu, Lijuan; Lind, P Monica; Sugars, Rachael; Andersson, Göran; Jacobson, Annica; Melhus, Håkan

2012-03-01

Vitamin A is the only known compound that produces spontaneous fractures in rats. In an effort to resolve the molecular mechanism behind this effect, we fed young male rats high doses of vitamin A and performed microarray analysis of diaphyseal bone with and without marrow after 1 week, i.e., just before the first fractures appeared. Of the differentially expressed genes in cortical bone, including marrow, 98% were upregulated. In contrast, hypervitaminotic cortical bone without marrow showed reduced expression of 37% of differentially expressed genes. Gene ontology (GO) analysis revealed that only samples containing bone marrow were associated with a GO term, which principally represented extracellular matrix. This is consistent with the histological findings of increased endosteal/marrow osteoblast number. Fourteen genes, including Cyp26b1, which is known to be upregulated by vitamin A, were selected and verified by real-time PCR. In addition, immunohistochemical staining of bone sections confirmed that the bone-specific molecule osteoadherin was upregulated. Further analysis of the major gene-expression changes revealed apparent augmented Wnt signaling in the sample containing bone marrow but reduced Wnt signaling in cortical bone. Moreover, induced expression of hypoxia-associated genes was found only in samples containing bone marrow. Together, these results highlight the importance of compartment-specific analysis of bone and corroborate previous observations of compartment-specific effects of vitamin A, with reduced activity in cortical bone but increased activity in the endosteal/marrow compartment. We specifically identify potential key osteoblast-, Wnt signaling-, and hypoxia-associated genes in the processes leading to spontaneous fractures.

Getting to the Heart of Being the Match: A Qualitative Analysis of Bone Marrow Donor Recruitment and Retention among College Students

ERIC Educational Resources Information Center

Kaster, Elizabeth C.; Rogers, Charles R.; Jeon, Kwon Chan; Rosen, Brittany

2014-01-01

Introduction: For those with certain blood or bone cancers, bone marrow donation can mean the difference between life and death. The National Marrow Donor Program® (NMDP) operates the largest bone marrow registry of potential donors; however, at times when potential matches are identified, many donors opt not to donate. The purpose of this study…

Automated classification of bone marrow cells in microscopic images for diagnosis of leukemia: a comparison of two classification schemes with respect to the segmentation quality

NASA Astrophysics Data System (ADS)

Krappe, Sebastian; Benz, Michaela; Wittenberg, Thomas; Haferlach, Torsten; Münzenmayer, Christian

2015-03-01

The morphological analysis of bone marrow smears is fundamental for the diagnosis of leukemia. Currently, the counting and classification of the different types of bone marrow cells is done manually with the use of bright field microscope. This is a time consuming, partly subjective and tedious process. Furthermore, repeated examinations of a slide yield intra- and inter-observer variances. For this reason an automation of morphological bone marrow analysis is pursued. This analysis comprises several steps: image acquisition and smear detection, cell localization and segmentation, feature extraction and cell classification. The automated classification of bone marrow cells is depending on the automated cell segmentation and the choice of adequate features extracted from different parts of the cell. In this work we focus on the evaluation of support vector machines (SVMs) and random forests (RFs) for the differentiation of bone marrow cells in 16 different classes, including immature and abnormal cell classes. Data sets of different segmentation quality are used to test the two approaches. Automated solutions for the morphological analysis for bone marrow smears could use such a classifier to pre-classify bone marrow cells and thereby shortening the examination duration.

Bone marrow involvement is rare in superficial gastric mucosa-associated lymphoid tissue lymphoma.

PubMed

Park, Jae Yong; Kim, Sang Gyun; Kim, Joo Sung; Jung, Hyun Chae

2016-01-01

The initial staging work-up of gastric mucosa-associated lymphoid tissue (MALT) lymphoma includes bone marrow examination. Since gastric MALT lymphoma is mostly detected in early stages with the national cancer screening programme in Korea, bone marrow is rarely involved. To investigate the incidence of bone marrow involvement in gastric MALT lymphomas and the role of bone marrow examination for an initial staging work-up. Patients diagnosed with gastric MALT lymphoma at Seoul National University Hospital from January 2005 to July 2014 were enrolled. Clinical databases of the patients were retrospectively reviewed. Out of 105 patients, 91 (86.7%) were classified as stage IE1. Among these patients, 78 patients with Helicobacter pylori infection underwent eradication therapy, and complete remission was achieved in 74 cases (94.9%). Twelve out of 13 patients (92.3%) without H. pylori infection underwent radiotherapy or surgery and all achieved complete remission. Bone marrow involvement was proven in only one patient (1.0%). Bone marrow involvement was rare in patients with only superficial gastric MALT lymphoma without extragastric invasion. Further studies are warranted to identify the risk factors of bone marrow involvement in gastric MALT lymphoma. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Reduced immune responses in chimeric mice engrafted with bone marrow cells from mice with airways inflammation.

PubMed

Scott, Naomi M; Ng, Royce L X; McGonigle, Terence A; Gorman, Shelley; Hart, Prue H

2015-11-01

During respiratory inflammation, it is generally assumed that dendritic cells differentiating from the bone marrow are immunogenic rather than immunoregulatory. Using chimeric mice, the outcomes of airways inflammation on bone marrow progenitor cells were studied. Immune responses were analyzed in chimeric mice engrafted for >16 weeks with bone marrow cells from mice with experimental allergic airways disease (EAAD). Responses to sensitization and challenge with the allergen causing inflammation in the bone marrow-donor mice were significantly reduced in the chimeric mice engrafted with bone marrow cells from mice with EAAD (EAAD-chimeric). Responses to intranasal LPS and topical fluorescein isothiocyanate (non-specific challenges) were significantly attenuated. Fewer activated dendritic cells from the airways and skin of the EAAD-chimeric mice could be tracked to the draining lymph nodes, and may contribute to the significantly reduced antigen/chemical-induced hypertrophy in the draining nodes, and the reduced immune responses to sensitizing allergens. Dendritic cells differentiating in vitro from the bone marrow of >16 weeks reconstituted EAAD-chimeric mice retained an ability to poorly prime immune responses when transferred into naïve mice. Dendritic cells developing from bone marrow progenitors during airways inflammation are altered such that daughter cells have reduced antigen priming capabilities.

Nucleomedical studies on the reticuloendothelial system in bone marrow. 5. Reticuloendothelial uptake of intravenous hemolysates: a simulation of the intravascular hemolytic sequelae

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okuyama, S.; Ito, Y.; Sato, T.

1972-11-01

In exploration of prospects and possible limitations of /sup 113m/ Inchondroitin sulfate colloid (/sup 113m/In-ChS) as an improved bone marrow seeker developed in our laboratory, saponin was observed to induce extreme reticuloendothelial (RE) hypofunction. Possible RE blockade from saponin-induced hemolysis was suspected beside its toxic and suppressive effects on marrow RE activity. RE function was assessed with /sup 113m/In-ChS at various intervals after intravenous hemolysates in the rabbit by organ radioassay technic. The hemolysate resulted in immediate RE hypofunction, especially in the spleen and liver. Marrow RE suppression was visualized by marrow scanning. The hypofunction may result from phagocytosis ofmore » the ghost cells and homoglobin by cells of the RE organs; the saponin-induced marrow RE hypofunction, however, is much severer than this. The studies indicate that /sup 113m/In-ChS is especially suitable for assessment of the marrow RE activity and its imaging. (auth)« less

Role of hepatocyte growth factor in the development of dendritic cells from CD34+ bone marrow cells.

PubMed

Ovali, E; Ratip, S; Kibaroglu, A; Tekelioglu, Y; Cetiner, M; Karti, S; Aydin, F; Bayik, M; Akoglu, T

2000-05-01

Hepatocyte growth factor (HGF) is known to augment the effects of stem cell factor, interleukin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoetin, and granulocyte colony-stimulating factor, all of which are involved in hematopoiesis. HGF is also known to have a role in immune responses. The aim of this study was to investigate whether HGF is involved in the development of dendritic cells (DC) from CD34+ bone marrow cells. CD34+ cells obtained from three healthy donors were incubated in various combinations of HGF, GM-CSF, and tumor necrosis factor (TNF) for 12 days. Developing cell populations were analyzed for surface markers, morphology and functional capacities by flow cytometry, light microscopy and mixed lymphocyte reaction, respectively. Incubation with HGF alone generated greater number of dendritic cells from CD34+ bone marrow cells than incubation with GM-CSF, or a combination of GM-CSF with TNF. HGF was also found to potentiate the effect of GM-CSF on DC and monocyte development. The effects of HGF were inhibited by the concurrent use of TNF. HGF appears to be a significant factor in the development of dendritic cells from CD34+ bone marrow cells.

Therapeutic effect comparison of hepatocyte-like cells and bone marrow mesenchymal stem cells in acute liver failure of rats.

PubMed

Li, Dongliang; Fan, Jingjing; He, Xiuhua; Zhang, Xia; Zhang, Zhiqiang; Zeng, Zhiyu; Ruan, Mei; Cai, Lirong

2015-01-01

To evaluate the therapeutic efficacy of rat bone marrow mesenchymal stem cells (BMSCs) induced into hepatocyte-like cells and of un-induced BMSCs in acute liver failure rats. BMSCs in highly homogenous passage 3 were cultured using the whole bone marrow adherent culture method. Hepatic-related characters were confirmed with morphology, RT-PCR analysis, glycogen staining and albumin (ALB) immunofluorescence assay. Carbon tetrachloride (CCl4) was injected intraperitoneally to establish an acute rat liver failure model. Hepatocyte-like cells or un-induced BMSCs were respectively injected into the models to examine rats' appearance, liver function assay and liver tissue pathology. Hepatocyte-like morphology, higher expression of cytokeratin 18 (CK18) mRNA and ALB protein, and glycogen accumulation were confirmed in the induced BMSCs. The transplanted DAPI-labeled BMSCs were localized in the liver tissue 3-14 days after transplantation. The levels of liver function indicators (AST, ALT, ALP, and TBIL) from transplanted rats were significant decreased and pathology was improved, indicating the recovery of liver function. However, the differences were statistically insignificant. Both hepatocyte-like cells and un-induced BMSCs had a similarly positively therapeutic efficacy on liver regeneration in rat liver failure model.

NEW APPLICATIONS OF ADAPTOGENS TO REDUCE RADIATION SIDE EFFECTS.

PubMed

Alekseeva, S N; Antipina, U D; Arzhakova, L I; Protodyakonov, S V

2015-01-01

One of the live medical issues today is to find medication to prevent adverse effects of ionizing radiation on the immune and hematopoietic systems. In Yakutia where in most of its regions the overall environmental situation is getting worse due to the development of natural deposits including radioactive deposits, this problem remains vital. The purpose of this work is to study radioprotective properties of adaptogens in the case of the hematopoietic system under irradiation. The studies were conducted on certain groups of hybrid mice. We used the methods of radiation exposure by a radiological apparatus RUM-25 on hybrid mice followed by studying the cellularity of bone marrow, spleen and thymus. The functional activity of all compartments of early hematopoiesis (bone marrow hematopoiesis) was identified by the exogenous colony forming method. The study found that the extracts of reindeer and moose antlers have a stimulating effect on the functional activity of the hematopoietic precursors in response to radiation. The study medication stimulates regeneration processes in the thymus and bone marrow after irradiation. Further, the adaptogens stimulatory effect on CFU functional activity was identified. The most pronounced effect has the extracts of reindeer antlers "Epsorin".

Relative importance of the bone marrow and spleen in the production and dissemination of B lymphocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosse, C.; Cole, S.B.; Appleton, C.

1978-04-01

The relative importance of the bone marrow and spleen in the production of B lymphocytes was investigated in guinea pigs by the combined use of (/sup 3/H)TdR radioautography and fluorescent microscopy after the staining of B cells by FITC-F (ab')/sub 2/-goat-anti-guinea pig Ig. Large and small lymphoid cells possess sIg in the marrow and spleen but B cell turnover in the marrow exceeds that in the spleen. That newly generated bone marrow B cells are not derived from an extramyeloid bursa equivalent was demonstrated by the absence of (/sup 3/H)TdR labeled B cells in tibial marrow 72 hr after (/supmore » 3/H)TdR was administered systemically, while the circulation to the hind limbs was occluded. Pulse and chase studies with (/sup 3/H)TdR showed that large marrow B cells are derived from sIg-negative, proliferating precursors resident in the bone marrow and not from the enlargement of activated small B lymphocytes. The acquisition of (/sup 3/H)TdR by splenic B cells lagged behind that observed in the marrow. Three days after topical labeling of tibial and femoral bone marrow with (/sup 3/H)TdR, a substantial proportion of splenic B cells were replaced by cells that had seeded there from the labeled marrow. The studies unequivocally identify the bone marrow as the organ of primary importance in B cell generation, and indicate that in the guinea pig rapidly renewed B lymphocytes of the spleen are replaced by lymphocytes recently generated in bone marrow. The rate of replacement of B lymphocytes in the lymph node by cells newly generated in the bone marrow takes place at a slower tempo than in the spleen.« less

Elevated expression of CX3C chemokine receptor 1 mediates recruitment of T cells into bone marrow of patients with acquired aplastic anaemia.

PubMed

Ren, J; Hou, X Y; Ma, S H; Zhang, F K; Zhen, J H; Sun, L; Sun, Y X; Hao, Y L; Cheng, Y F; Hou, M; Xu, C G; Zhang, M H; Peng, J

2014-11-01

Acquired aplastic anaemia (AA) is a T-cell-mediated, organ-specific autoimmune disease characterized by haematopoietic stem cell destruction in the bone marrow. The exact molecular mechanism of T-cell trafficking into the bone marrow is unclear in AA. Very late activation antigen-4 (VLA-4) and CX3C chemokine receptor 1 (CX3CR1) play active roles in many autoimmune diseases. Therefore, we investigated whether VLA-4 and CX3CR1 also contribute to T-cell migration into the bone marrow in acquired AA. Expression levels of CX3CR1 and VLA-4 and their ligands [fractalkine (CX3CL1) and vascular cell adhesion molecule-1 (VCAM-1)] were examined in 63 patients with AA and 21 healthy control subjects. T-cell chemotaxis and adhesion were analysed in 17 patients with severe AA. We also prospectively evaluated the expression pattern of CX3CR1 during treatment with antithymocyte globulin plus cyclosporine in 11 patients with severe AA. The proportion of peripheral and bone marrow CD4(+) and CD8(+) T cells expressing CX3CR1 and the level of CX3CL1 was increased in patients with AA. However, there was no significant difference in VLA-4 expression or VCAM-1 levels. Functional studies demonstrated that chemotaxis towards autologous bone marrow plasma or soluble CX3CL1 was significantly higher in T cells from AA patients and could be blocked by CX3CR1 inhibitors. CX3CR1-mediated T-cell adhesion was also upregulated in these patients. The expression of CX3CR1 was associated with the efficacy of immunosuppressive therapy. The present findings demonstrate that CX3CR1 plays a pivotal role in recruitment of T cells into the bone marrow in acquired AA and is a potential therapeutic target for treatment of this disorder. © 2014 The Association for the Publication of the Journal of Internal Medicine.

In vitro osteoblastic differentiation of human bone marrow cells in the presence of metal ions.

PubMed

Morais, S; Dias, N; Sousa, J P; Fernandes, M H; Carvalho, G S

1999-02-01

For periods up to 21 days human bone marrow was cultured in control conditions that favor the proliferation and differentiation of osteoblastic cells. The effect of AISI 316L corrosion products and the corresponding major separate metal ions (Fe, Cr, and Ni) were studied in three different phases of the culture period in order to investigate the effects of metal ions in cell populations representative of osteoblastic cells in different stages of differentiation. Toxicity consequences of the presence of metal ions in bone marrow cultures were evaluated by biochemical parameters (enzymatic reduction of MTT, alkaline phosphatase activity, and total protein content), histochemical assays (identification of ALP-positive cells and Ca and phosphates deposits), and observation of the cultures by light and scanning electron microscopy. Culture media were analyzed for total and ionized Ca and P and also for metal ions (Fe, Cr, and Ni). The presence of AISI 316L corrosion products and Ni salt in bone marrow cultures during the first and second weeks of culture significantly disturbs the normal behavior of these cultures, interfering in the lag phase and exponential phase of cell growth and ALP expression. However, the presence of these species during the third week of culture, when expression of osteoblastic functions occurs (mineralization process), did not result in any detectable effect. Fe salt also disturbs the behavior of bone marrow cell cultures when present during the lag phase and proliferation phase, and a somewhat compromised response between the normal pattern (control cultures) and intense inhibition (AISI 316L corrosion products and Ni salt-added cultures) was observed. Fe did not affect the progression of the mineralization phase. Osteogenic cultures exposed to Cr salt (Cr3+) presented a pattern similar to the controls, indicating that this element does not interfere, in the concentration studied, in the osteoblastic differentiation of bone marrow cells. Quantification of metal ions in the culture media showed that Cr (originated from AISI 316L corrosion products but from not Cr3+ salt) and Ni (originated from AISI 316L corrosion products and Ni salt) appear to be retained by the bone marrow cultures. Copyright 1999 John Wiley & Sons, Inc.

Enhancement of the repair of dog alveolar cleft by an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture.

PubMed

Yuanzheng, Chen; Yan, Gao; Ting, Li; Yanjie, Fu; Peng, Wu; Nan, Bai

2015-05-01

Autologous bone graft has been regarded as the criterion standard for the repair of alveolar cleft. However, the most prominent issue in alveolar cleft treatment is the high absorption rate of the bone graft. The authors' objective was to investigate the effects of an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture on the repair of dog alveolar cleft. Twenty beagle dogs with unilateral alveolar clefts created by surgery were divided randomly into four groups: group A underwent repair with an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture; group B underwent repair with autologous iliac bone and bone marrow-derived mesenchymal stem cells; group C underwent repair with autologous iliac bone and platelet-rich fibrin; and group D underwent repair with autologous iliac bone as the control. One day and 6 months after transplantation, the transplant volumes and bone mineral density were assessed by quantitative computed tomography. All of the transplants were harvested for hematoxylin and eosin staining 6 months later. Bone marrow-derived mesenchymal stem cells and platelet-rich fibrin transplants formed the greatest amounts of new bone among the four groups. The new bone formed an extensive union with the underlying maxilla in groups A, B, and C. Transplants with the bone marrow-derived mesenchymal stem cells, platelet-rich fibrin, and their mixture retained the majority of their initial volume, whereas the transplants in the control group showed the highest absorption rate. Bone mineral density of transplants with the bone marrow-derived mesenchymal stem cells, platelet-rich fibrin, and their mixture 6 months later was significantly higher than in the control group (p < 0.05), and was the highest in bone marrow-derived mesenchymal stem cells and platelet-rich fibrin mixed transplants. Hematoxylin and eosin staining showed that the structure of new bones formed the best in group A. Both bone marrow-derived mesenchymal stem cells and platelet-rich fibrin are capable of improving the repair of dog alveolar cleft, and the mixture of them is more potent than each one of them used singly for enhancing new bone regeneration.

Evaluation of Bone Marrow Processing Protocol for Therapeutic Applications via Culture and Characterization of Mesenchymal Stem Cells.

PubMed

Verma, Poonam; Bansal, Himanshu; Agrawal, Anupama; Leon, Jerry; Sundell, I Birgitta; Koka, Prasad S

Human mesenchymal stem cells from bone marrow (hMSCs) have broad therapeutic potential. These cells can be are readily isolated from bone marrow by their property to adhere to tissue culture treated culture wares. However, the proliferation rates and other properties of the cells gradually change during expansion. This study aims to validate the protocol of isolation and differentiation of hMSCs from bone marrow for therapeutic applications. Sixty ml of bone marrow was extracted from 5 patients and MSCs were isolated. These were characterized by Flow Cytometry, CFU assay and were differentiated into bone, fat cells and neurocytes. The cells were having healthy morphology. These were positive for the markers CD105, CD90 and CD73 and negative for CD45, CD34 and HLA-DR. The cells could differentiate into fat, bone and neural cells. MSCs from the bone marrow were isolated and differentiated. These cells were morphologically healthy and passed CFU assay. The cells exhibited differentiation potential into bone, fat and neural tissue. These cells can be used in therapeutic applications.

The C-terminal fragment of parathyroid hormone-related peptide promotes bone formation in diabetic mice with low-turnover osteopaenia

PubMed Central

Lozano, D; Fernández-de-Castro, L; Portal-Núñez, S; López-Herradón, A; Dapía, S; Gómez-Barrena, E; Esbrit, P

2011-01-01

BACKGROUND AND PURPOSE Current data suggest that parathyroid hormone (PTH)-related peptide (PTHrP) domains other than the N-terminal PTH-like domain contribute to its role as an endogenous bone anabolic factor. PTHrP-107-139 inhibits bone resorption, a fact which has precluded an unequivocal demonstration of its possible anabolic action in vivo. We thus sought to characterize the osteogenic effects of this peptide using a mouse model of diabetic low-turnover osteopaenia. EXPERIMENTAL APPROACH PTHrP-107-139 was administered to streptozotocin-induced diabetic mice, with or without bone marrow ablation, for 13 days. Osteopaenia was confirmed by dual-energy X-ray absorptiometry and microcomputed tomography analysis. Histological analysis was performed on paraffin-embedded bone tissue sections by haematoxylin/eosin and Masson's staining, and tartrate-resistent acid phosphatase immunohistochemistry. Mouse bone marrow stromal cells and osteoblastic MC3T3-E1 cells were cultured in normal and/or high glucose (HG) medium. Osteogenic and adipogenic markers were assessed by real-time PCR, and PTHrP and the PTH1 receptor protein expression by Western blot analysis. KEY RESULTS PTHrP-107-139 reversed the alterations in bone structure and osteoblast function, and also promoted bone healing after marrow ablation without affecting the number of osteoclast-like cells in diabetic mice. This peptide also reversed the high-glucose-induced changes in osteogenic differentiation in both bone marrow stromal cells and the more differentiated MC3T3-E1 cells. CONCLUSIONS AND IMPLICATIONS These findings demonstrate that PTHrP-107-139 promotes bone formation in diabetic mice. This mouse model and in vitro cell cultures allowed us to identify various anabolic effects of this peptide in this scenario. PMID:21175568

Improved bone marrow stromal cell adhesion on micropatterned titanium surfaces.

PubMed

Iskandar, Maria E; Cipriano, Aaron F; Lock, Jaclyn; Gott, Shannon C; Rao, Masaru P; Liu, Huinan

2012-01-01

Implant longevity is desired for all bone replacements and fixatives. Titanium (Ti) implants fail due to lack of juxtaposed bone formation, resulting in implant loosening. Implant surface modifications have shown to affect the interactions between the implant and bone. In clinical applications, it is crucial to improve osseointegration and implant fixation at the implant and bone interface. Moreover, bone marrow derived cells play a significant role for implant and tissue integration. Therefore, the objective of this study is to investigate how surface micropatterning on Ti influences its interactions with bone marrow derived cells containing mesenchymal and hematopoietic stem cells. Bone marrow derived mesenchymal stem cells (BMSC) have the capability of differentiating into osteoblasts that contribute to bone growth, and therefore implant/bone integration. Hematopoietic stem cell derivatives are precursor cells that contribute to inflammatory response. By using all three cells naturally contained within bone marrow, we mimic the physiological environment to which an implant is exposed. Primary rat bone marrow derived cells were seeded onto Ti with surfaces composed of arrays of grooves of equal width and spacing ranging from 0.5 to 50 µm, fabricated using a novel plasma-based dry etching technique. Results demonstrated enhanced total cell adhesion on smaller micrometer-scale Ti patterns compared with larger micrometer-scale Ti patterns, after 24-hr culture. Further studies are needed to determine bone marrow derived cell proliferation and osteogenic differentiation potential on micropatterned Ti, and eventually nanopatterned Ti.

Bone-marrow transplant - series (image)

MedlinePlus

Bone-marrow transplants are performed for: deficiencies in red blood cells (aplastic anemia) and white blood cells (leukemia or ... Bone-marrow transplants prolong the life of patients who might otherwise die. As with all major organ transplants, however, ...

[Effect of intravenous treatment with OK-432 on the bone marrow in patients with lung cancer].

PubMed

Fujii, M; Ishikawa, M; Toki, H

1984-03-01

We studied effects of OK-432 on the bone marrow and peripheral blood cells of lung cancer patients. The nuclear cell count of bone marrow increased in 5 to 7 patients upon intravenous treatment with OK-432 compared with 3 of 6 patients who were intramuscularly treated with OK-432. Serial neutrophil counts of bone marrow increased in all 7 patients treated intravenously compared with 3 of 6 patients treated intramuscularly. The mean nuclear cell count or the serial neutrophil count of bone marrow in intravenously treated patients was significantly higher than the pretreatment values (p less than 0.001). In the peripheral blood picture, the difference in white blood cells or neutrophils before and after intravenous treatment was also statistically significant (p less than 0.01). There was no change in the erythrocytic series count of bone marrow and the hemoglobin count. Our results support the superiority of intravenous OK-432 treatment over intramuscular treatment in the growth-accelerating effect on bone marrow cells, especially regarding the neutrophil series.

Bone Marrow Aspirate Concentrate-Enhanced Marrow Stimulation of Chondral Defects

PubMed Central

Eichler, Hermann; Orth, Patrick

2017-01-01

Mesenchymal stem cells (MSCs) from bone marrow play a critical role in osteochondral repair. A bone marrow clot forms within the cartilage defect either as a result of marrow stimulation or during the course of the spontaneous repair of osteochondral defects. Mobilized pluripotent MSCs from the subchondral bone migrate into the defect filled with the clot, differentiate into chondrocytes and osteoblasts, and form a repair tissue over time. The additional application of a bone marrow aspirate (BMA) to the procedure of marrow stimulation is thought to enhance cartilage repair as it may provide both an additional cell population capable of chondrogenesis and a source of growth factors stimulating cartilage repair. Moreover, the BMA clot provides a three-dimensional environment, possibly further supporting chondrogenesis and protecting the subchondral bone from structural alterations. The purpose of this review is to bridge the gap in our understanding between the basic science knowledge on MSCs and BMA and the clinical and technical aspects of marrow stimulation-based cartilage repair by examining available data on the role and mechanisms of MSCs and BMA in osteochondral repair. Implications of findings from both translational and clinical studies using BMA concentrate-enhanced marrow stimulation are discussed. PMID:28607559

Reciprocal Relation between Marrow Adiposity and the Amount of Bone in the Axial and Appendicular Skeleton of Young Adults

PubMed Central

Di Iorgi, Natascia; Rosol, Michael; Mittelman, Steven D.; Gilsanz, Vicente

2008-01-01

Background: Studies in the elderly suggest a reciprocal relation between increased marrow adiposity and bone loss, supporting basic research data indicating that osteoblasts and adipocytes share a common progenitor cell. However, whether this relation represents a preferential differentiation of stromal cells from osteoblasts to adipocytes or whether a passive accumulation of fat as bone is lost and marrow space increases with aging is unknown. To address this question and avoid the confounding effect of bone loss, we examined teenagers and young adults. Methods: Using computed tomography, we obtained measurements of bone density and cross-sectional area of the lumbar vertebral bodies and cortical bone area, cross-sectional area, marrow canal area, and fat density in the marrow of the femurs in 255 sexually mature subjects (126 females, 129 males; 15–24.9 yr of age). Additionally, values for total body fat were obtained with dual-energy x-ray absorptiometry. Results: Regardless of gender, reciprocal relations were found between fat density and measures of vertebral bone density and femoral cortical bone area (r = 0.19–0.39; all P values ≤ .03). In contrast, there was no relation between marrow canal area and cortical bone area in the femurs, neither between fat density and the cross-sectional dimensions of the bones. We also found no relation between anthropometric or dual-energy x-ray absorptiometry fat values and measures for marrow fat density. Conclusions: Our results indicate an inverse relation between bone marrow adiposity and the amount of bone in the axial and appendicular skeleton and support the notion of a common progenitor cell capable of mutually exclusive differentiation into the cell lineages responsible for bone and fat formation. PMID:18381577

Pulmonary Embolization of Fat and Bone Marrow in Cynomolgus Macaques (Macaca fascicularis)

PubMed Central

Fong, Derek L.; Murnane, Robert D.; Hotchkiss, Charlotte E.; Green, Damian J.; Hukkanen, Renee R.

2011-01-01

Fat embolization (FE), the introduction of bone marrow elements into circulation, is a known complication of bone fractures. Although FE has been described in other animal models, this study represents the first reported cases of FE and bone marrow embolism in nonhuman primates. Histopathologic findings from cynomolgus macaques (Macaca fascicularis) indicated that in all 5 cases, fat and bone marrow embolization occurred subsequent to multiple bone marrow biopsies. In the most severe case, extensive embolization was associated pulmonary damage consistent with acute respiratory distress syndrome. Fat embolism syndrome (FES) is an infrequent clinical outcome of FE and is triggered by systemic biochemical and mechanical responses to fat in circulation. Although clinical criteria diagnostic of FES were not investigated at the time of death, this severe case may represent the fulminant form of FES, which occurs within 12 h after trauma. Bone marrow biopsy as an etiology of FES has been reported only once in humans. In addition, the association of embolization with bone marrow biopsies suggests that nonhuman primates may be a useful animal model of FE. FE and FES represent important research confounders and FES should be considered as a differential diagnosis for clinical complications subsequent to skeletal trauma. PMID:21819686

Pulmonary embolization of fat and bone marrow in cynomolgus Macaques (Macaca fascicularis).

PubMed

Fong, Derek L; Murnane, Robert D; Hotchkiss, Charlotte E; Green, Damian J; Hukkanen, Renee R

2011-02-01

Fat embolization (FE), the introduction of bone marrow elements into circulation, is a known complication of bone fractures. Although FE has been described in other animal models, this study represents the first reported cases of FE and bone marrow embolism in nonhuman primates. Histopathologic findings from cynomolgus macaques (Macaca fascicularis) indicated that in all 5 cases, fat and bone marrow embolization occurred subsequent to multiple bone marrow biopsies. In the most severe case, extensive embolization was associated pulmonary damage consistent with acute respiratory distress syndrome. Fat embolism syndrome (FES) is an infrequent clinical outcome of FE and is triggered by systemic biochemical and mechanical responses to fat in circulation. Although clinical criteria diagnostic of FES were not investigated at the time of death, this severe case may represent the fulminant form of FES, which occurs within 12 h after trauma. Bone marrow biopsy as an etiology of FES has been reported only once in humans. In addition, the association of embolization with bone marrow biopsies suggests that nonhuman primates may be a useful animal model of FE. FE and FES represent important research confounders and FES should be considered as a differential diagnosis for clinical complications subsequent to skeletal trauma.

Skeletal (stromal) stem cells: an update on intracellular signaling pathways controlling osteoblast differentiation.

PubMed

Abdallah, Basem M; Jafari, Abbas; Zaher, Walid; Qiu, Weimin; Kassem, Moustapha

2015-01-01

Skeletal (marrow stromal) stem cells (BMSCs) are a group of multipotent cells that reside in the bone marrow stroma and can differentiate into osteoblasts, chondrocytes and adipocytes. Studying signaling pathways that regulate BMSC differentiation into osteoblastic cells is a strategy for identifying druggable targets for enhancing bone formation. This review will discuss the functions and the molecular mechanisms of action on osteoblast differentiation and bone formation; of a number of recently identified regulatory molecules: the non-canonical Notch signaling molecule Delta-like 1/preadipocyte factor 1 (Dlk1/Pref-1), the Wnt co-receptor Lrp5 and intracellular kinases. This article is part of a Special Issue entitled: Stem Cells and Bone. Copyright © 2014 Elsevier Inc. All rights reserved.

Percutaneous osteoplasty with a bone marrow nail for fractures of long bones: experimental study.

PubMed

Nakata, Kouhei; Kawai, Nobuyuki; Sato, Morio; Cao, Guang; Sahara, Shinya; Tanihata, Hirohiko; Takasaka, Isao; Minamiguchi, Hiroyuki; Nakai, Tomoki

2010-09-01

To develop percutaneous osteoplasty with the use of a bone marrow nail for fixation of long-bone fractures, and to evaluate its feasibility and safety in vivo and in vitro. Six long bones in three healthy swine were used in the in vivo study. Acrylic cement was injected through an 11-gauge bone biopsy needle and a catheter into a covered metallic stent placed within the long bone, creating a bone marrow nail. In the in vitro study, we determined the bending, tug, and compression strengths of the acrylic cement nails 9 cm long and 8 mm in diameter (N = 10). The bending strength of the artificially fractured bones (N = 6) restored with the bone marrow nail and cement augmentation was then compared with that of normal long bones (N = 6). Percutaneous osteoplasty with a bone marrow nail was successfully achieved within 1 hour for all swine. After osteoplasty, all swine regained the ability to run until they were euthanized. Blood tests and pathologic findings showed no adverse effects. The mean bending, tug, and compression strengths of the nail were 91.4 N/mm(2) (range, 75.0-114.1 N/mm(2)), 20.9 N/mm(2) (range, 6.6-30.4 N/mm(2)), and 103.0 N/mm(2) (range, 96.3-110.0 N/mm(2)), respectively. The bending strength ratio of artificially fractured bones restored with bone marrow nail and cement augmentation to normal long bone was 0.32. Percutaneous osteoplasty with use of a bone marrow nail and cement augmentation appears to have potential in treating fractures of non-weight-bearing long bones. Copyright 2010 SIR. Published by Elsevier Inc. All rights reserved.

The Analysis of the Adverse Reaction of Traditional Chinese Medicine Tumor Bone Marrow Suppression

NASA Astrophysics Data System (ADS)

Wei, Zhenzhen; Fang, Xiaoyan; Miao, Mingsan

2018-01-01

With the rapid increase of cancer patients, chemotherapy is the main method for the clinical treatment of cancer, but also in the treatment of the adverse reactions--bone marrow suppression is often a serious infection caused by patients after chemotherapy and the important cause of mortality. Chinese medicine has obvious advantages in the prevention and treatment of bone marrow depression after chemotherapy. According to tumor bone marrow suppression after chemotherapy of etiology and pathogenesis of traditional Chinese medicine and China national knowledge internet nearly 10 years of traditional Chinese medicine in the prevention and control of the status of clinical and laboratory research of tumor bone marrow suppression, the author analyzed and summarized its characteristics, so as to provide the basis for treating bone marrow suppression of drug research and development, and promote small adverse reactions of the development and utilization of natural medicine and its preparations.

High-fidelity organic preservation of bone marrow in ca. 10 Ma amphibians

NASA Astrophysics Data System (ADS)

McNamara, Maria E.; Orr, Patrick J.; Kearns, Stuart L.; Alcalá, Luis; Anadón, Pere; Peñalver-Mollá, Enrique

2006-08-01

Bone marrow in ca. 10 Ma frogs and salamanders from the Miocene of Libros, Spain, represents the first fossilized example of this extremely decay-prone tissue. The bone marrow, preserved in three dimensions as an organic residue, retains the original texture and red and yellow color of hematopoietic and fatty marrow, respectively; moldic osteoclasts and vascular structures are also present. We attribute exceptional preservation of the fossilized bone marrow to cryptic preservation: the bones of the amphibians formed protective microenvironments, and inhibited microbial infiltration. Specimens in which bone marrow is preserved vary in their completeness and articulation and in the extent to which the body outline is preserved as a thin film of organically preserved bacteria. Cryptic preservation of these labile tissues is thus to a large extent independent of, and cannot be predicted by, the taphonomic history of the remainder of the specimen.

Stem cells rejuvenate radiation-impaired vasculogenesis in murine distraction osteogenesis.

PubMed

Deshpande, Sagar S; Gallagher, Kathleen K; Donneys, Alexis; Nelson, Noah S; Guys, Nicholas P; Felice, Peter A; Page, Erin E; Sun, Hongli; Krebsbach, Paul H; Buchman, Steven R

2015-03-01

Radiotherapy is known to be detrimental to bone and soft-tissue repair. Bone marrow stromal cells have been shown to enhance bone regeneration during distraction osteogenesis following radiation therapy. The authors posit that transplanted bone marrow stromal cells will significantly augment the mandibular vascularity devastated by radiation therapy. Nineteen male Lewis rats were split randomly into three groups: distraction osteogenesis only (n = 5), radiation therapy plus distraction osteogenesis (n = 7), and radiation therapy plus distraction osteogenesis with intraoperative placement of 2 million bone marrow stromal cells (n = 7). A mandibular osteotomy was performed, and an external fixator device was installed. From postoperative days 4 through 12, rats underwent a gradual 5.1-mm distraction followed by a 28-day consolidation period. On postoperative day 40, Microfil was perfused into the vasculature and imaging commenced. Vascular radiomorphometric values were calculated for regions of interest. An analysis of variance with post hoc Tukey or Games-Howell tests was used, dependent on data homogeneity. Stereologic analysis indicated significant remediation in vasculature in the bone marrow stromal cell group compared with the radiation therapy/distraction osteogenesis group. Each of five metrics idicated significant improvements from radiation therapy/distraction osteogenesis to the bone marrow stromal cell group, with no difference between the bone marrow stromal cell group and the distraction osteogenesis group. Bone marrow stromal cells used together with distraction osteogenesis can rejuvenate radiation-impaired vasculogenesis in the mandible, reversing radiation therapy-induced isotropy and creating a robust vascular network. Bone marrow stromal cells may offer clinicians an alternative reconstructive modality that could improve the lifestyle of patients with hypovascular bone.

Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin.

PubMed

Seo, Aaron; Ben-Harosh, Miri; Sirin, Mehtap; Stein, Jerry; Dgany, Orly; Kaplelushnik, Joseph; Hoenig, Manfred; Pannicke, Ulrich; Lorenz, Myriam; Schwarz, Klaus; Stockklausner, Clemens; Walsh, Tom; Gulsuner, Suleyman; Lee, Ming K; Sendamarai, Anoop; Sanchez-Bonilla, Marilyn; King, Mary-Claire; Cario, Holger; Kulozik, Andreas E; Debatin, Klaus-Michael; Schulz, Ansgar; Tamary, Hannah; Shimamura, Akiko

2017-08-17

We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin ( THPO ): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family. Both mutations result in a lack of THPO in the patients' serum. For the 2 surviving patients, improvement in trilineage hematopoiesis was achieved following treatment with a THPO receptor agonist. These studies demonstrate that biallelic loss-of-function mutations in THPO cause BMF, which is unresponsive to transplant due to a hematopoietic cell-extrinsic mechanism. These studies provide further support for the critical role of the MPL-THPO pathway in hematopoiesis and highlight the importance of accurate genetic diagnosis to inform treatment decisions for BMF. © 2017 by The American Society of Hematology.

ROS-mediated iron overload injures the hematopoiesis of bone marrow by damaging hematopoietic stem/progenitor cells in mice

PubMed Central

Chai, Xiao; Li, Deguan; Cao, Xiaoli; Zhang, Yuchen; Mu, Juan; Lu, Wenyi; Xiao, Xia; Li, Chengcheng; Meng, Juanxia; Chen, Jie; Li, Qing; Wang, Jishi; Meng, Aimin; Zhao, Mingfeng

2015-01-01

Iron overload, caused by hereditary hemochromatosis or repeated blood transfusions in some diseases, such as beta thalassemia, bone marrow failure and myelodysplastic syndrome, can significantly induce injured bone marrow (BM) function as well as parenchyma organ dysfunctions. However, the effect of iron overload and its mechanism remain elusive. In this study, we investigated the effects of iron overload on the hematopoietic stem and progenitor cells (HSPCs) from a mouse model. Our results showed that iron overload markedly decreased the ratio and clonogenic function of murine HSPCs by the elevation of reactive oxygen species (ROS). This finding is supported by the results of NAC or DFX treatment, which reduced ROS level by inhibiting NOX4 and p38MAPK and improved the long-term and multi-lineage engrafment of iron overload HSCs after transplantation. Therefore, all of these data demonstrate that iron overload injures the hematopoiesis of BM by enhancing ROS through NOX4 and p38MAPK. This will be helpful for the treatment of iron overload in patients with hematopoietic dysfunction. PMID:25970748

Hemopoietic progenitor cell function after HLA-identical sibling bone marrow transplantation: influence of chronic graft-versus-host disease.

PubMed

Atkinson, K; Norrie, S; Chan, P; Zehnwirth, B; Downs, K; Biggs, J

1986-05-01

We examined hemopoietic reconstitution during the first 12 months post-transplant in 31 patients given high-dose cyclophosphamide, total body irradiation and an HLA-identical sibling marrow transplant for hematological malignancy. Unexpectedly, we found marrow CFU-gm and marrow CFU-e cells to be denser than normal throughout the first year post-transplant. While functionally adequate neutrophil and platelet counts were achieved in the first six weeks post-transplant, there were defects in hemopoietic progenitor cell function during the first year post-transplant. Although we could detect no influence from acute graft-versus-host disease (GVHD), chronic GVHD adversely affected the growth of both myeloid and erythroid blood progenitor cells.

Question of bone marrow stromal fibroblast traffic

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maloney, M.A.; Lamela, R.A.; Patt, H.M.

Bone marrow stromal fibroblasts (CFU-F) normally do not exchange bone marrow sites in vivo. Restitution of the CFU-F after radiation damage is primarily recovery by the local fibroblasts from potentially lethal damage. Migration of stromal fibroblasts from shielded sites to an irradiated site makes a minimal contribution, if any, to CFU-F recovery. Determination of the relative contribution of donor stromal cells in bone marrow transplants by karyotyping the proliferating bone marrow stromal cells in vitro may not reflect the relative distribution of fibroblasts in the marrow. If there is residual damage to the host stromal fibroblasts from treatment before transplantation,more » these cells may not be able to proliferate in vitro. Therefore, an occasional transplanted fibroblast may contribute most of the metaphase figures scored for karyotype.« less

Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion

PubMed Central

Carbonaro, Denise A.; Jin, Xiangyang; Cotoi, Daniel; Mi, Tiejuan; Yu, Xiao-Jin; Skelton, Dianne C.; Dorey, Frederick; Kellems, Rodney E.; Blackburn, Michael R.

2008-01-01

Adenosine deaminase (ADA)–deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose–dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy. PMID:18356486

Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion.

PubMed

Carbonaro, Denise A; Jin, Xiangyang; Cotoi, Daniel; Mi, Tiejuan; Yu, Xiao-Jin; Skelton, Dianne C; Dorey, Frederick; Kellems, Rodney E; Blackburn, Michael R; Kohn, Donald B

2008-06-15

Adenosine deaminase (ADA)-deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose-dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy.

Histological features of bone marrow in paediatric patients during the asymptomatic phase of early-stage Black African sickle cell anaemia.

PubMed

Mauriello, Alessandro; Giacobbi, Erica; Saggini, Andrea; Isgrò, Antonella; Facchetti, Simone; Anemona, Lucia

2017-04-01

Bone marrow histological features of sickle cell anaemia (SCA) patients during early stages and in the asymptomatic phase of the disease appear an interesting area of study, representing early-stage consequences of SCA with a close relation to its pathophysiology. Unfortunately, this field of research has never been specifically addressed before. Bone marrow biopsies from 26 consecutive Black African SCA patients (M:F=1.6:1; age 2-17 years), free of clinical signs of chronic bone marrow damage, with no recent history of symptomatic vaso-occlusive episodes, and waiting for haematopoietic stem cell transplantation (HSCT), underwent morphological, immunohistochemical and electron microscopy evaluation. Additional comparison with three bone marrow specimens from post-HSCT SCA patients and 10 bone marrow specimens from AS healthy carriers was performed. Bone marrow of SCA patients was normocellular or slighly hypercellular in all cases. Erythroid hyperplasia was a common feature. Myeloid lineage was slightly decreased with normal to slightly diminished neutrophilic granulocytes; CD68 positive monocytic-macrophagic cells appeared slightly increased, with a predominant CD163 positive M2/M(Hb) phenotype. A positive correlation was found between haemoglobin values and number of bone marrow erythroid cells (R 2 =0.15, p=0.05). Intravascular and interstitial clusters of erythroid sickle cells were found in bone marrow of pre-HSCT homozygous SS SCA patients, as well as heterozygous AS healthy carriers, and the single post-HSCT patient matched to an AS health carrier donor. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Asthma progression to airway remodeling and bone marrow eosinophil responses in genetically distinct strains of mice.

PubMed

Hogan, Mary Beth; Piktel, Debra; Hubbs, Ann F; McPherson, Leslie E; Landreth, Kenneth S

2008-12-01

Patient factors that cause long-term airway remodeling are largely unidentified. This suggests that genetic differences may determine which asthmatic patients develop airway remodeling. A murine model with repeated allergen exposure leading to peribronchial fibrosis in complement factor 5 (C5)-deficient A/J mice has been used to study asthma progression. No studies have addressed the systemic effects of allergen sensitization or chronic allergen exposure on bone marrow eosinophilopoiesis in this mouse strain. To investigate bone marrow eosinophil responses during acute sensitization and chronic allergen exposure using genetically distinct mouse strains differing in persistent airway reactivity and remodeling. The C5-sufficient BALB/c and C5-deficient A/J mice were repetitively exposed to intranasal ovalbumin for 12 weeks. Subsequently, the mice were evaluated for airway eosinophilia, mucus-containing goblet cells, and peribronchial fibrosis. Both strains of mice were also acutely sensitized to ovalbumin. Bone marrow eosinophil progenitor cells and mature eosinophils were enumerated. BALB/c and A/J mice have similar bone marrow responses after acute allergen exposure, with elevations in bone marrow eosinophil progenitor cell and eosinophil numbers. After chronic allergen exposure, only C5-deficient A/J mice that developed peribronchial fibrosis exhibited bone marrow eosinophilia. BALB/c mice lacked peribronchial fibrosis and extinguished accelerated eosinophil production after long-term allergen challenge. Chronic airway remodeling after repeated allergen exposure in genetically different mice correlated with differences in long-term bone marrow eosinophilopoiesis. Preventing asthma from progressing to chronic airway remodeling with fibrosis may involve identifying genetically determined influences on bone marrow responses to chronic allergen exposure.

Granulocyte-mobilized bone marrow.

PubMed

Arcese, William; De Angelis, Gottardo; Cerretti, Raffaella

2012-11-01

In the last few years, mobilized peripheral blood has overcome bone marrow as a graft source, but, despite the evidence of a more rapid engraftment, the incidence of chronic graft-versus-host disease is significantly higher with, consequently, more transplant-related mortality on the long follow-up. Overall, the posttransplant outcome of mobilized peripheral blood recipients is similar to that of patients who are bone marrow grafted. More recently, the use of bone marrow after granulocyte colony-stimulating factor (G-CSF) donor priming has been introduced in the transplant practice. Herein, we review biological acquisitions and clinical results on the use of G-CSF-primed bone marrow as a source of hematopoietic stem cells (HSC) for allogeneic stem cell transplantation. G-CSF the increases the HSC compartment and exerts an intense immunoregulatory effect on marrow T-cells resulting in the shift from Th1 to Th2 phenotype with higher production of anti-inflammatory cytokines. The potential advantages of these biological effects have been translated in the clinical practice by using G-CSF primed unmanipulated bone marrow in the setting of transplant from human leukocyte antigen (HLA)-haploidentical donor with highly encouraging results. For patients lacking an HLA-identical sibling, the transplant of G-CSF primed unmanipulated bone marrow from a haploidentical donor combined with an intense in-vivo immunosuppression is a valid alternative achieving results that are well comparable with those reported for umbilical cord blood, HLA-matched unrelated peripheral blood/bone marrow or T-cell-depleted haploidentical transplant.

The Role of the Progressive Ankylosis Protein (ANK) in Adipogenic/Osteogenic Fate Decision of Precursor Cells

PubMed Central

Minashima, Takeshi; Quirno, Martin; Lee, You Jin; Kirsch, Thorsten

2017-01-01

The progressive ankylosis protein (ANK) is a transmembrane protein that transports intracellular pyrophosphate (PPi) to the extracellular milieu. In this study we show increased fatty degeneration of the bone marrow of adult ank/ank mice, which lack a functional ANK protein. In addition, isolated bone marrow stromal cells (BMSCs) isolated from ank/ank mice showed a decreased proliferation rate and osteogenic differentiation potential, and an increased adipogenic differentiation potential compared to BMSCs isolated from wild type (WT) littermates. Wnt signaling pathway PCR array analysis revealed that Wnt ligands, Wnt receptors and Wnt signaling proteins that stimulate osteoblast differentiation were expressed at markedly lower levels in ank/ank BMSCs than in WT BMSCs. Lack of ANK function also resulted in impaired bone fracture healing, as indicated by a smaller callus formed and delayed bone formation in the callus site. Whereas 5 weeks after fracture, the fractured bone in WT mice was further remodeled and restored to original shape, the fractured bone in ank/ank mice was not fully restored and remodeled to original shape. In conclusion, our study provides evidence that ANK plays a critical role in the adipogenic/osteogenic fate decision of adult mesenchymal precursor cells. ANK functions in precursor cells are required for osteogenic differentiation of these cells during adult bone homeostasis and repair, whereas lack of ANK functions favors adipogenic differentiation. PMID:28286238

[Assessment of therapeutic results for simple bone cyst with percutaneous injection of autogenous bone marrow].

PubMed

Wang, Enbo; Zhao, Qun; Zhang, Lijun

2006-09-01

To evaluate the therapeutic results of percutaneous injection of autogenous bone marrow for simple bone cyst and to analyze the prognostic factors of the treatment. From March 2000 to June 2005, 31 patients with simple bone cysts were treated by percutaneous injection of autogenous bone marrow. Of 31 patients, there were 18 males and 13 females, aged 5 years and 7 months to 15 years. The locations were proximal humerus in 18 cases, proximal femur in 7 cases and other sites in 6 cases. Two cases were treated with repeated injections. The operative process included percutaneous aspiration of fluid in the bone cysts and injection of autogenous bone marrow aspirated from posterior superior iliac spine. The mean volume of marrow injected was 40 ml (30-70 ml). No complications were noted during treatment. Thirty patients were followed for an average of 2.2 years (1-5 years) with 2 cases out of follow-up. After one injection of bone marrow, 9 cysts (29.0%) were healed up completely, 7 cysts (22.6%) basically healed up, 13 cysts (41.9%) healed up partially and 2 (6.5%) had no response. The satisfactory and effective rates were 67.7% and 93.5% respectively. There was significant difference between active stage group and resting stage group(P<0.05). There were no statistically significant difference in therapeutic results between groups of different ages, lesion sites or bone marrow hyperplasia(P>0.05). Percutaneous injection of autogenous bone marrow is a safe and effective method to treat simple bone cyst, but repeated injections is necessary for some patients. The therapeutic results are better in cysts at resting stage than those at active stage.

Primary Hyperparathyroidism: The Influence of Bone Marrow Adipose Tissue on Bone Loss and of Osteocalcin on Insulin Resistance

PubMed Central

Mendonça, Maira L.; Batista, Sérgio L.; Nogueira-Barbosa, Marcello H.; Salmon, Carlos E.G.; de Paula, Francisco J.A.

2016-01-01

OBJECTIVES: Bone marrow adipose tissue has been associated with low bone mineral density. However, no data exist regarding marrow adipose tissue in primary hyperparathyroidism, a disorder associated with bone loss in conditions of high bone turnover. The objective of the present study was to investigate the relationship between marrow adipose tissue, bone mass and parathyroid hormone. The influence of osteocalcin on the homeostasis model assessment of insulin resistance was also evaluated. METHODS: This was a cross-sectional study conducted at a university hospital, involving 18 patients with primary hyperparathyroidism (PHPT) and 21 controls (CG). Bone mass was assessed by dual-energy x-ray absorptiometry and marrow adipose tissue was assessed by 1H magnetic resonance spectroscopy. The biochemical evaluation included the determination of parathyroid hormone, osteocalcin, glucose and insulin levels. RESULTS: A negative association was found between the bone mass at the 1/3 radius and parathyroid hormone levels (r = -0.69; p<0.01). Marrow adipose tissue was not significantly increased in patients (CG = 32.8±11.2% vs PHPT = 38.6±12%). The serum levels of osteocalcin were higher in patients (CG = 8.6±3.6 ng/mL vs PHPT = 36.5±38.4 ng/mL; p<0.005), but no associations were observed between osteocalcin and insulin or between insulin and both marrow adipose tissue and bone mass. CONCLUSION: These results suggest that the increment of adipogenesis in the bone marrow microenvironment under conditions of high bone turnover due to primary hyperparathyroidism is limited. Despite the increased serum levels of osteocalcin due to primary hyperparathyroidism, these patients tend to have impaired insulin sensitivity. PMID:27626477

Bone Marrow Stem Cells in Clinical Application: Harnessing Paracrine Roles and Niche Mechanisms

NASA Astrophysics Data System (ADS)

Backly, Rania M. El; Cancedda, Ranieri

The being of any individual throughout life is a dynamic process relying on the capacity to retain processes of self-renewal and differentiation, both of which are hallmarks of stem cells. Although limited in the adult human organism, regeneration and repair do take place in virtue of the presence of adult stem cells. In the bone marrow, two major populations of stem cells govern the dynamic equilibrium of both hemopoiesis and skeletal homeostasis; the hematopoietic and the mesenchymal stem cells. Recent cell based clinical trials utilizing bone marrow-derived stem cells as therapeutic agents have revealed promising results, while others have failed to display as such. It is therefore imperative to strive to understand the mechanisms by which these cells function in vivo, how their properties can be maintained ex-vivo, and to explore further their recently highlighted immunomodulatory and trophic effects.

Effects of short-term hypothermal and contrast exposure on immunophysiological parameters of laboratory animals.

PubMed

Kalenova, L F; Fisher, T A; Suhovey, J G; Besedin, I M

2009-05-01

Experiments on inbred animals showed that short-term exposure in cold water significantly modified structural and functional parameters of the immune system at different levels of its organization, from bone marrow hemopoiesis to effector stage of the immune response to antigen. The thermal factor caused changes in nonspecific and specific mechanisms of the immune system. Hypothermal exposure (7-9 degrees C, 5 sec) increased the thymic index and bone marrow lymphocyte count, reduced absorption capacity and stimulated metabolic activity of phagocytes, stimulated cell-mediated and suppressed humoral immunity. Contrast exposure in cold and hot water (7-9 degrees C, 5 sec/40-42 degrees C, 30 sec) increased monocyte count in bone marrow and reduced it in the their peripheral blood, reduced metabolic activity of phagocytes, stimulated cell-mediated and suppressed humoral immunity. These data demonstrate physiological mechanisms of interactions between the thermoregulatory and immune systems.

Benzene-induced myelotoxicity: application of flow cytofluorometry for the evaluation of early proliferative change in bone marrow.

PubMed Central

Irons, R D

1981-01-01

A detailed description of flow cytofluorometric DNA cell cycle analysis is presented. A number of studies by the author and other investigators are reviewed in which a method is developed for the analysis of cell cycle phase in bone marrow of experimental animals. Bone marrow cell cycle analysis is a sensitive indicator of changes in bone marrow proliferative activity occurring early in chemically-induced myelotoxicity. Cell cycle analysis, used together with other hematologic methods, has revealed benzene-induced toxicity in proliferating bone marrow cells to be cycle specific, appearing to affect a population in late S phase which then accumulate in G2/M. PMID:7016521

The diagnostic utility of bone marrow aspiration and biopsy in patients with acquired immunodeficiency syndrome.

PubMed

Gluckman, R J; Rosner, F; Guarneri, J J

1989-02-01

Diagnostic bone marrow aspiration, biopsy, and culture are useful procedures in the evaluation of patients with suspected or proven acquired immunodeficiency syndrome (AIDS) who are febrile. In as many as one fourth of these patients, the information provided by the bone marrow examination may establish a diagnosis of a disseminated opportunistic infection when other studies are not informative. We have also discovered a previously unreported association between thrombocytopenia and the presence of bone marrow granulomas in our patients with AIDS and suggest that thrombocytopenia may be a clue to enable the clinician to predict a positive bone marrow result more accurately. The explanation for this apparent association remains to be elucidated.

Breast Cancer Cell Colonization of the Human Bone Marrow Adipose Tissue Niche.

PubMed

Templeton, Zach S; Lie, Wen-Rong; Wang, Weiqi; Rosenberg-Hasson, Yael; Alluri, Rajiv V; Tamaresis, John S; Bachmann, Michael H; Lee, Kitty; Maloney, William J; Contag, Christopher H; King, Bonnie L

2015-12-01

Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche. Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry. Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment. Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Automated morphological analysis of bone marrow cells in microscopic images for diagnosis of leukemia: nucleus-plasma separation and cell classification using a hierarchical tree model of hematopoesis

NASA Astrophysics Data System (ADS)

Krappe, Sebastian; Wittenberg, Thomas; Haferlach, Torsten; Münzenmayer, Christian

2016-03-01

The morphological differentiation of bone marrow is fundamental for the diagnosis of leukemia. Currently, the counting and classification of the different types of bone marrow cells is done manually under the use of bright field microscopy. This is a time-consuming, subjective, tedious and error-prone process. Furthermore, repeated examinations of a slide may yield intra- and inter-observer variances. For that reason a computer assisted diagnosis system for bone marrow differentiation is pursued. In this work we focus (a) on a new method for the separation of nucleus and plasma parts and (b) on a knowledge-based hierarchical tree classifier for the differentiation of bone marrow cells in 16 different classes. Classification trees are easily interpretable and understandable and provide a classification together with an explanation. Using classification trees, expert knowledge (i.e. knowledge about similar classes and cell lines in the tree model of hematopoiesis) is integrated in the structure of the tree. The proposed segmentation method is evaluated with more than 10,000 manually segmented cells. For the evaluation of the proposed hierarchical classifier more than 140,000 automatically segmented bone marrow cells are used. Future automated solutions for the morphological analysis of bone marrow smears could potentially apply such an approach for the pre-classification of bone marrow cells and thereby shortening the examination time.

The chemokine receptor CXCR6 contributes to recruitment of bone marrow-derived fibroblast precursors in renal fibrosis

PubMed Central

Xia, Yunfeng; Yan, Jingyin; Jin, Xiaogao; Entman, Mark L.; Wang, Yanlin

2014-01-01

Bone marrow-derived fibroblasts in circulation are of hematopoietic origin, proliferate, differentiate into myofibroblasts, and express the chemokine receptor CXCR6. Since chemokines mediate the trafficking of circulating cells to sites of injury, we studied the role of CXCR6 in mouse models of renal injury. Significantly fewer bone marrow-derived fibroblasts accumulated in the kidney of CXCR6 knockout mice in response to injury, expressed less profibrotic chemokines and cytokines, displayed fewer myofibroblasts, and expressed less α-smooth muscle actin in the obstructed kidneys compared with wild-type mice. CXCR6 deficiency inhibited total collagen deposition and suppressed expression of collagen I and fibronectin in the obstructed kidneys. Furthermore, wild type mice engrafted with CXCR6−/− bone marrow cells displayed fewer bone marrow-derived fibroblasts in the kidneys with obstructive injury and showed less severe renal fibrosis compared with wild-type mice engrafted with CXCR6+/+ bone marrow cells. Transplant of wild type bone marrow into CXCR6−/− recipients restored recruitment of myeloid fibroblasts and susceptibility to fibrosis. Hematopoietic fibroblasts migrate into injured kidney and proliferate and differentiate into myofibroblasts. Thus, CXCR6, together with other chemokines and their receptors, may play important roles in the recruitment of bone marrow-derived fibroblast precursors into the kidney and contribute to the pathogenesis of renal fibrosis. PMID:24646857

The chemokine receptor CXCR6 contributes to recruitment of bone marrow-derived fibroblast precursors in renal fibrosis.

PubMed

Xia, Yunfeng; Yan, Jingyin; Jin, Xiaogao; Entman, Mark L; Wang, Yanlin

2014-08-01

Bone marrow-derived fibroblasts in circulation are of hematopoietic origin, and they proliferate, differentiate into myofibroblasts, and express the chemokine receptor CXCR6. As chemokines mediate the trafficking of circulating cells to sites of injury, we studied the role of CXCR6 in mouse models of renal injury. Significantly, the kidney of CXCR6 knockout mice accumulated fewer bone marrow-derived fibroblasts in response to injury, expressed less profibrotic chemokines and cytokines, displayed fewer myofibroblasts, and expressed less α-smooth muscle actin in the obstructed kidneys compared with wild-type (WT) mice. CXCR6 deficiency inhibited total collagen deposition and suppressed the expression of collagen I and fibronectin in the obstructed kidneys. Furthermore, WT mice engrafted with CXCR6(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts in the kidneys with obstructive injury and showed less severe renal fibrosis compared with WT mice engrafted with CXCR6(+/+) bone marrow cells. Transplant of WT bone marrow into CXCR6(-/-) recipients restored recruitment of myeloid fibroblasts and susceptibility to fibrosis. Hematopoietic fibroblasts migrate into injured kidney and proliferate and differentiate into myofibroblasts. Thus, CXCR6, together with other chemokines and their receptors, may have important roles in the recruitment of bone marrow-derived fibroblast precursors into the kidney and contribute to the pathogenesis of renal fibrosis.

[Effects of recombinant human alpha-2b and gamma interferons on bone marrow megakaryocyte progenitors (CFU-Meg) from patients with chronic myelocytic leukemia].

PubMed

Tanabe, Y; Dan, K; Kuriya, S; Nomura, T

1989-10-01

The effects of recombinant human interferon (IFN) alpha-2b and gamma on the bone marrow megakaryocyte progenitors (CFU-Meg) were compared between eight patients in the chronic phase of Ph1-positive chronic myelocytic leukemia (CML) and five hematologically normal patients. CFU-Meg was assayed in plasma clot culture added with phytohemagglutinin-stimulated leukocyte-conditioned medium as a source of colony stimulating activity. The average count of CFU-Meg colonies formed from the bone marrow of CML patients was 5.5 times that of normal controls. Spontaneous CFU-Meg colonies were grown in seven of eight CML patients, but in none of five controls. Colony formation by CFU-Meg in CML as well as normal bone marrow was suppressed by the two preparations of IFN in a dose dependent fashion. Their suppressive influence on colonies from CFU-Meg was comparable between CML and normal bone marrow at lower concentrations, but was less marked for CML than normal bone marrow at higher concentrations. The formation of CFU-Meg colonies from CML bone marrow was more severely suppressed by IFN-gamma than IFN-alpha-2b. Depletion of either T lymphocytes or adherent cells from the CML bone marrow cells diminished the suppressive effects of IFN-gamma, but had no influence on the effects of IFN-alpha-2b.

Early loss of subchondral bone following microfracture is counteracted by bone marrow aspirate in a translational model of osteochondral repair

PubMed Central

Gao, Liang; Orth, Patrick; Müller-Brandt, Kathrin; Goebel, Lars K. H.; Cucchiarini, Magali; Madry, Henning

2017-01-01

Microfracture of cartilage defects may induce alterations of the subchondral bone in the mid- and long-term, yet very little is known about their onset. Possibly, these changes may be avoided by an enhanced microfracture technique with additional application of bone marrow aspirate. In this study, full-thickness chondral defects in the knee joints of minipigs were either treated with (1) debridement down to the subchondral bone plate alone, (2) debridement with microfracture, or (3) microfracture with additional application of bone marrow aspirate. At 4 weeks after microfracture, the loss of subchondral bone below the defects largely exceeded the original microfracture holes. Of note, a significant increase of osteoclast density was identified in defects treated with microfracture alone compared with debridement only. Both changes were significantly counteracted by the adjunct treatment with bone marrow. Debridement and microfracture without or with bone marrow were equivalent regarding the early cartilage repair. These data suggest that microfracture induced a substantial early resorption of the subchondral bone and also highlight the potential value of bone marrow aspirate as an adjunct to counteract these alterations. Clinical studies are warranted to further elucidate early events of osteochondral repair and the effect of enhanced microfracture techniques. PMID:28345610

Can bone marrow differentiate into renal cells?

PubMed

Imai, Enyu; Ito, Takahito

2002-10-01

A considerable plasticity of adult stem cells has been confirmed in a wide variety of tissues. In particular, the pluripotency of bone marrow-derived stem cells may influence the regeneration of injured tissues and may provide novel avenues in regenerative medicine. Bone marrow contains at least hematopoietic and mesenchymal stem cells, and both can differentiate into a wide range of differentiated cells. Side population (SP) cells, which are originally defined in bone marrow cells by high efflux of DNA-binding dye, seem to be a new class of multipotent stem cells. Irrespective of the approach used to obtain stem cells, the fates of marrow-derived cells following bone marrow transplantation can be traced by labeling donor cells with green fluorescence protein or by identifying donor Y chromosome in female recipients. So far, bone marrow-derived cells have been reported to differentiate into renal cells, including mesangial cells, endothelial cells, podocytes, and tubular cells in the kidney, although controversy exists. Further studies are required to address this issue. Cell therapy will be promising when we learn to control stem cells such as bone marrow-derived stem cells, embryonic stem cells, and resident stem cells in the kidney. Identification of factors that support stem cells or promote their differentiation should provide a relevant step towards cell therapy.

Morphological study of bone marrow to assess the effects of lead acetate on haemopoiesis and aplasia and the ameliorating role of Carica papaya extract

PubMed Central

THAM, CHING S.; CHAKRAVARTHI, SRIKUMAR; HALEAGRAHARA, NAGARAJA; DE ALWIS, RANJIT

2013-01-01

Lead causes damage to the body by inducing oxidative stress. The sites of damage include the bone marrow, where marrow hypoplasia and osteosclerosis may be observed. Leaves of Carica papaya, which have antioxidant and haemopoietic properties, were tested against the effect of lead acetate in experimental rats. The rats were divided into 8 groups; control, lead acetate only, Carica papaya (50 mg and 200 mg), post-treatment with Carica papaya (50 mg and 200 mg) following lead acetate administration and pre-treatment with Carica papaya (50 mg and 200 mg) followed by lead acetate administration. The substances were administered for 14 days. The effects were evaluated by measuring protein carbonyl content (PCC) and glutathione content (GC) in the bone marrow. Histological changes in the bone marrow were also observed. The results showed that Carica papaya induced a significant reduction in the PCC activity and significantly increased the GC in the bone marrow. Carica papaya also improved the histology of the bone marrow compared with that of the lead acetate-treated group. In summary, Carica papaya was effective against the oxidative damage caused by lead acetate in the bone marrow and had a stimulatory effect on haemopoiesis. PMID:23403524

Morphological study of bone marrow to assess the effects of lead acetate on haemopoiesis and aplasia and the ameliorating role of Carica papaya extract.

PubMed

Tham, Ching S; Chakravarthi, Srikumar; Haleagrahara, Nagaraja; DE Alwis, Ranjit

2013-02-01

Lead causes damage to the body by inducing oxidative stress. The sites of damage include the bone marrow, where marrow hypoplasia and osteosclerosis may be observed. Leaves of Carica papaya, which have antioxidant and haemopoietic properties, were tested against the effect of lead acetate in experimental rats. The rats were divided into 8 groups; control, lead acetate only, Carica papaya (50 mg and 200 mg), post-treatment with Carica papaya (50 mg and 200 mg) following lead acetate administration and pre-treatment with Carica papaya (50 mg and 200 mg) followed by lead acetate administration. The substances were administered for 14 days. The effects were evaluated by measuring protein carbonyl content (PCC) and glutathione content (GC) in the bone marrow. Histological changes in the bone marrow were also observed. The results showed that Carica papaya induced a significant reduction in the PCC activity and significantly increased the GC in the bone marrow. Carica papaya also improved the histology of the bone marrow compared with that of the lead acetate-treated group. In summary, Carica papaya was effective against the oxidative damage caused by lead acetate in the bone marrow and had a stimulatory effect on haemopoiesis.

Association of murine lupus and thymic full-length endogenous retroviral expression maps to a bone marrow stem cell

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krieg, A.M.; Gourley, M.F.; Steinberg, A.D.

1991-05-01

Recent studies of thymic gene expression in murine lupus have demonstrated 8.4-kb (full-length size) modified polytropic (Mpmv) endogenous retroviral RNA. In contrast, normal control mouse strains do not produce detectable amounts of such RNA in their thymuses. Prior studies have attributed a defect in experimental tolerance in murine lupus to a bone marrow stem cell rather than to the thymic epithelium; in contrast, infectious retroviral expression has been associated with the thymic epithelium, rather than with the bone marrow stem cell. The present study was designed to determine whether the abnormal Mpmv expression associated with murine lupus mapped to thymicmore » epithelium or to a marrow precursor. Lethally irradiated control and lupus-prone mice were reconstituted with T cell depleted bone marrow; one month later their thymuses were studied for endogenous retroviral RNA and protein expression. Recipients of bone marrow from nonautoimmune donors expressed neither 8.4-kb Mpmv RNA nor surface MCF gp70 in their thymuses. In contrast, recipients of bone marrow from autoimmune NZB or BXSB donors expressed thymic 8.4-kb Mpmv RNA and mink cell focus-forming gp70. These studies demonstrate that lupus-associated 8.4-kb Mpmv endogenous retroviral expression is determined by bone marrow stem cells.« less

Accelerated functional recovery after skeletal muscle ischemia-reperfusion injury using freshly isolated bone marrow cells.

PubMed

Corona, Benjamin T; Rathbone, Christopher R

2014-05-01

Relatively little information exists regarding the usefulness of bone marrow-derived cells for skeletal muscle ischemia-reperfusion injury (I/R), especially when compared with I/R that occurs in other tissues. The objectives of this study were to evaluate the ability of freshly isolated bone marrow cells to home to injured skeletal muscle and to determine their effects on muscle regeneration. Freshly isolated lineage-depleted bone marrow cells (Lin(-) BMCs) were injected intravenously 2 d after I/R. Bioluminescent imaging was used to evaluate cell localization for up to 28 d after injury. Muscle function, the percentage of fibers with centrally located nuclei, and the capillary-to-fiber ratio were evaluated 14 d after delivery of either saline (Saline) or saline containing Lin(-) BMCs (Lin(-) BMCs). Bioluminescence was higher in the injured leg than the contralateral control leg for up to 7 d after injection (P < 0.05) suggestive of cell homing to the injured skeletal muscle. Fourteen days after injury, there was a significant improvement in maximal tetanic torque (40% versus 22% deficit; P < 0.05), a faster rate of force production (+dP/dt) (123.6 versus 94.5 Nmm/S; P < 0.05), and a reduction in the percentage of fibers containing centrally located nuclei (40 versus 17%; P < 0.05), but no change in the capillary-to-fiber ratio in the Lin(-) BMC as compared with the Saline group. The homing of freshly isolated BMCs to injured skeletal muscle after I/R is associated with an increase in functional outcomes. Published by Elsevier Inc.

Long-Term Outcomes of Cord Blood Transplantation from an HLA-Identical Sibling for Patients with Bone Marrow Failure Syndromes: A Report From Eurocord, Cord Blood Committee and Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation.

PubMed

Pagliuca, Simona; Peffault de Latour, Régis; Volt, Fernanda; Locatelli, Franco; Zecca, Marco; Dalle, Jean-Hugues; Comoli, Patrizia; Vettenranta, Kim; Diaz, Miguel Angel; Reuven, Or; Bertrand, Yves; Diaz de Heredia, Cristina; Nagler, Arnon; Ghavamzadeh, Ardeshir; Sufliarska, Sabina; Lawson, Sarah; Kenzey, Chantal; Rocha, Vanderson; Dufour, Carlo; Gluckman, Eliane; Passweg, Jakob; Ruggeri, Annalisa

2017-11-01

Cord blood transplantation (CBT) from HLA-identical siblings is an attractive option for patients with bone marrow failure (BMF) syndrome because of the low risk of graft-versus-host disease (GVHD) and the absence of risk to the donor. We analyzed outcomes of 117 patients with inherited or acquired BMF syndrome who received CBT from a related HLA-identical donor in European Society for Blood and Marrow Transplantation centers between 1988 and 2014. Ninety-seven patients had inherited and 20 patients acquired BMF syndrome. Eighty-two patients received a single cord blood (CB) unit, whereas 35 patients received a combination of CB and bone marrow cells from the same donor. Median age at CBT was 6.7 years, and median follow-up was 86.7 months. The cumulative incidence function (CIF) of neutrophil recovery was 88.8% (95% CI, 83.1% to 94.9%), 100-day CIF of grades II to IV acute GVHD was 15.2%, and 7-year CIF of chronic GVHD was 14.5%. Overall survival at 7 years was 87.9% (95% CI, 80.8% to 92.6%), 89% for inherited and 81% for acquired BMF syndromes (P = .66). Results of this study are consistent with outcomes of bone marrow transplantation shown by previous series in the same setting and indicate that in pediatric patients with BMF syndrome, CBT from an HLA-identical sibling donor is associated with excellent long-term outcomes and that collection of CB unit at birth of a new sibling is strongly recommended. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

90Yttrium Ibritumomab Tiuxetan Therapy in Allogeneic Transplantation in B-cell Lymphoma with Extensive Marrow involvement and Chronic Lymphocytic Leukemia: Utility of Pre-transplantation Biodistribution

PubMed Central

Matesan, Manuela; Rajendran, Joseph; Press, Oliver W.; Maloney, David G.; Storb, Rainer F.; Cassaday, Ryan D.; Pagel, John M.; Oliveira, George; Gopal, Ajay K.

2014-01-01

Biodistribution data to-date using 111In- ibritumomab tiuxetan has been initially obtained in patients with <25% lymphomatous bone marrow involvement and adequate hematopoietic synthetic function. In this article we present the results of an analysis of the biodistribution data obtained from a cohort of patients with extensive bone marrow involvement, baseline cytopenias, and chronic lymphocytic leukemia (CLL). Thirty nine patients with diagnosis of B-cell lymphoma or CLL expressing the CD20 antigen, who had failed at least one prior regimen, and had evidence of persistent disease were included in this analysis, however only 38 of these completed the treatment. Semiquantitative analysis of the biodistribution was performed using regions of interest (ROI) over the liver, lungs, kidneys, spleen and sacrum. The observed interpatient variability including higher liver uptake in 4 patients is discussed. No severe solid organs toxicity was observed at the maximum administered activity of 1184 MBq (32 mCi) 90Yibritumomab tiuxetan. After accounting for differences in marrow involvement, patients with CLL exhibit comparable biodistributions to those with B-NHL. We found that the estimated sacral marrow uptake on 48 hour images in patients with bone marrow involvement may be an indicator of bone marrow involvement. There was no correlation between tumor visualization and response to treatment. These data suggest that the imaging step is not critical when the administered activity is below 1184 MBq (32 mCi). However our analysis confirms that the semiquantitative imaging data can be used to identify patients at risk for liver toxicity when higher doses of 90Y- ibritumomab tiuxetan are used. Patients with CLL can have excellent targeting of disease by 111Inibritumomab tiuxetan, indicating potential efficacy in this patient population. PMID:25076159

Why does starvation make bones fat?

PubMed Central

Devlin, Maureen J.

2011-01-01

Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. Here I review the possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? To evaluate these possibilities, here I review what is known about the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance. PMID:21793093

Why does starvation make bones fat?

PubMed

Devlin, Maureen J

2011-01-01

Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. This review considers several possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? These possibilities are evaluated in terms of the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance. Copyright © 2011 Wiley-Liss, Inc.

Isolated juvenile xanthogranuloma in the bone marrow: report of a case and review of the literature.

PubMed

Kesserwan, Chimen; Boué, Daniel R; Kahwash, Samir B

2007-01-01

We report a case of juvenile xanthogranuloma limited to involvement of the bone marrow in a 6-week-old male infant. Evaluation of the bone marrow was a part of the workup for peripheral blood cytopenia. Examination showed hypercellular marrow with paratrabecular clusters of lipidized histiocytes positive for CD68, CD4, and factor XIII(a) and negative for S100 and CD1a. Clinical and radiological workup showed no associated skin lesions or osseous or visceral involvement. The patient was started on chemotherapy with clinical improvement and gradual decreased bone marrow involvement. The child is alive and well at 16 months of age. This case represents, to the best of our knowledge, the 1st documented case of juvenile xanthogranuloma with isolated bone marrow involvement sparing skin and viscera.

Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group.

PubMed

Burchill, Susan A; Beiske, Klaus; Shimada, Hiroyuki; Ambros, Peter F; Seeger, Robert; Tytgat, Godelieve A M; Brock, Penelope R; Haber, Michelle; Park, Julie R; Berthold, Frank

2017-04-01

The current study was conducted to expedite international standardized reporting of bone marrow disease in children with neuroblastoma and to improve equivalence of care. A multidisciplinary International Neuroblastoma Response Criteria Bone Marrow Working Group was convened by the US National Cancer Institute in January 2012 with representation from Europe, North America, and Australia. Practical transferable recommendations to standardize the reporting of bone marrow disease were developed. To the authors' knowledge, the current study is the first to comprehensively present consensus criteria for the collection, analysis, and reporting of the percentage area of bone marrow parenchyma occupied by tumor cells in trephine-biopsies. The quantitative analysis of neuroblastoma content in bone marrow aspirates by immunocytology and reverse transcriptase-quantitative polymerase chain reaction are revised. The inclusion of paired-like homeobox 2b (PHOX2B) for immunohistochemistry and reverse transcriptase-quantitative polymerase chain reaction is recommended. Recommendations for recording bone marrow response are provided. The authors endorse the quantitative assessment of neuroblastoma cell content in bilateral core needle biopsies-trephines and aspirates in all children with neuroblastoma, with the exception of infants, in whom the evaluation of aspirates alone is advised. It is interesting to note that 5% disease is accepted as an internationally achievable level for disease assessment. The quantitative assessment of neuroblastoma cells is recommended to provide data from which evidence-based numerical criteria for the reporting of bone marrow response can be realized. This is particularly important in the minimal disease setting and when neuroblastoma detection in bone marrow is intermittent, where clinical impact has yet to be validated. The wide adoption of these harmonized criteria will enhance the ability to compare outcomes from different trials and facilitate collaborative trial design. Cancer 2017;123:1095-1105. © 2016 American Cancer Society. © 2016 American Cancer Society.

Autologous intravenous bone marrow mononuclear cell therapy for patients with subacute ischaemic stroke: A pilot study

PubMed Central

Prasad, Kameshwar; Mohanty, Sujata; Bhatia, Rohit; Srivastava, M.V.P.; Garg, Ajay; Srivastava, Achal; Goyal, Vinay; Tripathi, Manjari; Kumar, Amit; Bal, Chandrashekar; Vij, Aarti; Mishra, Nalini Kant

2012-01-01

Background & objectives: Bone marrow mononuclear cell therapy has emerged as one of the option for the treatment of Stroke. Several preclinical studies have shown that the treatment with mononuclear cell (MNCs) can reduce the infarct size and improve the functional outcome. We evaluated the feasibility, safety and clinical outcome of administering bone marrow mononuclear cell (MNCs) intravenously to patients with subacute ischaemic stroke. Methods: In a non-randomized phase-I clinical study, 11 consecutive, eligible and consenting patients, aged 30-70 yr with ischaemic stroke involving anterior circulation within 7 to 30 days of onset of stroke were included. Bone marrow was aspirated from iliac crest and the harvested mononuclear cells were infused into antecubital vein. Outcomes measured for safety included immediate reactions after cell infusion and evidence of tumour formation at one year in whole body PET scan. Patients were followed at week 1, 4-6, 24 and 52 to determine clinical progress using National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), modified Rankin Scale (mRS), MRI, EEG and PET. Feasibility outcomes included target-dose feasibility. Favourable clinical outcome was defined as mRS score of 2 or less or BI score of 75 to 100 at six months after stem cell therapy. Results: Between September 2006 and April 2007, 11 patients were infused with bone-marrow mononuclear cells (mean 80 million with CD-34+ mean 0.92 million). Protocol was target-dose feasible in 9 patients (82%). FDG-PET scan at 24 and 52 wk in nine patients did not reveal evidence of tumour formation. Seven patients had favourable clinical outcome. Interpretation & conclusions: Intravenous bone marrow mononuclear cell therapy appears feasible and safe in patients with subacute ischaemic stroke. Further, a randomized controlled trial to examine its efficacy is being conducted. PMID:22960888

Influence of clinical status and parasite load on erythropoiesis and leucopoiesis in dogs naturally infected with leishmania (Leishmania) chagasi.

PubMed

Trópia de Abreu, Raquel; Carvalho, Maria das Graças; Carneiro, Cláudia Martins; Giunchetti, Rodolfo Cordeiro; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Coura-Vital, Wendel; Corrêa-Oliveira, Rodrigo; Reis, Alexandre Barbosa

2011-05-10

The bone marrow is considered to be an important storage of parasites in Leishmania-infected dogs, although little is known about cellular genesis in this organ during canine visceral leishmaniasis (CVL). The aim of the present study was to evaluate changes in erythropoiesis and leucopoiesis in bone marrow aspirates from dogs naturally infected with Leishmania chagasi and presenting different clinical statuses and bone marrow parasite densities. The evolution of CVL from asymptomatic to symptomatic status was accompanied by increasing parasite density in the bone marrow. The impact of bone marrow parasite density on cellularity was similar in dogs at different clinical stages, with animals in the high parasite density group. Erythroid and eosinophilic hypoplasia, proliferation of neutrophilic precursor cells and significant increases in lymphocytes and plasma cell numbers were the major alterations observed. Differential bone marrow cell counts revealed increases in the myeloid:erythroid ratio associated to increased numbers of granulopoietic cells in the different clinical groups compared with non-infected dogs. Analysis of the data obtained indicated that the assessment of bone marrow constitutes an additional and useful tool by which to elaborate a prognosis for CVL.

Influence of Clinical Status and Parasite Load on Erythropoiesis and Leucopoiesis in Dogs Naturally Infected with Leishmania (Leishmania) chagasi

PubMed Central

Trópia de Abreu, Raquel; Carvalho, Maria das Graças; Carneiro, Cláudia Martins; Giunchetti, Rodolfo Cordeiro; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Coura-Vital, Wendel; Corrêa-Oliveira, Rodrigo; Reis, Alexandre Barbosa

2011-01-01

Background The bone marrow is considered to be an important storage of parasites in Leishmania-infected dogs, although little is known about cellular genesis in this organ during canine visceral leishmaniasis (CVL). Methodology/Principal Findings The aim of the present study was to evaluate changes in erythropoiesis and leucopoiesis in bone marrow aspirates from dogs naturally infected with Leishmania chagasi and presenting different clinical statuses and bone marrow parasite densities. The evolution of CVL from asymptomatic to symptomatic status was accompanied by increasing parasite density in the bone marrow. The impact of bone marrow parasite density on cellularity was similar in dogs at different clinical stages, with animals in the high parasite density group. Erythroid and eosinophilic hypoplasia, proliferation of neutrophilic precursor cells and significant increases in lymphocytes and plasma cell numbers were the major alterations observed. Differential bone marrow cell counts revealed increases in the myeloid:erythroid ratio associated to increased numbers of granulopoietic cells in the different clinical groups compared with non-infected dogs. Conclusions Analysis of the data obtained indicated that the assessment of bone marrow constitutes an additional and useful tool by which to elaborate a prognosis for CVL. PMID:21572995

Local injection of autologous bone marrow cells to regenerate muscle in patients with traumatic brachial plexus injury: a pilot study.

PubMed

Hogendoorn, S; Duijnisveld, B J; van Duinen, S G; Stoel, B C; van Dijk, J G; Fibbe, W E; Nelissen, R G H H

2014-01-01

Traumatic brachial plexus injury causes severe functional impairment of the arm. Elbow flexion is often affected. Nerve surgery or tendon transfers provide the only means to obtain improved elbow flexion. Unfortunately, the functionality of the arm often remains insufficient. Stem cell therapy could potentially improve muscle strength and avoid muscle-tendon transfer. This pilot study assesses the safety and regenerative potential of autologous bone marrow-derived mononuclear cell injection in partially denervated biceps. Nine brachial plexus patients with insufficient elbow flexion (i.e., partial denervation) received intramuscular escalating doses of autologous bone marrow-derived mononuclear cells, combined with tendon transfers. Effect parameters included biceps biopsies, motor unit analysis on needle electromyography and computerised muscle tomography, before and after cell therapy. No adverse effects in vital signs, bone marrow aspiration sites, injection sites, or surgical wound were seen. After cell therapy there was a 52% decrease in muscle fibrosis (p = 0.01), an 80% increase in myofibre diameter (p = 0.007), a 50% increase in satellite cells (p = 0.045) and an 83% increase in capillary-to-myofibre ratio (p < 0.001) was shown. CT analysis demonstrated a 48% decrease in mean muscle density (p = 0.009). Motor unit analysis showed a mean increase of 36% in motor unit amplitude (p = 0.045), 22% increase in duration (p = 0.005) and 29% increase in number of phases (p = 0.002). Mononuclear cell injection in partly denervated muscle of brachial plexus patients is safe. The results suggest enhanced muscle reinnervation and regeneration. Cite this article: Bone Joint Res 2014;3:38-47.

[The morphofunctional state of the bone marrow in lead and zinc intoxication].

PubMed

Vladimtseva, T M; Pashkevich, I A; Salmina, A B

2006-01-01

The nucleolus is a compulsory nuclear structure of all cells of eukaryotes. The quantitative and qualitative characteristics of nuclei show the functional activity of a cell, the rate of its synthesis of RNA and portents, and its metabolic state. Heavy metals (zinc chloride and lead acetate) were comparatively investigated for their effects on the nucleolar apparatus of bone marrow cells in in vivo experiments. Zinc chloride and lead acetate were ascertained to damage the nucleolar apparatus of cells, thus decreasing their transcriptional activity or irreversibly damaging them.

Rapid isolation of bone marrow mesenchymal stromal cells using integrated centrifuge-based technology.

PubMed

Meppelink, Amanda M; Wang, Xing-Hua; Bradica, Gino; Barron, Kathryn; Hiltz, Kathleen; Liu, Xiang-Hong; Goldman, Scott M; Vacanti, Joseph P; Keating, Armand; Hoganson, David M

2016-06-01

The use of bone marrow-derived mesenchymal stromal cells (MSCs) in cell-based therapies is currently being developed for a number of diseases. Thus far, the clinical results have been inconclusive and variable, in part because of the variety of cell isolation procedures and culture conditions used in each study. A new isolation technique that streamlines the method of concentration and demands less time and attention could provide clinical and economic advantages compared with current methodologies. In this study, we evaluated the concentrating capability of an integrated centrifuge-based technology compared with standard Ficoll isolation. MSCs were concentrated from bone marrow aspirate using the new device and the Ficoll method. The isolation capabilities of the device and the growth characteristics, secretome production, and differentiation capacity of the derived cells were determined. The new MSC isolation device concentrated the bone marrow in 90 seconds and resulted in a mononuclear cell yield 10-fold higher and with a twofold increase in cell retention compared with Ficoll. The cells isolated using the device were shown to exhibit similar morphology and functional activity as assessed by growth curves and secretome production compared to the Ficoll-isolated cells. The surface marker and trilineage differentiation profile of the device-isolated cells was consistent with the known profile of MSCs. The faster time to isolation and greater cell yield of the integrated centrifuge-based technology may make this an improved approach for MSC isolation from bone marrow aspirates. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Expression of receptors for atrial natriuretic peptide on the murine bone marrow-derived stromal cells.

PubMed

Agui, T; Yamada, T; Legros, G; Nakajima, T; Clark, M; Peschel, C; Matsumoto, K

1992-05-01

Atrial natriuretic peptide (ANP) receptors were identified on both murine bone marrow-derived stromal cell lines A-3 and ALC and primary cultured cells using [125I]ANP binding assays and Northern blot analyses. The binding of [125I] ANP to the stromal cells was rapid, saturable, and of high affinity. The dissociation constants between ANP and its receptors on these cells showed no difference among cell types, while maximal binding capacity values were different among cell types. Competitive inhibition of [125I]ANP binding with C-atrial natriuretic factor, specific for ANP clearance receptor (ANPR-C), revealed that most of [125I]ANP-binding sites corresponded to ANPR-C. Northern blotting data corroborated that bone marrow-derived stromal cells expressed ANPR-C. However, in ALC cells, ANP biological receptors (either ANPR-A or ANPR-B), the mol wt of which is approximately 130K, were detected, and cGMP was accumulated after stimulation with ANP. On the other hand, in another stromal cell clone, A-3 cells, the expression of biological receptor was not detected in the affinity cross-linking and competitive inhibition experiments using [125I]ANP. However, A-3 cells accumulated cGMP by responding to ANPR-B-specific ligand, C-type natriuretic peptide. These results suggest that ALC cells equally express ANPR-A and ANPR-B, while A-3 cells express ANPR-B dominantly. Although the physiological roles of these receptors in the bone marrow is still not resolved, ANP is expected to play a role in the regulation of stromal cell functions in bone marrow.

Bone Marrow Aspirate Concentrate for Cartilage Defects of the Knee: From Bench to Bedside Evidence.

PubMed

Cotter, Eric J; Wang, Kevin C; Yanke, Adam B; Chubinskaya, Susan

2018-04-01

Objective To critically evaluate the current basic science, translational, and clinical data regarding bone marrow aspirate concentrate (BMAC) in the setting of focal cartilage defects of the knee and describe clinical indications and future research questions surrounding the clinical utility of BMAC for treatment of these lesions. Design A literature search was performed using the PubMed and Ovid MEDLINE databases for studies in English (1980-2017) using keywords, including ["bone marrow aspirate" and "cartilage"], ["mesenchymal stem cells" and "cartilage"], and ["bone marrow aspirate" and "mesenchymal stem cells" and "orthopedics"]. A total of 1832 articles were reviewed by 2 independent authors and additional literature found through scanning references of cited articles. Results BMAC has demonstrated promising results in the clinical application for repair of chondral defects as an adjuvant procedure or as an independent management technique. A subcomponent of BMAC, bone marrow derived-mesenchymal stem cells (MSCs) possess the ability to differentiate into cells important for osteogenesis and chondrogenesis. Modulation of paracrine signaling is perhaps the most important function of BM-MSCs in this setting. In an effort to increase the cellular yield, authors have shown the ability to expand BM-MSCs in culture while maintaining phenotype. Conclusions Translational studies have demonstrated good clinical efficacy of BMAC both concomitant with cartilage restoration procedures, at defined time points after surgery, and as isolated injections. Early clinical data suggests BMAC may help stimulate a more robust hyaline cartilage repair tissue response. Numerous questions remain regarding BMAC usage, including cell source, cell expansion, optimal pathology, and injection timing and quantity.

Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis

PubMed Central

Ding, Lin; Liu, Tianju; Wu, Zhe; Hu, Biao; Nakashima, Taku; Ullenbruch, Matthew; De Los Santos, Francina Gonzalez; Phan, Sem H.

2016-01-01

Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis but its cellular source and role in regeneration vs. fibrosis remain unclear. In this study we hypothesize that AREG induced in bone marrow derived CD11c+ cells is essential for pulmonary fibrosis. Thus the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout (KO) mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c+ cells. Moreover depletion of bone marrow derived CD11c+ cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c+ cells from BLM-treated donor mice exacerbated pulmonary fibrosis but not if the donor cells were made AREG-deficient prior to transfer. CD11c+ cell conditioned media or co-culture stimulated fibroblast proliferation, activation and myofibroblast differentiation in an AREG dependent manner. Furthermore recombinant AREG induced telomerase reverse transcriptase (TERT) which appeared to be essential for the proliferative effect. Finally AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c+ cells promoted bleomycin induced pulmonary fibrosis by activation of fibroblast TERT dependent proliferation, motility and indirectly, myofibroblast differentiation. PMID:27206766

Transplantation of bone marrow stem cells as well as mobilization by granulocyte-colony stimulating factor promotes recovery after spinal cord injury in rats.

PubMed

Urdzíková, Lucia; Jendelová, Pavla; Glogarová, Katerina; Burian, Martin; Hájek, Milan; Syková, Eva

2006-09-01

Emerging clinical studies of treating brain and spinal cord injury (SCI) with autologous adult stem cells led us to compare the effect of an intravenous injection of mesenchymal stem cells (MSCs), an injection of a freshly prepared mononuclear fraction of bone marrow cells (BMCs) or bone marrow cell mobilization induced by granulocyte colony stimulating factor (G-CSF) in rats with a balloon- induced spinal cord compression lesion. MSCs were isolated from rat bone marrow by their adherence to plastic, labeled with iron-oxide nanoparticles and expanded in vitro. Seven days after injury, rats received an intravenous injection of MSCs or BMCs or a subcutaneous injection of GCSF (from day 7 to 11 post-injury). Functional status was assessed weekly for 5 weeks after SCI, using the Basso-Beattie-Bresnehan (BBB) locomotor rating score and the plantar test. Animals with SCI treated with MSCs, BMCs, or G-CSF had higher BBB scores and better recovery of hind limb sensitivity than controls injected with saline. Morphometric measurements showed an increase in the spared white matter. MR images of the spinal cords were taken ex vivo 5 weeks after SCI using a Bruker 4.7-T spectrometer. The lesions populated by grafted MSCs appeared as dark hypointense areas. Histology confirmed a large number of iron-containing and PKH 26-positive cells in the lesion site. We conclude that treatment with three different bone marrow cell populations had a positive effect on behavioral outcome and histopathological assessment after SCI, which was most pronounced after MSC injection.

Demonstration of early functional compromise of bone marrow derived hematopoietic progenitor cells during bovine neonatal pancytopenia through in vitro culture of bone marrow biopsies.

PubMed

Laming, Eleanor; Melzi, Eleonora; Scholes, Sandra F E; Connelly, Maira; Bell, Charlotte R; Ballingall, Keith T; Dagleish, Mark P; Rocchi, Mara S; Willoughby, Kim

2012-10-30

Bovine neonatal pancytopenia (BNP) is a syndrome characterised by thrombocytopenia associated with marked bone marrow destruction in calves, widely reported since 2007 in several European countries and since 2011 in New Zealand. The disease is epidemiologically associated with the use of an inactivated bovine virus diarrhoea (BVD) vaccine and is currently considered to be caused by absorption of colostral antibody produced by some vaccinated cows ("BNP dams"). Alloantibodies capable of binding to the leukocyte surface have been detected in BNP dams and antibodies recognising bovine MHC class I and β-2-microglobulin have been detected in vaccinated cattle. In this study, calves were challenged with pooled colostrum collected from BNP dams or from non-BNP dams and their bone marrow hematopoietic progenitor cells (HPC) cultured in vitro from sternal biopsies taken at 24 hours and 6 days post-challenge. Clonogenic assay demonstrated that CFU-GEMM (colony forming unit-granulocyte/erythroid/macrophage/megakaryocyte; pluripotential progenitor cell) colony development was compromised from HPCs harvested as early as 24 hour post-challenge. By 6 days post challenge, HPCs harvested from challenged calves failed to develop CFU-E (erythroid) colonies and the development of both CFU-GEMM and CFU-GM (granulocyte/macrophage) was markedly reduced. This study suggests that the bone marrow pathology and clinical signs associated with BNP are related to an insult which compromises the pluripotential progenitor cell within the first 24 hours of life but that this does not initially include all cell types.

Role of bone marrow-derived CD11c+ dendritic cells in systolic overload-induced left ventricular inflammation, fibrosis and hypertrophy.

PubMed

Wang, Huan; Kwak, Dongmin; Fassett, John; Liu, Xiaohong; Yao, Wu; Weng, Xinyu; Xu, Xin; Xu, Yawei; Bache, Robert J; Mueller, Daniel L; Chen, Yingjie

2017-05-01

Inflammatory responses play an important role in the development of left ventricular (LV) hypertrophy and dysfunction. Recent studies demonstrated that increased T-cell infiltration and T-cell activation contribute to LV hypertrophy and dysfunction. Dendritic cells (DCs) are professional antigen-presenting cells that orchestrate immune responses, especially by modulating T-cell function. In this study, we investigated the role of bone marrow-derived CD11c + DCs in transverse aortic constriction (TAC)-induced LV fibrosis and hypertrophy in mice. We observed that TAC increased the number of CD11c + cells and the percentage of CD11c + MHCII + (major histocompatibility complex class II molecule positive) DCs in the LV, spleen and peripheral blood in mice. Using bone marrow chimeras and an inducible CD11c + DC ablation model, we found that depletion of bone marrow-derived CD11c + DCs significantly attenuated LV fibrosis and hypertrophy in mice exposed to 24 weeks of moderate TAC. CD11c + DC ablation significantly reduced TAC-induced myocardial inflammation as indicated by reduced myocardial CD45 + cells, CD11b + cells, CD8 + T cells and activated effector CD8 + CD44 + T cells in LV tissues. Moreover, pulsing of autologous DCs with LV homogenates from TAC mice promoted T-cell proliferation. These data indicate that bone marrow-derived CD11c + DCs play a maladaptive role in hemodynamic overload-induced cardiac inflammation, hypertrophy and fibrosis through the presentation of cardiac self-antigens to T cells.

MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation.

PubMed

Li, Chang-Jun; Cheng, Peng; Liang, Meng-Ke; Chen, Yu-Si; Lu, Qiong; Wang, Jin-Yu; Xia, Zhu-Ying; Zhou, Hou-De; Cao, Xu; Xie, Hui; Liao, Er-Yuan; Luo, Xiang-Hang

2015-04-01

Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-dependent reduction in osteogenesis that is accompanied by an increased propensity toward adipocyte differentiation. This switch increases adipocyte numbers and decreases the number of osteoblasts, contributing to age-related bone loss. Here, we found that the level of microRNA-188 (miR-188) is markedly higher in BMSCs from aged compared with young mice and humans. Compared with control mice, animals lacking miR-188 showed a substantial reduction of age-associated bone loss and fat accumulation in bone marrow. Conversely, mice with transgenic overexpression of miR-188 in osterix+ osteoprogenitors had greater age-associated bone loss and fat accumulation in bone marrow relative to WT mice. Moreover, using an aptamer delivery system, we found that BMSC-specific overexpression of miR-188 in mice reduced bone formation and increased bone marrow fat accumulation. We identified histone deacetylase 9 (HDAC9) and RPTOR-independent companion of MTOR complex 2 (RICTOR) as the direct targets of miR-188. Notably, BMSC-specific inhibition of miR-188 by intra-bone marrow injection of aptamer-antagomiR-188 increased bone formation and decreased bone marrow fat accumulation in aged mice. Together, our results indicate that miR-188 is a key regulator of the age-related switch between osteogenesis and adipogenesis of BMSCs and may represent a potential therapeutic target for age-related bone loss.

Comparison between the effects of platelet-rich plasma and bone marrow concentrate on defect consolidation in the rabbit tibia

PubMed Central

Batista, Marco Antonio; Leivas, Tomaz Puga; Rodrigues, Consuelo Junqueira; Arenas, Géssica Cantadori Funes; Belitardo, Donizeti Rodrigues; Guarniero, Roberto

2011-01-01

OBJECTIVE: To perform a comparative analysis of the effects of platelet-rich plasma and centrifuged bone marrow aspirate on the induction of bone healing in rabbits. METHOD: Twenty adult, male New Zealand rabbits were randomly separated into two equal groups, and surgery was performed to create a bone defect (a cortical orifice 3.3 mm in diameter) in the proximal metaphysis of each rabbit's right tibia. In the first group, platelet-rich plasma was implanted in combination with β-tricalcium phosphate (platelet-rich plasma group), and in the second group, centrifuged bone marrow in combination with β-tricalcium phosphate (centrifuged bone marrow group) was implanted. After a period of four weeks, the animals were euthanized, and the tibias were evaluated using digital radiography, computed tomography, and histomorphometry. RESULTS: Seven samples from each group were evaluated. The radiographic evaluation confirmed the absence of fractures in the postoperative limb and identified whether bone consolidation had occurred. The tomographic evaluation revealed a greater amount of consolidation and the formation of a greater cortical bone thickness in the platelet-rich plasma group. The histomorphometry revealed a greater bone density in the platelet-rich plasma group compared with the centrifuged bone marrow group. CONCLUSION: After four weeks, the platelet-rich plasma promoted a greater amount of bone consolidation than the bone marrow aspirate concentrate. PMID:22012052

The Analysis of Fixed Final State Optimal Control in Bilinear System Applied to Bone Marrow by Cell-Cycle Specific (CCS) Chemotherapy

NASA Astrophysics Data System (ADS)

Rainarli, E.; E Dewi, K.

2017-04-01

The research conducted by Fister & Panetta shown an optimal control model of bone marrow cells against Cell Cycle Specific chemotherapy drugs. The model used was a bilinear system model. Fister & Panetta research has proved existence, uniqueness, and characteristics of optimal control (the chemotherapy effect). However, by using this model, the amount of bone marrow at the final time could achieve less than 50 percent from the amount of bone marrow before given treatment. This could harm patients because the lack of bone marrow cells made the number of leukocytes declining and patients will experience leukemia. This research would examine the optimal control of a bilinear system that applied to fixed final state. It will be used to determine the length of optimal time in administering chemotherapy and kept bone marrow cells on the allowed level at the same time. Before simulation conducted, this paper shows that the system could be controlled by using a theory of Lie Algebra. Afterward, it shows the characteristics of optimal control. Based on the simulation, it indicates that strong chemotherapy drug given in a short time frame is the most optimal condition to keep bone marrow cells spine on the allowed level but still could put playing an effective treatment. It gives preference of the weight of treatment for keeping bone marrow cells. The result of chemotherapy’s effect (u) is not able to reach the maximum value. On the other words, it needs to make adjustments of medicine’s dosage to satisfy the final treatment condition e.g. the number of bone marrow cells should be at the allowed level.

Gamma Radiation Induces Micronucleated Reticulocytes in 3-D Bone Marrow Bioreactors in Vitro

PubMed Central

Sun, Hongliang; Dertinger, Stephen D.; Hyrien, Ollivier; David Wu, J. H.; Chen, Yuhchyau

2009-01-01

Radiation injury to the bone marrow is potentially lethal due to the potent DNA-damaging effects on cells of the hematopoietic system, including bone marrow stem cell, progenitor, and the precursor cell populations. Investigation of radiation genotoxic effects on bone marrow progenitor/precursor cells has been challenged by the lack of optimal in vitro surrogate organ culture systems, and the overall difficulty to sustain lineage-specific proliferation and differentiation of hematopoiesis in vitro. We report the investigation of radiation genotoxic effects in bone marrow cultures of C57Bl/6 mice established in 3-D bioreactors, which sustain long-term bone marrow cultures. For these studies, genotoxicity is measured by the induction of micronucleated reticulocytes (MN-RET). The kinetics and dose-response relationship of MN-RET induction in response to gamma-radiation of bioreactor-maintained bone marrow cultures are presented. Our data showed that 3-D long-term bone marrow cultures had sustained erythropoiesis capable of generating reticulocytes up to 8 weeks. The peak time-interval of viable cell output and percentage of reticulocytes increased steadily and reached the initial peak between the 14th to 21st days after inoculations. This was followed by a rebound or staying relatively constant until week 8. The percentage of MN-RET reached the maximum between 24 and 32 hours post 1 Gy gamma-ray. There was a near linear MN-RET induction by gamma radiation from 0 Gy to 1.0 Gy, followed by an attenuated increase to 1.5 – 2.0 Gy. The MN-RET response showed a downtrend beyond 2 Gy. Our data suggest that bone marrow culture in the 3-D bioreactor may be a useful organ culture system for the investigation of radiation genotoxic effect in vitro. PMID:19786117

NELL-1 Injection Maintains Long-Bone Quantity and Quality in an Ovariectomy-Induced Osteoporotic Senile Rat Model

PubMed Central

Kwak, Jinny; Zara, Janette N.; Chiang, Michael; Ngo, Richard; Shen, Jia; James, Aaron W.; Le, Khoi M.; Moon, Crystal; Zhang, Xinli; Gou, Zhongru; Ting, Kang

2013-01-01

Over 10 million Americans have osteoporosis, and is the predominant cause of fractures in the elderly. Treatment of fractures in the setting of osteoporosis is complicated by a suboptimal bone regenerative response due to a decline in the number of osteoblasts, their function, and survival. Consequently, an osteogenic therapeutic to prevent and treat fractures in patients with osteoporosis is needed. Nel-like molecule-1 (NELL-1), a novel osteoinductive growth factor, has been shown to promote bone regeneration. In this study, we aim to demonstrate the capacity of recombinant NELL-1 to prevent ovariectomy (OVX)-induced osteoporosis in a senile rat model. Ten-month-old female Sprague-Dawley rats underwent either sham surgery or OVX. Subsequently, 50 μL of 600 μg/mL NELL-1 lyophilized onto a 0–50-μm tricalcium phosphate (TCP) carrier was injected into the femoral bone marrow cavity while phosphate-buffered saline (PBS) control was injected into the contralateral femur. Our microcomputed tomography results showed that OVX+PBS/TCP control femurs showed a continuous decrease in the bone volume (BV) and bone mineral density (BMD) from 2 to 8 weeks post-OVX. In contrast, OVX+NELL-1/TCP femurs showed resistance to OVX-induced bone resorption showing BV and BMD levels similar to that of SHAM femurs at 8 weeks post-OVX. Histology showed increased endosteal-woven bone, as well as decreased adipocytes in the bone marrow of NELL-1-treated femurs compared to control. NELL-1-treated femurs also showed increased immunostaining for bone differentiation markers osteopontin and osteocalcin. These findings were validated in vitro, in which addition of NELL-1 in OVX bone marrow stem cells resulted in increased osteogenic differentiation. Thus, NELL-1 effectively enhances in situ osteogenesis in the bone marrow, making it potentially useful in the prevention and treatment of osteoporotic fractures. PMID:23083222

Selective Shielding of Bone Marrow: An Approach to Protecting Humans from External Gamma Radiation.

PubMed

Waterman, Gideon; Kase, Kenneth; Orion, Itzhak; Broisman, Andrey; Milstein, Oren

2017-09-01

The current feasibility of protecting emergency responders through bone marrow selective shielding is highlighted in the recent OECD/NEA report on severe accident management. Until recently, there was no effective personal protection from externally penetrating gamma radiation. In Chernobyl, first-responders wore makeshift lead sheeting, whereas in Fukushima protective equipment from gamma radiation was not available. Older protective solutions that use thin layers of shielding over large body surfaces are ineffective for energetic gamma radiation. Acute exposures may result in Acute Radiation Syndrome where the survival-limiting factor up to 10 Gy uniform, homogeneous exposure is irreversible bone marrow damage. Protracted, lower exposures may result in malignancies of which bone marrow is especially susceptible, being compounded by leukemia's short latency time. This highlights the importance of shielding bone marrow for preventing both deterministic and stochastic effects. Due to the extraordinary regenerative potential of hematopoietic stem cells, to effectively prevent the deterministic effects of bone marrow exposure, it is sufficient to protect only a small fraction of this tissue. This biological principle allows for a new class of equipment providing unprecedented attenuation of radiation to select marrow-rich regions, deferring the hematopoietic sub-syndrome of Acute Radiation Syndrome to much higher doses. As approximately half of the body's active bone marrow resides within the pelvis region, shielding this area holds great promise for preventing the deterministic effects of bone marrow exposure and concomitantly reducing stochastic effects. The efficacy of a device that selectively shields this region and other radiosensitive organs in the abdominal area is shown here.

Missing Cells: Pathophysiology, Diagnosis, and Management of (Pan)Cytopenia in Childhood

PubMed Central

Erlacher, Miriam; Strahm, Brigitte

2015-01-01

Peripheral blood cytopenia in children can be due to a variety of acquired or inherited diseases. Genetic disorders affecting a single hematopoietic lineage are frequently characterized by typical bone marrow findings, such as lack of progenitors or maturation arrest in congenital neutropenia or a lack of megakaryocytes in congenital amegakaryocytic thrombocytopenia, whereas antibody-mediated diseases such as autoimmune neutropenia are associated with a rather unremarkable bone marrow morphology. By contrast, pancytopenia is frequently associated with a hypocellular bone marrow, and the differential diagnosis includes acquired aplastic anemia, myelodysplastic syndrome, inherited bone marrow failure syndromes such as Fanconi anemia and dyskeratosis congenita, and a variety of immunological disorders including hemophagocytic lymphohistiocytosis. Thorough bone marrow analysis is of special importance for the diagnostic work-up of most patients. Cellularity, cellular composition, and dysplastic signs are the cornerstones of the differential diagnosis. Pancytopenia in the presence of a normo- or hypercellular marrow with dysplastic changes may indicate myelodysplastic syndrome. More challenging for the hematologist is the evaluation of the hypocellular bone marrow. Although aplastic anemia and hypocellular refractory cytopenia of childhood (RCC) can reliably be differentiated on a morphological level, the overlapping pathophysiology remains a significant challenge for the choice of the therapeutic strategy. Furthermore, inherited bone marrow failure syndromes are usually associated with the morphological picture of RCC, and the recognition of these entities is essential as they often present a multisystem disease requiring different diagnostic and therapeutic approaches. This paper gives an overview over the different disease entities presenting with (pan)cytopenia, their pathophysiology, characteristic bone marrow findings, and therapeutic approaches. PMID:26217651

Transplantation of neurotrophin-3-transfected bone marrow mesenchymal stem cells for the repair of spinal cord injury.

PubMed

Dong, Yuzhen; Yang, Libin; Yang, Lin; Zhao, Hongxing; Zhang, Chao; Wu, Dapeng

2014-08-15

Bone marrow mesenchymal stem cell transplantation has been shown to be therapeutic in the repair of spinal cord injury. However, the low survival rate of transplanted bone marrow mesenchymal stem cells in vivo remains a problem. Neurotrophin-3 promotes motor neuron survival and it is hypothesized that its transfection can enhance the therapeutic effect. We show that in vitro transfection of neurotrophin-3 gene increases the number of bone marrow mesenchymal stem cells in the region of spinal cord injury. These results indicate that neurotrophin-3 can promote the survival of bone marrow mesenchymal stem cells transplanted into the region of spinal cord injury and potentially enhance the therapeutic effect in the repair of spinal cord injury.

The diagnostic utility of bone marrow aspiration and biopsy in patients with acquired immunodeficiency syndrome.

PubMed Central

Gluckman, R. J.; Rosner, F.; Guarneri, J. J.

1989-01-01

Diagnostic bone marrow aspiration, biopsy, and culture are useful procedures in the evaluation of patients with suspected or proven acquired immunodeficiency syndrome (AIDS) who are febrile. In as many as one fourth of these patients, the information provided by the bone marrow examination may establish a diagnosis of a disseminated opportunistic infection when other studies are not informative. We have also discovered a previously unreported association between thrombocytopenia and the presence of bone marrow granulomas in our patients with AIDS and suggest that thrombocytopenia may be a clue to enable the clinician to predict a positive bone marrow result more accurately. The explanation for this apparent association remains to be elucidated. PMID:2733050

Transglutaminases factor XIII-A and TG2 regulate resorption, adipogenesis and plasma fibronectin homeostasis in bone and bone marrow

PubMed Central

Mousa, Aisha; Cui, Cui; Song, Aimei; Myneni, Vamsee D; Sun, Huifang; Li, Jin Jin; Murshed, Monzur; Melino, Gerry; Kaartinen, Mari T

2017-01-01

Appropriate bone mass is maintained by bone-forming osteoblast and bone-resorbing osteoclasts. Mesenchymal stem cell (MSC) lineage cells control osteoclastogenesis via expression of RANKL and OPG (receptor activator of nuclear factor κB ligand and osteoprotegerin), which promote and inhibit bone resorption, respectively. Protein crosslinking enzymes transglutaminase 2 (TG2) and Factor XIII-A (FXIII-A) have been linked to activity of myeloid and MSC lineage cells; however, in vivo evidence has been lacking to support their function. In this study, we show in mice that TG2 and FXIII-A control monocyte-macrophage cell differentiation into osteoclasts as well as RANKL production in MSCs and in adipocytes. Long bones of mice lacking TG2 and FXIII-A transglutaminases, show compromised biomechanical properties and trabecular bone loss in axial and appendicular skeleton. This was caused by increased osteoclastogenesis, a cellular phenotype that persists in vitro. The increased potential of TG2 and FXIII-A deficient monocytes to form osteoclasts was reversed by chemical inhibition of TG activity, which revealed the presence of TG1 in osteoclasts and assigned different roles for the TGs as regulators of osteoclastogenesis. TG2- and FXIII-A-deficient mice had normal osteoblast activity, but increased bone marrow adipogenesis, MSCs lacking TG2 and FXIII-A showed high adipogenic potential and significantly increased RANKL expression as well as upregulated TG1 expression. Chemical inhibition of TG activity in the null cells further increased adipogenic potential and RANKL production. Altered differentiation of TG2 and FXIII-A null MSCs was associated with plasma fibronectin (FN) assembly defect in cultures and FN retention in serum and marrow in vivo instead of assembly into bone. Our findings provide new functions for TG2, FXIII-A and TG1 in bone cells and identify them as novel regulators of bone mass, plasma FN homeostasis, RANKL production and myeloid and MSC cell differentiation. PMID:28387755

The Effect of Different Bone Marrow Stimulation Techniques on Human Talar Subchondral Bone: A Micro-Computed Tomography Evaluation.

PubMed

Gianakos, Arianna L; Yasui, Youichi; Fraser, Ethan J; Ross, Keir A; Prado, Marcelo P; Fortier, Lisa A; Kennedy, John G

2016-10-01

To evaluate morphological alterations, microarchitectural disturbances, and the extent of bone marrow access to the subchondral bone marrow compartment using micro-computed tomography analysis in different bone marrow stimulation (BMS) techniques. Nine zones in a 3 × 3 grid pattern were assigned to 5 cadaveric talar dome articular surfaces. A 1.00-mm microfracture awl (s.MFX), a 2.00-mm standard microfracture awl (l.MFX), or a 1.25-mm Kirschner wire (K-wire) drill hole was used to penetrate the subchondral bone in each grid zone. Subchondral bone holes and adjacent tissue areas were assessed by micro-computed tomography to analyze adjacent bone area destruction and communicating channels to the bone marrow. Grades 1 to 3 were assigned, where 1 = minimal compression/sclerosis; 2 = moderate compression/sclerosis; 3 = severe compression/sclerosis. Bone volume/total tissue volume, bone surface area/bone volume, trabecular thickness, and trabecular number were calculated in the region of interest. Visual assessment revealed that the s.MFX had significantly more grade 1 holes (P < .001) and that the l.MFX had significantly more poor/grade 3 holes (P = .002). Bone marrow channel assessment showed a statistically significant increase in the number of channels in the s.MFX when compared with both K-wire and l.MFX holes (P < .001). Bone volume fraction for the s.MFX was significantly less than that of the l.MFX (P = .029). BMS techniques using instruments with larger diameters resulted in increased trabecular compaction and sclerosis in areas adjacent to the defect. K-wire and l.MFX techniques resulted in less open communicating bone marrow channels, denoting a reduction in bone marrow access. The results of this study indicate that BMS using larger diameter devices results in greater microarchitecture disturbances. The current study suggests that the choice of a BMS technique should be carefully considered as the results indicate that smaller diameter hole sizes may diminish the amount of microarchitectural disturbances in the subchondral bone. Copyright © 2016 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Bone-marrow densitometry: Assessment of marrow space of human vertebrae by single energy high resolution-quantitative computed tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peña, Jaime A.; Damm, Timo; Bastgen, Jan

Purpose: Accurate noninvasive assessment of vertebral bone marrow fat fraction is important for diagnostic assessment of a variety of disorders and therapies known to affect marrow composition. Moreover, it provides a means to correct fat-induced bias of single energy quantitative computed tomography (QCT) based bone mineral density (BMD) measurements. The authors developed new segmentation and calibration methods to obtain quantitative surrogate measures of marrow-fat density in the axial skeleton. Methods: The authors developed and tested two high resolution-QCT (HR-QCT) based methods which permit segmentation of bone voids in between trabeculae hypothesizing that they are representative of bone marrow space. Themore » methods permit calculation of marrow content in units of mineral equivalent marrow density (MeMD). The first method is based on global thresholding and peeling (GTP) to define a volume of interest away from the transition between trabecular bone and marrow. The second method, morphological filtering (MF), uses spherical elements of different radii (0.1–1.2 mm) and automatically places them in between trabeculae to identify regions with large trabecular interspace, the bone-void space. To determine their performance, data were compared ex vivo to high-resolution peripheral CT (HR-pQCT) images as the gold-standard. The performance of the methods was tested on a set of excised human vertebrae with intact bone marrow tissue representative of an elderly population with low BMD. Results: 86% (GTP) and 87% (MF) of the voxels identified as true marrow space on HR-pQCT images were correctly identified on HR-QCT images and thus these volumes of interest can be considered to be representative of true marrow space. Within this volume, MeMD was estimated with residual errors of 4.8 mg/cm{sup 3} corresponding to accuracy errors in fat fraction on the order of 5% both for GTP and MF methods. Conclusions: The GTP and MF methods on HR-QCT images permit noninvasive localization and densitometric assessment of marrow fat with residual accuracy errors sufficient to study disorders and therapies known to affect bone marrow composition. Additionally, the methods can be used to correct BMD for fat induced bias. Application and testing in vivo and in longitudinal studies are warranted to determine the clinical performance and value of these methods.« less

Removing financial barriers to organ and bone marrow donation: the effect of leave and tax legislation in the U.S.

PubMed

Lacetera, Nicola; Macis, Mario; Stith, Sarah S

2014-01-01

Many U.S. states have passed legislation providing leave to organ and bone marrow donors and/or tax benefits for live and deceased organ and bone marrow donations and to employers of donors. We exploit cross-state variation in the timing of such legislation to analyze its impact on organ donations by living and deceased persons, on measures of the quality of the transplants, and on the number of bone marrow donations. We find that these provisions do not have a significant impact on the quantity of organs donated. The leave laws, however, do have a positive impact on bone marrow donations, and the effect increases with the size of the population of beneficiaries and with the generosity of the legislative provisions. Our results suggest that this legislation works for moderately invasive procedures such as bone marrow donation, but these incentives may be too low for organ donation, which is riskier and more burdensome. Copyright © 2013 Elsevier B.V. All rights reserved.

Tolerance to MHC class II disparate allografts through genetic modification of bone marrow

PubMed Central

Jindra, Peter T.; Tripathi, Sudipta; Tian, Chaorui; Iacomini, John; Bagley, Jessamyn

2012-01-01

Induction of molecular chimerism through genetic modification of bone marrow is a powerful tool for the induction of tolerance. Here we demonstrate for the first time that expression of an allogeneic MHC class II gene in autologous bone marrow cells, resulting in a state of molecular chimerism, induces tolerance to MHC class II mismatched skin grafts, a stringent test of transplant tolerance. Reconstitution of recipients with syngeneic bone marrow transduced with retrovirus encoding H-2I-Ab (I-Ab) resulted the long-term expression of the retroviral gene product on the surface of MHC class II-expressing bone marrow derived cell types. Mechanistically, tolerance was maintained by the presence of regulatory T cells, which prevented proliferation and cytokine production by alloreactive host T cells. Thus, the introduction of MHC class II genes into bone marrow derived cells through genetic engineering results in tolerance. These results have the potential to extend the clinical applicability of molecular chimerism for tolerance induction. PMID:22833118

CELLS INVOLVED IN THE IMMUNE RESPONSE

PubMed Central

Abdou, Nabih I.; Richter, Maxwell

1969-01-01

Rabbits were made immunologically tolerant to either human serum albumin or bovine gamma globulin by the neonatal administration of antigen. At 10 wk of age, they were challenged with the tolerogenic antigen and found to be non-responsive. However, these tolerant rabbits could respond with humoral antibody formation directed toward the tolerogenic antigen if they were treated with normal, allogeneic bone marrow or bone marrow obtained from a rabbit made tolerant toward a different antigen. They were incapable of responding if they were given bone marrow obtained from a rabbit previously made tolerant to the tolerogenic antigen. Irradiated rabbits were unable to respond if treated with tolerant bone marrow, but could respond well if given normal bone marrow. Since it has previously been demonstrated that the antibody-forming cell, in an irradiated recipient of allogeneic bone marrow, is of recipient and not donor origin, the data presented strongly indicate that the unresponsive cell in the immunologically tolerant rabbit is the antigen-reactive cell. PMID:4183777

Dynamic Fluid Flow Mechanical Stimulation Modulates Bone Marrow Mesenchymal Stem Cells.

PubMed

Hu, Minyi; Yeh, Robbin; Lien, Michelle; Teeratananon, Morgan; Agarwal, Kunal; Qin, Yi-Xian

2013-03-01

Osteoblasts are derived from mesenchymal stem cells (MSCs), which initiate and regulate bone formation. New strategies for osteoporosis treatments have aimed to control the fate of MSCs. While functional disuse decreases MSC growth and osteogenic potentials, mechanical signals enhance MSC quantity and bias their differentiation toward osteoblastogenesis. Through a non-invasive dynamic hydraulic stimulation (DHS), we have found that DHS can mitigate trabecular bone loss in a functional disuse model via rat hindlimb suspension (HLS). To further elucidate the downstream cellular effect of DHS and its potential mechanism underlying the bone quality enhancement, a longitudinal in vivo study was designed to evaluate the MSC populations in response to DHS over 3, 7, 14, and 21 days. Five-month old female Sprague Dawley rats were divided into three groups for each time point: age-matched control, HLS, and HLS+DHS. DHS was delivered to the right mid-tibiae with a daily "10 min on-5 min off-10 min on" loading regime for five days/week. At each sacrifice time point, bone marrow MSCs of the stimulated and control tibiae were isolated through specific cell surface markers and quantified by flow cytometry analysis. A strong time-dependent manner of bone marrow MSC induction was observed in response to DHS, which peaked on day 14. After 21 days, this effect of DHS was diminished. This study indicates that the MSC pool is positively influenced by the mechanical signals driven by DHS. Coinciding with our previous findings of mitigation of disuse bone loss, DHS induced changes in MSC number may bias the differentiation of the MSC population towards osteoblastogenesis, thereby promoting bone formation under disuse conditions. This study provides insights into the mechanism of time-sensitive MSC induction in response to mechanical loading, and for the optimal design of osteoporosis treatments.

The CardiAMP Heart Failure trial: A randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: Trial rationale and study design.

PubMed

Raval, Amish N; Cook, Thomas D; Duckers, Henricus J; Johnston, Peter V; Traverse, Jay H; Abraham, William T; Altman, Peter A; Pepine, Carl J

2018-07-01

Heart failure following myocardial infarction is a common, disabling, and deadly condition. Direct injection of autologous bone marrow mononuclear cells into the myocardium may result in improved functional recovery, relieve symptoms, and improve other cardiovascular outcomes. CardiAMP-HF is a randomized, double-blind, sham-controlled, pivotal trial designed to investigate the safety and efficacy of autologous bone marrow mononuclear cells treatment for patients with medically refractory and symptomatic ischemic cardiomyopathy. The primary end point is change in 6-minute walk distance adjusted for major adverse cardiovascular events at 12 months following treatment. Particularly novel aspects of this trial include a cell potency assay to screen subjects who have bone marrow cell characteristics that suggest a favorable response to treatment, a point-of-care treatment method, a high target dose of 200 million cells, and an efficient transcatheter intramyocardial delivery method that is associated with high cell retention. This novel approach may lead to a new treatment for those with ischemic heart disease suffering from medically refractory heart failure. Copyright © 2018 Elsevier Inc. All rights reserved.

Wild Type Bone Marrow Transplant Partially Reverses Neuroinflammation in Progranulin-Deficient Mice

PubMed Central

Yang, Yue; Aloi, Macarena S.; Cudaback, Eiron; Josephsen, Samuel R.; Rice, Samantha J.; Jorstad, Nikolas L.; Keene, C. Dirk; Montine, Thomas J.

2014-01-01

Frontotemporal dementia (FTD) is a neurodegenerative disease with devastating changes in behavioral performance and social function. Mutations in the progranulin gene (GRN) are one of the most common causes of inherited FTD due to reduced progranulin expression or activity, including in brain where it is expressed primarily by neurons and microglia. Thus, efforts aimed at enhancing progranulin levels might be a promising therapeutic strategy. Bone marrow-derived cells are able to engraft in the brain and adopt a microglial phenotype under myeloablative irradiation conditioning. This ability makes bone marrow (BM)-derived cells a potential cellular vehicle for transferring therapeutic molecules to the central nervous system. Here, we utilized BM cells from Grn+/+ (wild type or wt) mice labeled with green fluorescence protein for delivery of progranulin to progranulin deficient (Grn−/−) mice. Our results showed that wt bone marrow transplantation (BMT) partially reconstituted progranulin in the periphery and in cerebral cortex of Grn−/− mice. We demonstrated a pro-inflammatory effect in vivo and in ex vivo preparations of cerebral cortex of Grn−/− mice that was partially to fully reversed five months after BMT. Our findings suggest that BMT can be administered as a stem cell-based approach to prevent or to treat neurodegenerative diseases. PMID:25199051

Stimulation of angiogenesis, neurogenesis and regeneration by side population cells from dental pulp.

PubMed

Ishizaka, Ryo; Hayashi, Yuki; Iohara, Koichiro; Sugiyama, Masahiko; Murakami, Masashi; Yamamoto, Tsubasa; Fukuta, Osamu; Nakashima, Misako

2013-03-01

Mesenchymal stem cells (MSCs) have been used for cell therapy in various experimental disease models. However, the regenerative potential of MSCs from different tissue sources and the influence of the tissue niche have not been investigated. In this study, we compared the regenerative potential of dental pulp, bone marrow and adipose tissue-derived CD31(-) side population (SP) cells isolated from an individual porcine source. Pulp CD31(-) SP cells expressed the highest levels of angiogenic/neurotrophic factors and had the highest migration activity. Conditioned medium from pulp CD31(-) SP cells produced potent anti-apoptotic activity and neurite outgrowth, compared to those from bone marrow and adipose CD31(-) SP cells. Transplantation of pulp CD31(-) SP cells in a mouse hindlimb ischemia model produced higher blood flow and capillary density than transplantation of bone marrow and adipose CD31(-) SP cells. Motor function recovery and infarct size reduction were greater with pulp CD31(-) SP cells. Pulp CD31(-) SP cells induced maximal angiogenesis, neurogenesis and pulp regeneration in ectopic transplantation models compared to other tissue sources. These results demonstrate that pulp stem cells have higher angiogenic, neurogenic and regenerative potential and may therefore be superior to bone marrow and adipose stem cells for cell therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Bone marrow solid core biopsy needle: a critical assessment of the utility, benefits and limitations of the instruments employed in current day haematology and oncology.

PubMed

Islam, Anwarul

2018-06-01

The optimal clinical evaluation of the bone marrow requires an examination of air-dried and well-stained films of the aspirated tissue along with a histopathological evaluation of adequately processed and properly stained core biopsy specimens. A bone marrow evaluation can be essential in establishing a diagnosis, determining the efficacy of treatment in haematological disorders and to monitor haematological status of patients following bone marrow/stem cell transplantation. It is also an essential component of the staging process for newly diagnosed malignancies. Currently available bone marrow aspiration needles are quite satisfactory and if properly used provide good-quality specimens for morphological evaluation. However, if a bone marrow core biopsy is concerned, several needles are currently in use but not all of them provide good-quality biopsy specimens for histological evaluation or are user friendly. We have compared the recently introduced Moeller Medical single use bone marrow core biopsy needle with the Jamshidi needle with marrow acquisition cradle (CareFusion), J-needle (Cardinal Health) and OnControl device (Vidacare). It is concluded that the Moeller Medical needle system has definite advantages over others and is recommended for routine use. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

(18)F-FDG dynamic PET/CT in patients with multiple myeloma: patterns of tracer uptake and correlation with bone marrow plasma cell infiltration rate.

PubMed

Sachpekidis, Christos; Mai, Elias K; Goldschmidt, Hartmut; Hillengass, Jens; Hose, Dirk; Pan, Leyun; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

2015-06-01

The value of F-FDG PET in the diagnostic approach of multiple myeloma (MM) remains incompletely elicited. Little is known about the kinetics of F-FDG in the bone marrow and extramedullary sites in MM. This study aimed to evaluate quantitative data on kinetics and distribution patterns of F-FDG in MM patients with regard to pelvic bone marrow plasma cell infiltration. The study included 40 patients with primary MM. Dynamic PET/CT scanning of the lower lumbar spine and pelvis was performed after the administration of F-FDG. Whole-body PET/CT studies were performed. Sites of focal increased tracer uptake were considered as highly suggestive of myelomatous involvement after taking into account the patient history and CT findings. Bone marrow of the os ilium without pathologic tracer accumulation served as reference. The evaluation of dynamic PET/CT studies was based in addition to the conventional visual (qualitative) assessment, on semiquantitative (SUV) calculations, as well as on absolute quantitative estimations after application of a 2-tissue compartment model and a noncompartmental approach. F-FDG quantitative information and corresponding distribution patterns were correlated with pelvic bone marrow plasma cell infiltration. Fifty-two myelomatous lesions were detected in the pelvis. All parameters in suspected MM lesions ranged in significantly higher levels than in reference tissue (P < 0.01). Correlative analyses revealed that bone marrow plasma cell infiltration rate correlated significantly with SUVaverage, SUVmax, and the parameters K1, influx, and fractal dimension of F-FDG in reference bone marrow (P < 0.01). In addition, whole-body static PET/CT imaging demonstrated 4 patterns of tracer uptake; these are as follows: negative, focal, diffuse, and mixed (focal/diffuse) tracer uptake. Patients with a mixed pattern of radiotracer uptake had the highest mean plasma cell infiltration rate in their bone marrow, whereas those with negative PET/CT scans demonstrated the lowest bone marrow plasma cell infiltration. In total, 265 focal myeloma-indicative F-FDG-avid lesions were detected, 129 of which correlated with low-dose CT osteolytic findings. No significant correlation between the number of focal lesions detected in PET/CT and bone marrow infiltration was detected. The F-FDG kinetic parameters K1, influx, and fractal dimension as well as SUVaverage from reference tissue correlated significantly with bone marrow malignant plasma cell infiltration rate. Patients with negative PET/CT demonstrated the lowest bone marrow infiltration by malignant plasma cells, whereas those with a mixed pattern of tracer uptake had the highest infiltration.

Understanding chronic neutropenia: life is short.

PubMed

Bartels, Marije; Murphy, Kate; Rieter, Ester; Bruin, Marrie

2016-01-01

The pathophysiological mechanisms underlying chronic neutropenia are extensive, varying from haematopoietic stem cell disorders resulting in defective neutrophil production, to accelerated apoptosis of neutrophil progenitors or circulating mature neutrophils. While the knowledge concerning genetic defects associated with congenital neutropenia or bone marrow failure is increasing rapidly, the functional role and consequences of these genetic alterations is often not well understood. In addition, there is a large group of diseases, including primary immunodeficiencies and metabolic diseases, in which chronic neutropenia is one of the symptoms, while there is no clear bone marrow pathology or haematopoietic stem cell dysfunction. Altogether, these disease entities illustrate the complexity of normal neutrophil development, the functional role of the (bone marrow) microenvironment and the increased propensity to undergo apoptosis, which is typical for neutrophils. The large variety of disorders associated with chronic neutropenia makes classification almost impossible and possibly not desirable, based on the clinical phenotypes. However, a better understanding of the regulation of normal myeloid differentiation and neutrophil development is of great importance in the diagnostic evaluation of unexplained chronic neutropenia. In this review we propose insights in the pathophysiology of chronic neutropenia in the context of the functional role of key players during normal neutrophil development, neutrophil release and neutrophil survival. © 2015 John Wiley & Sons Ltd.

Acute Exposure to High Dose γ-Radiation Results in Transient Activation of Bone Lining Cells

PubMed Central

Turner, Russell T.; Iwaniec, Urszula T.; Wong, Carmen P.; Lindenmaier, Laurence B.; Wagner, Lindsay A.; Branscum, Adam J.; Menn, Scott A.; Taylor, James; Zhang, Ye; Wu, Honglu; Sibonga, Jean D.

2014-01-01

The present studies investigated the cellular mechanisms for the detrimental effects of high dose whole body γ-irradiation on bone. In addition, radioadaptation and bone marrow transplantation were assessed as interventions to mitigate the skeletal complications of irradiation. Increased trabecular thickness and separation and reduced fractional cancellous bone volume, connectivity density, and trabecular number were detected in proximal tibia and lumbar vertebra 14 days following γ-irradiation with 6 Gy. To establish the cellular mechanism for the architectural changes, vertebrae were analyzed by histomorphometry 1, 3, and 14 days following irradiation. Marrow cell density decreased within 1 day (67% reduction, p<0.0001), reached a minimum value after 3 days (86% reduction, p<0.0001), and partially rebounded by 14 days (30% reduction, p=0.0025) following irradiation. In contrast, osteoblast-lined bone perimeter was increased by 290% (1 day, p=0.04), 1230% (3 days, p<0.0001), and 530% (14 days, p=0.003), respectively. There was a strong association between radiation-induced marrow cell death and activation of bone lining cells to express the osteoblast phenotype (Pearson correlation −0.85, p<0.0001). An increase (p=0.004) in osteoclast-lined bone perimeter was also detected with irradiation. A priming dose of γ-radiation (0.5 mGy), previously shown to reduce mortality, had minimal effect on the cellular responses to radiation and did not prevent detrimental changes in bone architecture. Bone marrow transplantation normalized marrow cell density, bone turnover, and most indices of bone architecture following irradiation. In summary, radiation-induced death of marrow cells is associated with 1) a transient increase in bone formation due, at least in part, to activation of bone lining cells, and 2) an increase in bone resorption due to increased osteoclast perimeter. Bone marrow transplantation is effective in mitigating the detrimental effects of acute exposure to high dose whole body γ-radiation on bone turnover. PMID:23954507

[The pineal gland's peptides factors and the rhythms of functions of the thymus and bone marrow in animals during aging].

PubMed

Labunets, I F; Butenko, G M; Dragunova, V A; Magdich, L V; Kopylova, G V; Rodnichenko, A E; Mikhal'skiĭ, S A; Khavinson, V Kh; Azarskova, M V; Maksiuk, T V

2004-01-01

It was investigated the influence of pineal peptides on the aging changes both circadian rhythm of thymic serum factor (FTS) titer in male rats Wistar and circannual rhythms of FTS, the amount of stromal cells-precurcors (CFC-F), granulocyte-macrophage cells-precurcors (CFC-GM), CD4+, Mac-1+ and CD19+-cells in bone marrow of male mice CBA. Epithalamin was injected chronically beginning from 6 month in rats and 4 month in mice. In old animals the rhythmical disturbancers of the indices characterized by loss of fluctuations, displacement of seasonal acrophase, increased or diminished amplitude, inversion of rhythm and desynchronization. After epithalamin injections in rats of 11, 17, 27 months the FTS titer at night increased and in old mice of 23-24 months appeared the peak of hormone level in summer-autumn, restored the difference between the amount of CD4+, Mac-1+-cells in bone marrow in spring and autumn, increased CFC-GM amount in spring, diminished CFC-F in autumn and increased this indice in winter. Epithalon also diminished of CFC-GM and CFC-F amount in old mice in autumn. The retarding age-related disturbances of suprachiasmaticus nucleus of hypothalamus structure, the diminishing corticosterone and testosterone levels at night, the increasing hormones level in summer and the falling in winter plays role in the improvement of thymus and bone marrow rhythmical function in old animals, reseaved epithalamin. The rhythms of most indices rhythms in old animals showed a pattern of adult.

Mobilization of Endogenous Bone Marrow Derived Endothelial Progenitor Cells and Therapeutic Potential of Parathyroid Hormone after Ischemic Stroke in Mice

PubMed Central

Wang, Li-Li; Chen, Dongdong; Lee, Jinhwan; Gu, Xiaohuan; Alaaeddine, Ghina; Li, Jimei; Wei, Ling; Yu, Shan Ping

2014-01-01

Stroke is a major neurovascular disorder threatening human life and health. Very limited clinical treatments are currently available for stroke patients. Stem cell transplantation has shown promising potential as a regenerative treatment after ischemic stroke. The present investigation explores a new concept of mobilizing endogenous stem cells/progenitor cells from the bone marrow using a parathyroid hormone (PTH) therapy after ischemic stroke in adult mice. PTH 1-34 (80 µg/kg, i.p.) was administered 1 hour after focal ischemia and then daily for 6 consecutive days. After 6 days of PTH treatment, there was a significant increase in bone marrow derived CD-34/Fetal liver kinase-1 (Flk-1) positive endothelial progenitor cells (EPCs) in the peripheral blood. PTH treatment significantly increased the expression of trophic/regenerative factors including VEGF, SDF-1, BDNF and Tie-1 in the brain peri-infarct region. Angiogenesis, assessed by co-labeled Glut-1 and BrdU vessels, was significantly increased in PTH-treated ischemic brain compared to vehicle controls. PTH treatment also promoted neuroblast migration from the subventricular zone (SVZ) and increased the number of newly formed neurons in the peri-infarct cortex. PTH-treated mice showed significantly better sensorimotor functional recovery compared to stroke controls. Our data suggests that PTH therapy improves endogenous repair mechanisms after ischemic stroke with functional benefits. Mobilizing endogenous bone marrow-derived stem cells/progenitor cells using PTH and other mobilizers appears an effective and feasible regenerative treatment after ischemic stroke. PMID:24503654

Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro

PubMed Central

Elbaz, Alexandre; Wu, Xiying; Rivas, Daniel; Gimble, Jeffrey M; Duque, Gustavo

2010-01-01

Abstract Although increased bone marrow fat in age-related bone loss has been associated with lower trabecular mass, the underlying mechanism responsible remains unknown. We hypothesized that marrow adipocytes exert a lipotoxic effect on osteoblast function and survival through the reversible biosynthesis of fatty acids (FA) into the bone marrow microenvironment. We have used a two-chamber system to co-culture normal human osteoblasts (NHOst) with differentiating pre-adipocytes in the absence or presence of an inhibitor of FA synthase (cerulenin) and separated by an insert that allowed unidirectional trafficking of soluble factors only and prevented direct cell–cell contact. Supernatants were assayed for the presence of FA using mass spectophotometry. After 3 weeks in co-culture, NHOst showed significantly lower levels of differentiation and function based on lower mineralization and expression of alkaline phosphatase, osterix, osteocalcin and Runx2. In addition, NHOst survival was affected by the presence of adipocytes as determined by MTS-formazan and TUNEL assays as well as higher activation of caspases 3/7. These toxic effects were inhibited by addition of cerulenin. Furthermore, culture of NHOst with either adipocyte-conditioned media alone in the absence of adipocytes themselves or with the addition of the most predominant FA (stearate or palmitate) produced similar toxic results. Finally, Runx2 nuclear binding was affected by addition of either adipocyte conditioned media or FA into the osteogenic media. We conclude that the presence of FA within the marrow milieu can contribute to the age-related changes in bone mass and can be prevented by the inhibition of FA synthase. PMID:19382912

PET/CT versus bone marrow biopsy in the initial evaluation of bone marrow infiltration in various pediatric malignancies.

PubMed

Zapata, Claudia P; Cuglievan, Branko; Zapata, Catalina M; Olavarrieta, Raquel; Raskin, Scott; Desai, Kavita; De Angulo, Guillermo

2018-02-01

Accurate staging is essential in the prognosis and management of pediatric malignancies. Current protocols require screening for marrow infiltration with bone marrow biopsy (BMB) as the gold standard. Positron emission tomography-computed tomography (PET-CT) is commonly used to complete the staging process and can also be used to evaluate marrow infiltration. To compare PET-CT and BMB in the initial evaluation of bone marrow infiltration in pediatric cancers. We retrospectively reviewed new cases of EWS, rhabdomyosarcoma, neuroblastoma, and lymphoma diagnosed between January 2009 and October 2014. Each case had undergone both PET-CT and BMB within 4 weeks without treatment in the interval between screening modalities. We reviewed 69 cases. Bone marrow infiltration was demonstrated in 34 cases by PET-CT and in 18 cases by BMB. The sensitivity and negative predictive value of PET-CT were both 100%. Interestingly, the cases in which infiltration was not detected on BMB had an abnormal marrow signal on PET-CT focal or distant to iliac crest. PET-CT has a high sensitivity when assessing marrow infiltration in pediatric malignancies. Advances in radiologic modalities may obviate the use of invasive, painful, and costly procedures like BMB. Furthermore, biopsy results are limited by insufficient tissue or the degree of marrow infiltration (diffuse vs. focal disease). PET-CT can improve the precision of biopsy when used as a guiding tool. This study proposes the use of PET-CT as first-line screening for bone marrow infiltration to improve the accuracy of staging in new diagnoses. © 2017 Wiley Periodicals, Inc.

Transforming growth factor-{beta} inhibits CCAAT/enhancer-binding protein expression and PPAR{gamma} activity in unloaded bone marrow stromal cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahdjoudj, S.; Kaabeche, K.; Holy, X.

2005-02-01

The molecular mechanisms regulating the adipogenic differentiation of bone marrow stromal cells in vivo remain largely unknown. In this study, we investigated the regulatory effects of transforming growth factor beta-2 (TGF-{beta}2) on transcription factors involved in adipogenic differentiation induced by hind limb suspension in rat bone marrow stromal cells in vivo. Time course real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis of gene expression showed that skeletal unloading progressively increases the expression of CCAAT/enhancer-binding protein (C/EBP){alpha} and C/EBP{beta} {alpha} at 5 days in bone marrow stromal cells resulting in increased peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}2) transcripts at 7 days. TGF-{beta}2more » administration in unloaded rats corrected the rise in C/EBP{alpha} and C/EBP{beta} transcripts induced by unloading in bone marrow stromal cells. This resulted in inhibition of PPAR{gamma}2 expression that was associated with increased Runx2 expression. Additionally, the inhibition of C/EBP{alpha} and C/EBP{beta} expression by TGF-{beta}2 was associated with increased PPAR{gamma} serine phosphorylation in bone marrow stromal cells, a mechanism that inhibits PPAR{gamma} transactivating activity. The sequential inhibitory effect of TGF-{beta}2 on C/EBP{alpha}, C/EBP{beta}, and PPAR{gamma}2 resulted in reduced LPL expression and abolition of bone marrow stromal cell adipogenic differentiation, which contributed to prevent bone loss induced by skeletal unloading. We conclude that TGF-{beta}2 inhibits the excessive adipogenic differentiation of bone marrow stromal cells induced by skeletal unloading by inhibiting C/EBP{alpha}, C/EBP{beta}, and PPAR{gamma} expression and activity, which provides a sequential mechanism by which TGF-{beta}2 regulates adipogenic differentiation of bone marrow stromal cells in vivo.« less

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2014 CFR

2014-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2011 CFR

2011-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

78 FR 76507 - Revised Medical Criteria for Evaluating Cancer (Malignant Neoplastic Diseases)

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-17

... blast (immature) cells in the peripheral blood or bone marrow is 10 percent or greater. We propose this... evaluate cancer treatment by bone marrow or stem cell transplantation, including transplantation using stem... evaluate cancers treated with bone marrow or stem cell transplantation, including transplantation using...

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2010 CFR

2010-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2012 CFR

2012-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

Code of Federal Regulations, 2013 CFR

2013-07-01

... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Urman, M.; O'Sullivan, R.A.; Nugent, R.A.

This case concerns a patient with intracranial extramedullary hematopoiesis (EH) suspected on a CT scan and subsequently confirmed with In-111 chloride and Tc-99m SC bone marrow scans. The bone marrow scans also provided additional information by demonstrating other sites of EH in the paravertebral tissues and bone marrow expansion into the distal extremities.

Intrasinusoidal pattern of bone marrow infiltration by hepatosplenic T-cell lymphoma.

PubMed

Butler, Liesl Ann; Juneja, Surender

2018-04-01

Hepatosplenic T-cell lymphoma is a rare, aggressive form of extranodal lymphoma, which frequently involves the bone marrow. An intrasinusoidal pattern of infiltration is characteristic of the disease and is often best appreciated on immunohistochemical staining. Bone marrow biopsy can be a useful diagnostic tool.

Survival of Free and Encapsulated Human and Rat Islet Xenografts Transplanted into the Mouse Bone Marrow

PubMed Central

Meier, Raphael P. H.; Seebach, Jörg D.; Morel, Philippe; Mahou, Redouan; Borot, Sophie; Giovannoni, Laurianne; Parnaud, Geraldine; Montanari, Elisa; Bosco, Domenico; Wandrey, Christine; Berney, Thierry; Bühler, Leo H.; Muller, Yannick D.

2014-01-01

Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation. PMID:24625569

Selective differentiation and proliferation of hematopoietic cells induced by recombinant human interleukins.

PubMed Central

Saito, H; Hatake, K; Dvorak, A M; Leiferman, K M; Donnenberg, A D; Arai, N; Ishizaka, K; Ishizaka, T

1988-01-01

Effects of recombinant human interleukins on hematopoiesis were explored by using suspension cultures of mononuclear cells of human umbilical-cord blood and bone marrow. The results showed that interleukin 5 induced the selective differentiation and proliferation of eosinophils. After 3 weeks in culture with interleukin 5, essentially all nonadherent cells in both bone marrow and cord blood cell cultures became eosinophilic myelocytes. Culture of the same cells with interleukin 4 resulted in the selective growth of OKT3+ lymphocytes. However, OKT3+ cells did not develop if the bone marrow cells were depleted of OKT3+/OKT11+ cells prior to the culture, indicating that interleukin 4 induced the proliferation of a subpopulation of resting T cells present in cord blood and bone marrow cell preparations. In suspension cultures of bone marrow cells and cord blood cells grown in the presence of interleukin 3, basophilic, eosinophilic, and neutrophilic myelocytes and macrophages developed within 2 weeks. By 3 weeks, however, the majority of nonadherent cells became eosinophilic myelocytes. In contrast to mouse bone marrow cell cultures, neither interleukin 3 nor a combination of interleukins 3 and 4 induced the differentiation of mast cells in human bone marrow or cord blood cell cultures. Images PMID:3258425

X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muckelbauer, Jodi; Sack, John S.; Ahmed, Nazia

Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 {angstrom} resolution and PP2 at 1.9 {angstrom} resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-orderedmore » protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.« less

Translation and validation of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) version 4 quality of life instrument into Arabic language.

PubMed

Soudy, Hussein; Maghfoor, Irfan; Elhassan, Tusneem Ahmed M; Abdullah, Eman; Rauf, Shahzad M; Al Zahrani, Ahmed; Akhtar, Saad

2018-03-12

Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) has been translated from English into several languages. Currently, there is no validated translation of FACT-BMT in Arabic. Here, we are reporting the first Arabic translation and validation of the FACT-BMT. The study was approved by the Institutional Research Advisory Council. The Arabic translation followed the standard Functional Assessment of Chronic Illness Therapy (FACIT.org) translation methodology (with permission). Arabic FACT-BMT (50- items) was statistically validated. Cronbach's alpha for internal consistency, Spearman's rank correlation coefficients method for Inter-scale correlations and Principal Component Analysis for factorial construct validity was used. One hundred and eight consecutive relapsed /refractory lymphoma patients who underwent high dose chemotherapy and autologous stem cell transplant were enrolled. There were 68 males (63%) and 40 females (37%) with a median age of 29 years (range 14-62). After Arabic questionnaire pre-testing (Cronbach's alpha 0.744), the study included 108 patients. Cronbach's alpha for the entire FACT-BMT indicated an excellent internal consistency (0.90); range (0.67 to 0.91). Cronbach's alpha for sub-groups of social (0.78), emotional (0.67) and functional wellbeing was (0.88). Cronbach's alpha for bone marrow transplant (0.81), FACT-General (0.89), and FACT- Trial Outcome Index (TOI); (0.91) also revealed excellent internal consistency. Patients had high scores in all domains of quality of life, indicating that most patients were leading a normal life. This translation of FACT-BMT in Arabic was reviewed and approved for submission by the FACIT.org. Our data reports the first translated, validated and approved Arabic version of FACT-BMT. This will help large numbers of Arabic speaking patients undergoing stem cell/bone marrow transplantation, across the globe.

The inward rectifier potassium channel Kir2.1 is expressed in mouse neutrophils from bone marrow and liver.

PubMed

Masia, Ricard; Krause, Daniela S; Yellen, Gary

2015-02-01

Neutrophils are phagocytic cells that play a critical role in innate immunity by destroying bacterial pathogens. Channels belonging to the inward rectifier potassium channel subfamily 2 (Kir2 channels) have been described in other phagocytes (monocytes/macrophages and eosinophils) and in hematopoietic precursors of phagocytes. Their physiological function in these cells remains unclear, but some evidence suggests a role in growth factor-dependent proliferation and development. Expression of functional Kir2 channels has not been definitively demonstrated in mammalian neutrophils. Here, we show by RT-PCR that neutrophils from mouse bone marrow and liver express mRNA for the Kir2 subunit Kir2.1 but not for other subunits (Kir2.2, Kir2.3, and Kir2.4). In electrophysiological experiments, resting (unstimulated) neutrophils from mouse bone marrow and liver exhibit a constitutively active, external K(+)-dependent, strong inwardly rectifying current that constitutes the dominant current. The reversal potential is dependent on the external K(+) concentration in a Nernstian fashion, as expected for a K(+)-selective current. The current is not altered by changes in external or internal pH, and it is blocked by Ba(2+), Cs(+), and the Kir2-selective inhibitor ML133. The single-channel conductance is in agreement with previously reported values for Kir2.1 channels. These properties are characteristic of homomeric Kir2.1 channels. Current density in short-term cultures of bone marrow neutrophils is decreased in the absence of growth factors that are important for neutrophil proliferation [granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF)]. These results demonstrate that mouse neutrophils express functional Kir2.1 channels and suggest that these channels may be important for neutrophil function, possibly in a growth factor-dependent manner. Copyright © 2015 the American Physiological Society.

Bone marrow support of the heart in pressure overload is lost with aging.

PubMed

Sopko, Nikolai A; Turturice, Benjamin A; Becker, Mitchell E; Brown, Chase R; Dong, Feng; Popović, Zoran B; Penn, Marc S

2010-12-21

Exogenous stem cell delivery is under investigation to prevent and treat cardiac dysfunction. It is less studied as to the extent endogenous bone marrow derived stem cells contribute to cardiac homeostais in response to stress and the affects of aging on this stress response. To determine the role of bone marrow (BM) derived stem cells on cardiac homeostasis in response to pressure overload (PO) and how this response is altered by aging. Young (8 weeks) and old (>40 weeks) C57/b6 mice underwent homo- and heterochronic BM transplantation prior to transverse aortic constriction (TAC). We found that older BM is associated with decreased cardiac function following TAC. This decreased function is associated with decrease in BM cell engraftment, increased myocyte apoptosis, decreased myocyte hypertrophy, increased myocardial fibrosis and decreased cardiac function. Additionally, there is a decrease in activation of resident cells within the heart in response to PO in old mice. Interestingly, these effects are not due to alterations in vascular density or inflammation in response to PO or differences in ex vivo stem cell migration between young and old mice. BM derived stem cells are activated in response to cardiac PO, and the recruitment of BM derived cells are involved in cardiac myocyte hypertrophy and maintenance of function in response to PO which is lost with aging.

MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation

PubMed Central

Li, Chang-Jun; Cheng, Peng; Liang, Meng-Ke; Chen, Yu-Si; Lu, Qiong; Wang, Jin-Yu; Xia, Zhu-Ying; Zhou, Hou-De; Cao, Xu; Xie, Hui; Liao, Er-Yuan; Luo, Xiang-Hang

2015-01-01

Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-dependent reduction in osteogenesis that is accompanied by an increased propensity toward adipocyte differentiation. This switch increases adipocyte numbers and decreases the number of osteoblasts, contributing to age-related bone loss. Here, we found that the level of microRNA-188 (miR-188) is markedly higher in BMSCs from aged compared with young mice and humans. Compared with control mice, animals lacking miR-188 showed a substantial reduction of age-associated bone loss and fat accumulation in bone marrow. Conversely, mice with transgenic overexpression of miR-188 in osterix+ osteoprogenitors had greater age-associated bone loss and fat accumulation in bone marrow relative to WT mice. Moreover, using an aptamer delivery system, we found that BMSC-specific overexpression of miR-188 in mice reduced bone formation and increased bone marrow fat accumulation. We identified histone deacetylase 9 (HDAC9) and RPTOR-independent companion of MTOR complex 2 (RICTOR) as the direct targets of miR-188. Notably, BMSC-specific inhibition of miR-188 by intra–bone marrow injection of aptamer-antagomiR-188 increased bone formation and decreased bone marrow fat accumulation in aged mice. Together, our results indicate that miR-188 is a key regulator of the age-related switch between osteogenesis and adipogenesis of BMSCs and may represent a potential therapeutic target for age-related bone loss. PMID:25751060

HA and double-layer HA-P2O5/CaO glass coatings: influence of chemical composition on human bone marrow cells osteoblastic behavior.

PubMed

Ferraz, M P; Fernandes, M H; Santos, J D; Monteiro, F J

2001-07-01

Human osteoblastic bone marrow derived cells were cultured for 28 days onto the surface of a glass reinforced hydroxyapatite (HA) composite and a commercial type HA plasma sprayed coatings, both in the "as-received" condition and after an immersion treatment with culture medium during 21 days. Cell proliferation and differentiation were analyzed as a function of the chemical composition of the coatings and the immersion treatment. Cell attachment, growth and differentiation of osteoblastic bone marrow cells seeded onto "as-received" plasma sprayed coatings were strongly affected by the time-dependent variation of the surface structure occurring during the first hours of culture. Initial interactions leading to higher amounts of adsorbed protein and zeta potential shifts towards negative charges appeared to result in surface structures with better biological performance. Cultures grown onto the pretreated coatings showed higher rate of cell proliferation and increased functional activity, as compared to those grown onto the corresponding "as-received" materials. However, the cell behavior was similar in the glass composite and HA coatings. The results showed that the glass composites present better characteristics for bone cell growth and function than HA. In addition, this work also provide evidence that the biological performance of the glass composites can be modulated and improved by manipulations in the chemical composition, namely in the content of glass added to HA. Copyright 2001 Kluwer Academic Publishers

Bone marrow monosomy 7: hematologic and clinical manifestations in childhood and adolescence.

PubMed

Hutter, J J; Hecht, F; Kaiser-McCaw, B; Hays, T; Baranko, P; Cohen, J; Durie, B

1984-01-01

The hematologic manifestations and clinical course are described for six children and adolescents with bone marrow monosomy 7. One child with secondary acute myelogenous leukemia had monosomy 7 plus a marker chromosome; the remaining patients had marrow monosomy 7 as the only karyotypic abnormality. The hematologic abnormalities were diverse, but the majority of patients had a smoldering preleukemic or myeloproliferative phase. Leukemic blasts were either undifferentiated or demonstrated evidence of myeloid differentiation. All patients responded poorly to antileukemic therapy. Bone marrow monosomy 7 was observed in one patient with severe marrow hypoplasia. Antileukemic therapy in another patient with greater than 30 per cent marrow blasts was associated with the development of a bone marrow myeloproliferative disorder with persistence of the monosomy 7 karyotype. We speculate that monosomy 7 may be a specific marker for a pluripotent hematopoietic stem cell abnormality that is associated with either blastic leukemia or a myeloproliferative disorder.

Pressure and shear stress in trabecular bone marrow during whole bone loading.

PubMed

Metzger, Thomas A; Schwaner, Stephen A; LaNeve, Anthony J; Kreipke, Tyler C; Niebur, Glen L

2015-09-18

Skeletal adaptation to mechanical loading is controlled by mechanobiological signaling. Osteocytes are highly responsive to applied strains, and are the key mechanosensory cells in bone. However, many cells residing in the marrow also respond to mechanical cues such as hydrostatic pressure and shear stress, and hence could play a role in skeletal adaptation. Trabecular bone encapsulates marrow, forming a poroelastic solid. According to the mechanical theory, deformation of the pores induces motion in the fluid-like marrow, resulting in pressure and velocity gradients. The latter results in shear stress acting between the components of the marrow. To characterize the mechanical environment of trabecular bone marrow in situ, pore pressure within the trabecular compartment of whole porcine femurs was measured with miniature pressure transducers during stress-relaxation and cyclic loading. Pressure gradients ranging from 0.013 to 0.46 kPa/mm were measured during loading. This range was consistent with calculated pressure gradients from continuum scale poroelastic models with the same permeability. Micro-scale computational fluid dynamics models created from computed tomography images were used to calculate the micromechanical stress in the marrow using the measured pressure differentials as boundary conditions. The volume averaged shear stress in the marrow ranged from 1.67 to 24.55 Pa during cyclic loading, which exceeds the mechanostimulatory threshold for mesenchymal lineage cells. Thus, the loading of bone through activities of daily living may be an essential component of bone marrow health and mechanobiology. Additional studies of cell-level interactions during loading in healthy and disease conditions will provide further incite into marrow mechanobiology. Copyright © 2015 Elsevier Ltd. All rights reserved.

A hyperboliod representation of the bone-marrow interface within 3D NMR images of trabecular bone: applications to skeletal dosimetry

NASA Astrophysics Data System (ADS)

Rajon, D. A.; Shah, A. P.; Watchman, C. J.; Brindle, J. M.; Bolch, W. E.

2003-06-01

Recent advances in physical models of skeletal dosimetry utilize high-resolution NMR microscopy images of trabecular bone. These images are coupled to radiation transport codes to assess energy deposition within active bone marrow irradiated by bone- or marrow-incorporated radionuclides. Recent studies have demonstrated that the rectangular shape of image voxels is responsible for cross-region (bone-to-marrow) absorbed fraction errors of up to 50% for very low-energy electrons (<50 keV). In this study, a new hyperboloid adaptation of the marching cube (MC) image-visualization algorithm is implemented within 3D digital images of trabecular bone to better define the bone-marrow interface, and thus reduce voxel effects in the assessment of cross-region absorbed fractions. To test the method, a mathematical sample of trabecular bone was constructed, composed of a random distribution of spherical marrow cavities, and subsequently coupled to the EGSnrc radiation code to generate reference values for the energy deposition in marrow or bone. Next, digital images of the bone model were constructed over a range of simulated image resolutions, and coupled to EGSnrc using the hyperboloid MC (HMC) algorithm. For the radionuclides 33P, 117mSn, 131I and 153Sm, values of S(marrow←bone) estimated using voxel models of trabecular bone were shown to have relative errors of 10%, 9%, <1% and <1% at a voxel size of 150 µm. At a voxel size of 60 µm, these errors were 6%, 5%, <1% and <1%, respectively. When the HMC model was applied during particle transport, the relative errors on S(marrow←bone) for these same radionuclides were reduced to 7%, 6%, <1% and <1% at a voxel size of 150 µm, and to 2%, 2%, <1% and <1% at a voxel size of 60 µm. The technique was also applied to a real NMR image of human trabecular bone with a similar demonstration of reductions in dosimetry errors.

The skeletal cell-derived molecule sclerostin drives bone marrow adipogenesis.

PubMed

Fairfield, Heather; Falank, Carolyne; Harris, Elizabeth; Demambro, Victoria; McDonald, Michelle; Pettitt, Jessica A; Mohanty, Sindhu T; Croucher, Peter; Kramer, Ina; Kneissel, Michaela; Rosen, Clifford J; Reagan, Michaela R

2018-02-01

The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi-potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic-induced fracture, systemic adiposity, and the presence of bone-homing cancers. Herein we provide evidence that signals from the bone matrix (osteocytes) determine marrow adiposity by regulating adipogenesis in the bone marrow. Specifically, we found that physiologically relevant levels of Sclerostin (SOST), which is a Wnt-inhibitory molecule secreted from bone matrix-embedded osteocytes, can induce adipogenesis in 3T3-L1 cells, mouse ear- and BM-derived MSCs, and human BM-derived MSCs. We demonstrate that the mechanism of SOST induction of adipogenesis is through inhibition of Wnt signaling in pre-adipocytes. We also demonstrate that a decrease of sclerostin in vivo, via both genetic and pharmaceutical methods, significantly decreases bone marrow adipose tissue (BMAT) formation. Overall, this work demonstrates a direct role for SOST in regulating fate determination of BM-adipocyte progenitors. This provides a novel mechanism for which BMAT is governed by the local bone microenvironment, which may prove relevant in the pathogenesis of certain diseases involving marrow adipose. Importantly, with anti-sclerostin therapy at the forefront of osteoporosis treatment and a greater recognition of the role of BMAT in disease, these data are likely to have important clinical implications. © 2017 Wiley Periodicals, Inc.

Gain-of-function mutation in FGFR3 in mice leads to decreased bone mass by affecting both osteoblastogenesis and osteoclastogenesis

PubMed Central

Su, Nan; Sun, Qidi; Li, Can; Lu, Xiumin; Qi, Huabing; Chen, Siyu; Yang, Jing; Du, Xiaolan; Zhao, Ling; He, Qifen; Jin, Min; Shen, Yue; Chen, Di; Chen, Lin

2010-01-01

Achondroplasia (ACH) is a short-limbed dwarfism resulting from gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Previous studies have shown that ACH patients have impaired chondrogenesis, but the effects of FGFR3 on bone formation and bone remodeling at adult stages of ACH have not been fully investigated. Using micro-computed tomography and histomorphometric analyses, we found that 2-month-old Fgfr3G369C/+ mice (mouse model mimicking human ACH) showed decreased bone mass due to reduced trabecular bone volume and bone mineral density, defect in bone mineralization and increased osteoclast numbers and activity. Compared with primary cultures of bone marrow stromal cells (BMSCs) from wild-type mice, Fgfr3G369C/+ cultures showed decreased cell proliferation, increased osteogenic differentiation including up-regulation of alkaline phosphatase activity and expressions of osteoblast marker genes, and reduced bone matrix mineralization. Furthermore, our studies also suggest that decreased cell proliferation and enhanced osteogenic differentiation observed in Fgfr3G369C/+ BMSCs are caused by up-regulation of p38 phosphorylation and that enhanced Erk1/2 activity is responsible for the impaired bone matrix mineralization. In addition, in vitro osteoclast formation and bone resorption assays demonstrated that osteoclast numbers and bone resorption area were increased in cultured bone marrow cells derived from Fgfr3G369C/+ mice. These findings demonstrate that gain-of-function mutation in FGFR3 leads to decreased bone mass by regulating both osteoblast and osteoclast activities. Our studies provide new insight into the mechanism underlying the development of ACH. PMID:20053668

SBDS Protein Expression Patterns in the Bone Marrow

PubMed Central

Wong, Trisha E.; Calicchio, Monica L.; Fleming, Mark D.; Shimamura, Akiko; Harris, Marian H.

2010-01-01

Shwachman Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome caused by biallelic SBDS gene mutations. Here we examined SBDS protein levels in human bone marrow. SBDS protein expression was high in neutrophil progenitors, megakaryocytes, plasma cells and osteoblasts. In contrast, SBDS protein levels were low in all hematopoietic cell lineages from patients harboring the common SBDS mutations. We conclude that SBDS protein levels vary widely between specific marrow lineages. Uniformly low SBDS protein expression levels distinguish the majority of SDS patients from controls or other marrow failure syndromes. PMID:20658628

Amodiaquine induced agranulocytosis: inhibition of colony growth in bone marrow by antimalarial agents.

PubMed Central

Rhodes, E G; Ball, J; Franklin, I M

1986-01-01

Bone marrow was cultured in vitro for colonies of granulocytes and macrophages five months after a patient had recovered from amodiaquine induced agranulocytosis. The addition of amodiaquine, chloroquine, and sulfadoxine to the culture was followed by a dose dependent inhibition of colony growth in the patient's marrow but not in normal control bone marrow. Colony growth was, however, unaffected by proguanil, pyrimethamine, and quinine. These findings show that in vitro marrow culture may have important predictive value in some cases of drug induced agranulocytosis. PMID:3082409

Interferon Regulatory Factor 6 Has a Protective Role in the Host Response to Endotoxic Shock

PubMed Central

Volk, Paige; Moreland, Jessica G.; Dunnwald, Martine

2016-01-01

Interferon Regulatory Factor (IRF) 6, a member of the IRF family, is essential for epidermal and orofacial embryonic development. Irf6 is strongly expressed in keratinocytes, in which it regulates epidermal proliferation, differentiation, and migration. A recent role for Irf6 in Toll-like receptor 2-dependent chemokine gene expression was also reported in an epithelial cell line. However, a function for Irf6 in innate immune cells was not previously reported. In the present study, we investigated the expression and function of Irf6 in bone marrow-derived neutrophils and macrophages. We show here, using a conditional knockout of Irf6 in lysosymeM expressing cells, that Irf6 is required for resistance to LPS-induced endotoxic shock. In addition, Irf6-deficient bone marrow-derived neutrophils exhibited increased chemotactic index and velocity compared with wild-type cells in vitro. TLR4-specific KC and IL6 secretions were upregulated in Irf6-deficient bone marrow-derived macrophages in vitro. These cells also exhibited an increased level of phosphorylated IkBa. Collectively, our findings suggest a role for Irf6 in the resistance to endotoxic shock due to NFk-B-mediated alteration of cytokine production. PMID:27035130

Cosmos 2229 immunology study (Experiment K-8-07)

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1993-01-01

The purpose of the current study was to further validate use of the rhesus monkey as a model for humans in future space flight testing. The areas of immunological importance examined in the Cosmos 2229 flight were represented by two sets of studies. The first set of studies determined the effect of space flight on the ability of bone marrow cells to respond to granulocyte/monocyte colony stimulating factor (GM-CSF). GM-CSF is an important regulator in the differentiation of bone marrow cells of both monocyte/macrophage and granulocyte lineages and any change in the ability of these cells to respond to GM-CSF can result in altered immune function. A second set of studies determined space flight effects on the expression of cell surface markers on both spleen and bone marrow cells. Immune cell markers included in this study were those for T-cell, B-cell, natural killer cell, and interleukin-2 populations. Variations from a normal cell population percentage, as represented by these markers, can be correlated with alterations in immunological function. Cells were stained with fluorescein-labelled antibodies directed against the appropriate antigens, and then analyzed using a flow cytometer.

Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model

PubMed Central

2013-01-01

Introduction The acute respiratory distress syndrome (ARDS), affects up to 150,000 patients per year in the United States. We and other groups have demonstrated that bone marrow derived mesenchymal stromal stem cells prevent ARDS induced by systemic and local administration of endotoxin (lipopolysaccharide (LPS)) in mice. Methods A study was undertaken to determine the effects of the diverse populations of bone marrow derived cells on the pathophysiology of ARDS, using a unique ex-vivo swine preparation, in which only the ventilated lung and the liver are perfused with autologous blood. Six experimental groups were designated as: 1) endotoxin alone, 2) endotoxin + total fresh whole bone marrow nuclear cells (BMC), 3) endotoxin + non-hematopoietic bone marrow cells (CD45 neg), 4) endotoxin + hematopoietic bone marrow cells (CD45 positive), 5) endotoxin + buffy coat and 6) endotoxin + in vitro expanded swine CD45 negative adherent allogeneic bone marrow cells (cultured CD45neg). We measured at different levels the biological consequences of the infusion of the different subsets of cells. The measured parameters were: pulmonary vascular resistance (PVR), gas exchange (PO2), lung edema (lung wet/dry weight), gene expression and serum concentrations of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6. Results Infusion of freshly purified autologous total BMCs, as well as non-hematopoietic CD45(-) bone marrow cells significantly reduced endotoxin-induced pulmonary hypertension and hypoxemia and reduced the lung edema. Also, in the groups that received BMCs and cultured CD45neg we observed a decrease in the levels of IL-1β and TNF-α in plasma. Infusion of hematopoietic CD45(+) bone marrow cells or peripheral blood buffy coat cells did not protect against LPS-induced lung injury. Conclusions We conclude that infusion of freshly isolated autologous whole bone marrow cells and the subset of non-hematopoietic cells can suppress the acute humoral and physiologic responses induced by endotoxemia by modulating the inflammatory response, mechanisms that do not involve engraftment or trans-differentiation of the cells. These observations may have important implications for the design of future cell therapies for ARDS. PMID:23497755

The protocol for the isolation and cryopreservation of osteoclast precursors from mouse bone marrow and spleen.

PubMed

Boraschi-Diaz, Iris; Komarova, Svetlana V

2016-01-01

Osteoclasts are responsible for physiological bone remodeling as well as pathological bone destruction in osteoporosis, periodontitis and rheumatoid arthritis, and thus represent a pharmacological target for drug development. We aimed to characterize and compare the cytokine-induced osteoclastogenesis of bone marrow and spleen precursors. Established protocols used to generate osteoclasts from bone marrow were modified to examine osteoclastogenesis of the spleen cells of healthy mice. Osteoclast formation was successfully induced from spleen precursors using receptor activator of nuclear factor κB ligand (50 ng/ml) and macrophage colony stimulating factor (50 ng/ml). Compared to bone marrow cultures, differentiation from spleen required a longer cultivation time (9 days for spleen, as compared to 5 days for marrow cultures) and a higher plating density of non-adherent cells (75,000/cm(2) for spleen, as compared to 50,000/cm(2) for bone marrow). Osteoclasts generated from spleen precursors expressed osteoclast marker genes calcitonin receptor, cathepsin K and matrix metalloproteinase 9 and were capable of resorbing hydroxyapatite. The differentiation capacity of spleen and bone marrow precursors was comparable for BALB/c, C57BL/6 and FVB mice. We also developed and tested a cryopreservation protocol for the osteoclast precursors. While 70-80 % of cells were lost during the first week of freezing, during the subsequent 5 weeks the losses were within 2-5 % per week. Osteoclastogenesis from the recovered bone marrow precursors was successful up to 5 weeks after freezing. Spleen precursors retained their osteoclastogenic capacity for 1 week after freezing, but not thereafter. The described protocol is useful for the studies of genetically modified animals as well as for screening new osteoclast-targeting therapeutics.

Synergy of bone marrow transplantation and curcumin ensue protective effects at early onset of diabetes in mice.

PubMed

Arivazhagan, Arivarasan; Krishna, Soni; Yadav, Shivangi; Shah, Harshit Rajesh; Kumar, Pravir; Ambasta, Rashmi Kumar

2015-07-01

The aim of this study was to investigate the early onset effects of diabetes on pro-angiogenic signaling pathway, total number of bone marrow cells, organs (pancreas and kidney) damage and the reversal effect of diabetes by combinatorial treatment of curcumin and bone marrow transplantation in streptozotocin (STZ) induced diabetic mice. In the present study, Streptozotocin induced diabetic mice were transplanted with bone marrow cells (2 × 10(6) ) followed by the administration of curcumin (80 mg/kg bodyweight). Effect of diabetes on the different organs was studied by H&E, Western blotting and immunofluorescence using vascular endothelial growth factor (VEGF), platelet/endothelial cell adhesion molecule (PECAM), insulin, Caspase-9 and Caspase-3 antibodies. The effect of diabetes results in the reduction of the total cell number and viability of the bone marrow cells, organ degeneration and lower VEGF/PECAM expression. However, transplantation with normal bone marrow cells significantly reduced the blood glucose levels (above normal range) and initiated the organ regeneration via the VEGF/PECAM mediated manner. Curcumin treatment further reduced the blood glucose level (near normal); and accelerated the organ regeneration, enhanced VEGF/PECAM expression and decreased caspase expression level in the organs. Curcumin also had a protective role against the glucotoxicity test performed on the bone marrow cells. This study suggests that bone marrow transplantation and curcumin administration is an effective treatment in reversing the early onset effects of diabetes via the VEGF/PECAM signaling pathway. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury.

PubMed

Toro, Luis; Barrientos, Víctor; León, Pablo; Rojas, Macarena; Gonzalez, Magdalena; González-Ibáñez, Alvaro; Illanes, Sebastián; Sugikawa, Keigo; Abarzúa, Néstor; Bascuñán, César; Arcos, Katherine; Fuentealba, Carlos; Tong, Ana María; Elorza, Alvaro A; Pinto, María Eugenia; Alzamora, Rodrigo; Romero, Carlos; Michea, Luis

2018-05-01

It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression in vivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

[Hematopoietic stem-cell transplantation in aplastic anemia].

PubMed

Hernández-Rivera, E Gabriela

2005-01-01

Severe aplastic anemia is a rare syndrome characterized by bone marrow failure with cytopenias and hypocellular bone marrow biopsy (usually 10-15%), without blasts or myelodysplasia. The first choice treatment for these patients is allogeneic bone marrow transplantation from a sibling matched for HLA-A, HLA-B and HLA-DR. Unfortunately only 30% of patients have an HLA-matched sibling (a 25% chance per sibling). The alternative treatment for severe aplastic anemia for the rest of the patients (70%) is immunosuppression with antithymocyte globuline and cyclosporine. The evolution of bone marrow transplantation since 1970's has been positive in terms of survival and transplant success (initial overall survival 43% vs. 90% lately, and graft rejection of 29% vs. 4%). The favorable outcome of bone marrow transplantation for severe or very severe aplastic anemia is due to: the use of conditioning with antithymocyte globuline and cyclophosphamide, the use of graft-vs.-host disease prophylaxis with short curse methotrexate and cyclosporine and the use of filtrated and irradiated blood products. For those patients without an HLA-matched related donor the first treatment to use is the immunosuppression with antithymocyte globuline and cyclosporine. Another option emerged in the late 80's is the unrelated bone marrow transplantation, with survival hardly half of the HLA-identical related bone marrow transplants. In our country, the first allogeneic bone marrow transplant was done in the Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, in a patient with aplastic anemia, making possible to perform this procedure safely in our country.

Stem cell niches and other factors that influence the sensitivity of bone marrow to radiation-induced bone cancer and leukaemia in children and adults

PubMed Central

Richardson, Richard B

2011-01-01

Purpose: This paper reviews and reassesses the internationally accepted niches or ‘targets’ in bone marrow that are sensitive to the induction of leukaemia and primary bone cancer by radiation. Conclusions: The hypoxic conditions of the 10 μm thick endosteal/osteoblastic niche where preleukemic stem cells and hematopoietic stem cells (HSC) reside provides a radioprotective microenvironment that is 2-to 3-fold less radiosensitive than vascular niches. This supports partitioning the whole marrow target between the low haematological cancer risk of irradiating HSC in the endosteum and the vascular niches within central marrow. There is a greater risk of induced bone cancer when irradiating a 50 μm thick peripheral marrow adjacent to the remodelling/reforming portion of the trabecular bone surface, rather than marrow next to the quiescent bone surface. This choice of partitioned bone cancer target is substantiated by the greater radiosensitivity of: (i) Bone with high remodelling rates, (ii) the young, (iii) individuals with hypermetabolic benign diseases of bone, and (iv) the epidemiology of alpha-emitting exposures. Evidence is given to show that the absence of excess bone-cancer in atomic-bomb survivors may be partially related to the extremely low prevalence among Japanese of Paget's disease of bone. Radiation-induced fibrosis and the wound healing response may be implicated in not only radiogenic bone cancers but also leukaemia. A novel biological mechanism for adaptive response, and possibility of dynamic targets, is advocated whereby stem cells migrate from vascular niches to stress-mitigated, hypoxic niches. PMID:21204614

Autologous bone marrow transplantation in relapsed adult acute leukemia.

PubMed

Dicke, K A; Zander, A R; Spitzer, G; Verma, D S; Peters, L J; Vellekoop, L; Thomson, S; Stewart, D; Hester, J P; McCredie, K B

1979-01-01

From March, 1976 to February, 1979, 28 cases of adult acute leukemia of which 24 were evaluable were treated in irreversible relapse with high dose chemotherapy (piperazinedione) and supra-lethal total body irradiation (TBI) in conjunction with autologous bone marrow transplantation (ABMT). The marrow cells grafted were collected and stored in liquid nitrogen at the time of remission. In 12 patients the marrow cells were fractionated using discontinuous albumin gradients in an attempt to separate normal cells from residual leukemic cells. Twelve patients achieved complete remission (CR); in 9 additional patients signs of engraftment were evident but death occurred before achievement of CR. Seven of 12 AML patients, which were treated with bone marrow transplantation as first treatment of their relapse, achieved CR. Four of 5 patients with ALL, whose bone marrows were collected during first remission, reached CR. The median CR duration was 4+ months and the median survival of the patients reaching CR was 6+ months. Autologous bone marrow transplantation offers a good chance of CR (66%), when marrow is collected during first remission and used as first treatment for AML in third relapse and ALL in second relapse.

Autologous bone marrow transplantation in relapsed adult acute leukemia.

PubMed

Dicke, K A; Zander, A R; Spitzer, G; Verma, D S; Peters, L; Vellekoop, L; Thomson, S; Stewart, D; McCredie, K B

1980-01-01

From March, 1976 to February, 1979, 28 cases of adult acute leukemia of which 24 were evaluable were treated in irreversible relapse with high dose chemotherapy (piperazinedione) and supra-lethal total body irradiation (TBI) in conjunction with autologous bone marrow transplantation (ABMT). The marrow cells grafted were collected and stored in liquid nitrogen at the time of remission. In 12 patients the marrow cells were fractionated using discontinuous albumin gradients in an attempt to separate normal cells from residual leukemic cells. Twelve patients achieved complete remission (CR); in 9 additional patients signs of engraftment were evident but death occurred before achievement of CR. Seven of 12 AML patients, which were treated with bone marrow transplantation as first treatment of their relapse, achieved CR. Four of 5 patients with ALL, whose bone marrows were collected during first remission, reached CR. The median CR duration was 4+ months and the median survival of the patients reaching CR was 6+ months. Autologous bone marrow transplantation offers a good chance of CR (66%) when marrow is collected during first remission and used as first treatment for AML in third relapse and ALL in second relapse.

Response functions for computing absorbed dose to skeletal tissues from neutron irradiation

NASA Astrophysics Data System (ADS)

Bahadori, Amir A.; Johnson, Perry; Jokisch, Derek W.; Eckerman, Keith F.; Bolch, Wesley E.

2011-11-01

Spongiosa in the adult human skeleton consists of three tissues—active marrow (AM), inactive marrow (IM) and trabecularized mineral bone (TB). AM is considered to be the target tissue for assessment of both long-term leukemia risk and acute marrow toxicity following radiation exposure. The total shallow marrow (TM50), defined as all tissues lying within the first 50 µm of the bone surfaces, is considered to be the radiation target tissue of relevance for radiogenic bone cancer induction. For irradiation by sources external to the body, kerma to homogeneous spongiosa has been used as a surrogate for absorbed dose to both of these tissues, as direct dose calculations are not possible using computational phantoms with homogenized spongiosa. Recent micro-CT imaging of a 40 year old male cadaver has allowed for the accurate modeling of the fine microscopic structure of spongiosa in many regions of the adult skeleton (Hough et al 2011 Phys. Med. Biol. 56 2309-46). This microstructure, along with associated masses and tissue compositions, was used to compute specific absorbed fraction (SAF) values for protons originating in axial and appendicular bone sites (Jokisch et al 2011 Phys. Med. Biol. 56 6857-72). These proton SAFs, bone masses, tissue compositions and proton production cross sections, were subsequently used to construct neutron dose-response functions (DRFs) for both AM and TM50 targets in each bone of the reference adult male. Kerma conditions were assumed for other resultant charged particles. For comparison, AM, TM50 and spongiosa kerma coefficients were also calculated. At low incident neutron energies, AM kerma coefficients for neutrons correlate well with values of the AM DRF, while total marrow (TM) kerma coefficients correlate well with values of the TM50 DRF. At high incident neutron energies, all kerma coefficients and DRFs tend to converge as charged-particle equilibrium is established across the bone site. In the range of 10 eV to 100 MeV, substantial differences are observed among the kerma coefficients and DRF. As a result, it is recommended that the AM kerma coefficient be used to estimate the AM DRF, and that the TM kerma coefficient be used to estimate the TM50 DRF below 10 eV. Between 10 eV and 100 MeV, the appropriate DRF should be used as presented in this study. Above 100 MeV, spongiosa kerma coefficients apply well for estimating skeletal tissue doses. DRF values for each bone site as a function of energy are provided in an electronic annex to this article available at http://stacks.iop.org/0031-9155/56/6873/mmedia.

Response functions for computing absorbed dose to skeletal tissues from neutron irradiation.

PubMed

Bahadori, Amir A; Johnson, Perry; Jokisch, Derek W; Eckerman, Keith F; Bolch, Wesley E

2011-11-07

Spongiosa in the adult human skeleton consists of three tissues-active marrow (AM), inactive marrow (IM) and trabecularized mineral bone (TB). AM is considered to be the target tissue for assessment of both long-term leukemia risk and acute marrow toxicity following radiation exposure. The total shallow marrow (TM(50)), defined as all tissues lying within the first 50 µm of the bone surfaces, is considered to be the radiation target tissue of relevance for radiogenic bone cancer induction. For irradiation by sources external to the body, kerma to homogeneous spongiosa has been used as a surrogate for absorbed dose to both of these tissues, as direct dose calculations are not possible using computational phantoms with homogenized spongiosa. Recent micro-CT imaging of a 40 year old male cadaver has allowed for the accurate modeling of the fine microscopic structure of spongiosa in many regions of the adult skeleton (Hough et al 2011 Phys. Med. Biol. 56 2309-46). This microstructure, along with associated masses and tissue compositions, was used to compute specific absorbed fraction (SAF) values for protons originating in axial and appendicular bone sites (Jokisch et al 2011 Phys. Med. Biol. 56 6857-72). These proton SAFs, bone masses, tissue compositions and proton production cross sections, were subsequently used to construct neutron dose-response functions (DRFs) for both AM and TM(50) targets in each bone of the reference adult male. Kerma conditions were assumed for other resultant charged particles. For comparison, AM, TM(50) and spongiosa kerma coefficients were also calculated. At low incident neutron energies, AM kerma coefficients for neutrons correlate well with values of the AM DRF, while total marrow (TM) kerma coefficients correlate well with values of the TM(50) DRF. At high incident neutron energies, all kerma coefficients and DRFs tend to converge as charged-particle equilibrium is established across the bone site. In the range of 10 eV to 100 MeV, substantial differences are observed among the kerma coefficients and DRF. As a result, it is recommended that the AM kerma coefficient be used to estimate the AM DRF, and that the TM kerma coefficient be used to estimate the TM(50) DRF below 10 eV. Between 10 eV and 100 MeV, the appropriate DRF should be used as presented in this study. Above 100 MeV, spongiosa kerma coefficients apply well for estimating skeletal tissue doses. DRF values for each bone site as a function of energy are provided in an electronic annex to this article available at http://stacks.iop.org/0031-9155/56/6873/mmedia.

Atmospheric pressure as a force that fills developing bones with marrow and air.

PubMed

Kurbel, Sven; Radić, Radivoje; Kristek, Branka; Ivezić, Zdravko; Selthofer, Robert; Kotromanović, Zeljko

2004-01-01

Many theories try to explain the existence and function of paranasal sinuses. This paper is an attempt to correlate process of paranasal sinus development in human with bone pneumatization processes in animals. It is here proposed that this mechanism starts in utero and continues after birth. During endochondral development, a solid hyaline cartilage model transforms into long bones. Central chondrocytes hypertrophy and their lacunae become confluent. Dissolving of the cartilage intercellular matrix forms a primitive marrow cavity. It is soon invaded by the periostal bud. Once circulation is established in the developing bone, the dissolved hyaline matrix can be slowly washed away from the bone cavity. Circulation in the bone cavity can develop slight subatmospheric pressures, similar to negative interstitial pressures in subcutaneous tissues. The amniotic fluid conducts atmospheric pressure to the fetal body. The pressure is trying to fill enlarging bone cavities through the existing vascular openings, or to create new openings. Bone walls of developing paranasal bones are to weak to resist the pressure gradient on their walls. New openings form on the weakest spots allowing airway mucosa to form initial paranasal sinuses. The enlarging cavities of long bones that are remote from the body surface and airway also develop a slightly subatmospheric pressure that fills them with cellular elements. These elements enter bone through the feeding vessels and form bone marrow. During after birth skeletal growth, bone remodeling shapes paranasal sinuses in a process of slow evolution that do not require measurable pressure gradients. When two sinuses come in vicinity, their growth rate declines, since the remaining thin and fragile bone lamella between them does not retract anymore.

Bone Marrow Adipose Tissue: To Be or Not To Be a Typical Adipose Tissue?

PubMed

Hardouin, Pierre; Rharass, Tareck; Lucas, Stéphanie

2016-01-01

Bone marrow adipose tissue (BMAT) emerges as a distinct fat depot whose importance has been proved in the bone-fat interaction. Indeed, it is well recognized that adipokines and free fatty acids released by adipocytes can directly or indirectly interfere with cells of bone remodeling or hematopoiesis. In pathological states, such as osteoporosis, each of adipose tissues - subcutaneous white adipose tissue (WAT), visceral WAT, brown adipose tissue (BAT), and BMAT - is differently associated with bone mineral density (BMD) variations. However, compared with the other fat depots, BMAT displays striking features that makes it a substantial actor in bone alterations. BMAT quantity is well associated with BMD loss in aging, menopause, and other metabolic conditions, such as anorexia nervosa. Consequently, BMAT is sensed as a relevant marker of a compromised bone integrity. However, analyses of BMAT development in metabolic diseases (obesity and diabetes) are scarce and should be, thus, more systematically addressed to better apprehend the bone modifications in that pathophysiological contexts. Moreover, bone marrow (BM) adipogenesis occurs throughout the whole life at different rates. Following an ordered spatiotemporal expansion, BMAT has turned to be a heterogeneous fat depot whose adipocytes diverge in their phenotype and their response to stimuli according to their location in bone and BM. In vitro, in vivo, and clinical studies point to a detrimental role of BM adipocytes (BMAs) throughout the release of paracrine factors that modulate osteoblast and/or osteoclast formation and function. However, the anatomical dissemination and the difficulties to access BMAs still hamper our understanding of the relative contribution of BMAT secretions compared with those of peripheral adipose tissues. A further characterization of the phenotype and the functional regulation of BMAs are ever more required. Based on currently available data and comparison with other fat tissues, this review addresses the originality of the BMAT with regard to its development, anatomy, metabolic properties, and response to physiological cues.

Dynamic T2-mapping during magnetic resonance guided high intensity focused ultrasound ablation of bone marrow

NASA Astrophysics Data System (ADS)

Waspe, Adam C.; Looi, Thomas; Mougenot, Charles; Amaral, Joao; Temple, Michael; Sivaloganathan, Siv; Drake, James M.

2012-11-01

Focal bone tumor treatments include amputation, limb-sparing surgical excision with bone reconstruction, and high-dose external-beam radiation therapy. Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) is an effective non-invasive thermotherapy for palliative management of bone metastases pain. MR thermometry (MRT) measures the proton resonance frequency shift (PRFS) of water molecules and produces accurate (<1°C) and dynamic (<5s) thermal maps in soft tissues. PRFS-MRT is ineffective in fatty tissues such as yellow bone marrow and, since accurate temperature measurements are required in the bone to ensure adequate thermal dose, MR-HIFU is not indicated for primary bone tumor treatments. Magnetic relaxation times are sensitive to lipid temperature and we hypothesize that bone marrow temperature can be determined accurately by measuring changes in T2, since T2 increases linearly in fat during heating. T2-mapping using dual echo times during a dynamic turbo spin-echo pulse sequence enabled rapid measurement of T2. Calibration of T2-based thermal maps involved heating the marrow in a bovine femur and simultaneously measuring T2 and temperature with a thermocouple. A positive T2 temperature dependence in bone marrow of 20 ms/°C was observed. Dynamic T2-mapping should enable accurate temperature monitoring during MR-HIFU treatment of bone marrow and shows promise for improving the safety and reducing the invasiveness of pediatric bone tumor treatments.

Inherited Bone Marrow Failure Syndromes (IBMFS)

Cancer.gov

The NCI IBMFS Cohort Study consists of affected individuals and their immediate families in North America who have an inherited bone marrow failure syndrome (IBMFS)-either one that has been specifically identified and defined, or bone marrow failure that appears to be inherited but has not yet been clearly identified as having a genetic basis.

Fetal bovine bone marrow is a rich source of CD34+ hematopoietic progenitors with myelo-monocytic colony-forming activity.

PubMed

Pessa-Morikawa, Tiina; Niku, Mikael; Iivanainen, Antti

2012-03-01

The CD34 glycoprotein is an important marker of hematopoietic stem cells. We used a polyclonal rabbit anti-bovine CD34 antibody to stain fetal and adult bovine bone marrow cells. Flow cytometry revealed a low side scatter (SSC(low)) population of cells that were CD34(+) but negative for leukocyte lineage markers CD11b, CD14 or CD2. Hematopoietic colony assays with CD34(+) and CD34(-) bone marrow cells suggested that the colony-forming potential in SSC(low) bone marrow cells was confined to the CD34(+) fraction. In contrast, this population was not enriched for cells expressing high aldehyde dehydrogenase activity, a metabolic marker that has been used to characterize hematopoietic stem cells. Thus, the CD34 antigen can be used to identify and isolate bovine bone marrow cells exhibiting clonogenic potential in vitro. Moreover, the proportion of CD34(+) cells is very high in fetal bovine bone marrow, indicating it as a rich source of hematopoietic progenitors. Copyright © 2011 Elsevier Ltd. All rights reserved.

Immunophenotypic analysis of hematopoiesis in patients suffering from Shwachman-Bodian-Diamond Syndrome.

PubMed

Mercuri, Angela; Cannata, Elisa; Perbellini, Omar; Cugno, Chiara; Balter, Rita; Zaccaron, Ada; Tridello, Gloria; Pizzolo, Giovanni; De Bortoli, Massimiliano; Krampera, Mauro; Cipolli, Marco; Cesaro, Simone

2015-10-01

Shwachman-Diamond syndrome is a rare disorder characterized by exocrine pancreatic insufficiency, skeletal abnormalities, and bone marrow failure, with high risk of leukemic evolution. The aim of the study was the immunophenotypic characterization of bone marrow cells from patients with Shwachman-Diamond syndrome to assess the maturation pathway of blood progenitor cells and to identify the presence of recurrent abnormalities. Bone marrow samples from nineteen patients and eleven controls were analyzed by multiparameter flow cytometry. We found a low frequency of CD34+ cells (P = 0.0179) and myeloid progenitors (P = 0.025), in the bone marrow of patients with Shwachman-Diamond syndrome as compared to the controls. A significant reduction in the percentage of granulocytes (P = 0.002) and an increase of monocytes (P < 0.001) were also evident in the bone marrow of patients. On the basis of these observations, future prospective assessments may be useful to verify the contribution of bone marrow immunophenotype in the early identification of the evolution toward aplasia or myelodysplasia. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of low-doses of Bacillus spp. from permafrost on differentiation of bone marrow cells.

PubMed

Kalyonova, L F; Novikova, M A; Kostolomova, E G

2015-01-01

The effects of a new microorganism species (Bacillus spp., strain M3) isolated from permafrost specimens from Central Yakutia (Mamontova Mountain) on the bone marrow hemopoiesis were studied on laboratory mice. Analysis of the count and immunophenotype of bone marrow cells indicated that even in low doses (1000-5000 microbial cells) these microorganisms modulated hemopoiesis and lymphopoiesis activity. The percentage of early hemopoietic precursors (CD117(+)CD34(-)) increased, intensity of lymphocyte precursor proliferation and differentiation (CD25(+)CD44(-)) decreased, and the percentage of lymphocytes released from the bone marrow (CD25(+)CD44(+)) increased on day 21 after injection of the bacteria. These changes in activity of hemopoiesis were associated with changes in the level of regulatory T lymphocytes (reduced expression of TCRαβ) and were most likely compensatory. The possibility of modulating hemopoiesis activity in the bone marrow by low doses of one microorganism strain isolated from the permafrost could be useful for evaluating the effects of other low dose bacteria on the bone marrow hemopoiesis.

Association of bone marrow edema with temporomandibular joint (TMJ) osteoarthritis and internal derangements.

PubMed

Wahaj, Aiyesha; Hafeez, Kashif; Zafar, Muhammad Sohail

2017-01-01

This study reviewed the dental literature in order to determine the association of bone marrow edema with osteoarthritis and temporomandibular joint (TMJ) internal derangement disorders. A literature search was performed using electronic databases PubMed/Medline (National Library of Medicine, Bethesda, Maryland) and Cochrane for articles published during the last 15 years (January 2000-December 2014). A predetermined inclusion and exclusion criteria were used for filtering the scientific papers. Research articles fulfilling the basic inclusion criteria were included in the review. The reviewed studies showed that bone marrow edema is found in painful joints with osteoarthritis in a majority of cases. A few cases with no pain or significant degenerative changes are reported to have a bone marrow edema pattern as well. Bone marrow edema, increased fluid level, and pain are associated with osteoarthritis in the majority of patients reporting TMJ arthritis. Degenerative and disc displacement conditions are multifactorial and require further investigations. Magnetic resonance imaging can be employed to detect bone marrow edema even in the absence of pain and clinical symptoms in the patients of internal derangements.

Enrichment of human bone marrow aspirates for low-density mononuclear cells using a haemonetics discontinuous blood cell separator.

PubMed

Raijmakers, R; de Witte, T; Koekman, E; Wessels, J; Haanen, C

1986-01-01

Isopycnic density floatation centrifugation has been proven to be a suitable technique to enrich bone marrow aspirates for clonogenic cells on a small scale. We have tested a Haemonetics semicontinuous blood cell separator in order to process large volumes of bone marrow with minimal bone marrow manipulation. The efficacy of isopycnic density floatation was tested in a one and a two-step procedure. Both procedures showed a recovery of about 20% of the nucleated cells and 1-2% of the erythrocytes. The enrichment of clonogenic cells in the one-step procedure appeared superior to the two-step enrichment, first separating buffy coat cells. The recovery of clonogenic cells was 70 and 50%, respectively. Repopulation capacity of the low-density cell fraction containing the clonogenic cells was excellent after autologous reinfusion (6 cases) and allogeneic bone marrow transplantation (3 cases). Fast enrichment of large volumes of bone marrow aspirates with low-density cells containing the clonogenic cells by isopycnic density floatation centrifugation can be done safely using a Haemonetics blood cell separator.

Haematological validation of a computer-based bone marrow reporting system.

PubMed Central

Nguyen, D T; Diamond, L W; Cavenagh, J D; Parameswaran, R; Amess, J A

1997-01-01

AIMS: To prove the safety and effectiveness of "Professor Belmonte", a knowledge-based system for bone marrow reporting, a formal evaluation of the reports generated by the system was performed. METHODS: Three haematologists (a consultant, a senior registrar, and a junior registrar), none of whom were involved in the development of the software, compared the unedited reports generated by Professor Belmonte with the original bone marrow reports in 785 unselected cases. Each haematologist independently graded the quality of Belmonte's reports using one of four categories: (a) better than the original report (more informative, containing useful information missing in the original report); (b) equivalent to the original report; (c) satisfactory, but missing information that should have been included; and (d) unsatisfactory. RESULTS: The consultant graded 64 reports as more informative than the original, 687 as equivalent to the original, 32 as satisfactory, and two as unsatisfactory. The senior registrar considered 29 reports to be better than the original, 739 to be equivalent to the original, 15 to be satisfactory, and two to be unsatisfactory. The junior registrar found that 88 reports were better than the original, 681 were equivalent to the original, 14 were satisfactory, and two were unsatisfactory. Each judge found two different reports to be unsatisfactory according to their criteria. All 785 reports generated by the computer system received at least two scores of satisfactory or better. CONCLUSIONS: In this representative study, Professor Belmonte generated bone marrow reports that proved to be as accurate as the original reports in a large university hospital. The haematology knowledge contained within the system, the reasoning process, and the function of the software are safe and effective for assisting haematologists in generating high quality bone marrow reports. PMID:9215118

VAV1-Cre mediated hematopoietic deletion of CBL and CBL-B leads to JMML-like aggressive early-neonatal myeloproliferative disease

PubMed Central

An, Wei; Mohapatra, Bhopal C.; Zutshi, Neha; Bielecki, Timothy A.; Goez, Benjamin T.; Luan, Haitao; Iseka, Fany; Mushtaq, Insha; Storck, Matthew D.; Band, Vimla; Band, Hamid

2016-01-01

CBL and CBL-B ubiquitin ligases play key roles in hematopoietic stem cell homeostasis and their aberrations are linked to leukemogenesis. Mutations of CBL, often genetically-inherited, are particularly common in Juvenile Myelomonocytic Leukemia (JMML), a disease that manifests early in children. JMML is fatal unless corrected by bone marrow transplant, which is effective in only half of the recipients, stressing the need for animal models that recapitulate the key clinical features of this disease. However, mouse models established so far only develop hematological malignancy in adult animals. Here, using VAV1-Cre-induced conditional CBL/CBL-B double knockout (DKO) in mice, we established an animal model that exhibits a neonatal myeloproliferative disease (MPD). VAV1-Cre induced DKO mice developed a strong hematological phenotype at postnatal day 10, including severe leukocytosis and hepatomegaly, bone marrow cell hypersensitivity to cytokines including GM-CSF, and rapidly-progressive disease and invariable lethality. Interestingly, leukemic stem cells were most highly enriched in neonatal liver rather than bone marrow, which, along with the spleen and thymus, were hypo-cellular. Nonetheless, transplantation assays showed that both DKO bone marrow and liver cells can initiate leukemic disease in the recipient mice with seeding of both spleen and bone marrow. Together, our results support the usefulness of the new hematopoietic-specific CBL/CBL-B double KO animal model to study JMML-related pathogenesis and to further understand the function of CBL family proteins in regulating fetal and neonatal hematopoiesis. To our knowledge, this is the first mouse model that exhibits neonatal MPD in infancy, by day 10 of postnatal life. PMID:27449297

Quercetin potentiates transdifferentiation of bone marrow mesenchymal stem cells into the beta cells in vitro.

PubMed

Miladpour, B; Rasti, M; Owji, A A; Mostafavipour, Z; Khoshdel, Z; Noorafshan, A; Zal, F

2017-05-01

Type 1 diabetes is an autoimmune disease caused by the destruction of β-cells in the pancreas. Bone marrow mesenchymal stem cells are multipotent and easy accessible adult stem cells that may provide options in the treatment of type 1 diabetes. Injured pancreatic extract can promote the differentiation of rat bone marrow mesenchymal stem cells into β-cells. We aimed to observe the effect of quercetin in differentiation and insulin secretion in β-cells. Bone marrow mesenchymal stem cells were obtained from the tibiae of rats. Cell surface markers were analyzed by flow cytometry. The cells were treated with rat injured pancreatic extract and quercetin for 2 weeks. Insulin secretion was measured by ELISA. Insulin expression and some islet factors were evaluated by RT-PCR. PDX1, a marker for β-cell function and differentiation, was evaluated by both immunocytochemistry and Western blot. β-cell count was determined by stereology and cell count assay. ELISA showed significant differences in insulin secretion in the cells treated with RIPE + 20 μM quercetin (0.55 ± 0.01 µg/L) compared with the cells treated with RIPE alone (0.48 ± 0.01 µg/L) (P = 0.026). RT-PCR results confirmed insulin expression in both groups. PDX1 protein was detected in both groups by Western blot and immunocytochemistry. Stereology results showed a significant increase in β-cell number in the RIPE + quercetin-treated cells (47 ± 2.0) when compared with RIPE treatment alone (44 ± 2.5) (P = 0.015). Quercetin has a strengthening effect on the differentiation of rat bone marrow mesenchymal stem cells into β-cells and increases insulin secretion from the differentiated β-cells in vitro.

Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis.

PubMed

Ding, Lin; Liu, Tianju; Wu, Zhe; Hu, Biao; Nakashima, Taku; Ullenbruch, Matthew; Gonzalez De Los Santos, Francina; Phan, Sem H

2016-07-01

Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis, but its cellular source and role in regeneration versus fibrosis remain unclear. In this study, we hypothesize that AREG induced in bone marrow-derived CD11c(+) cells is essential for pulmonary fibrosis. Thus, the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction, and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c(+) cells. Moreover, depletion of bone marrow-derived CD11c(+) cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c(+) cells from bleomycin-treated donor mice exacerbated pulmonary fibrosis, but not if the donor cells were made AREG deficient prior to transfer. CD11c(+) cell-conditioned media or coculture stimulated fibroblast proliferation, activation, and myofibroblast differentiation in an AREG-dependent manner. Furthermore, recombinant AREG induced telomerase reverse transcriptase, which appeared to be essential for the proliferative effect. Finally, AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c(+) cells promoted bleomycin-induced pulmonary fibrosis by activation of fibroblast telomerase reverse transcriptase-dependent proliferation, motility, and indirectly, myofibroblast differentiation. Copyright © 2016 by The American Association of Immunologists, Inc.

Modeling Hematopoiesis and Responses to Radiation Countermeasures in a Bone Marrow-on-a-Chip.

PubMed

Torisawa, Yu-Suke; Mammoto, Tadanori; Jiang, Elisabeth; Jiang, Amanda; Mammoto, Akiko; Watters, Alexander L; Bahinski, Anthony; Ingber, Donald E

2016-05-01

Studies on hematopoiesis currently rely on animal models because in vitro culture methods do not accurately recapitulate complex bone marrow physiology. We recently described a bone marrow-on-a-chip microfluidic device that enables the culture of living hematopoietic bone marrow and mimics radiation toxicity in vitro. In the present study, we used this microdevice to demonstrate continuous blood cell production in vitro and model bone marrow responses to potential radiation countermeasure drugs. The device maintained mouse hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture. Increases in the number of leukocytes and red blood cells into the microfluidic circulation also could be detected over time, and addition of erythropoietin induced a significant increase in erythrocyte production. Exposure of the bone marrow chip to gamma radiation resulted in reduction of leukocyte production, and treatment of the chips with two potential therapeutics, granulocyte-colony stimulating factor or bactericidal/permeability-increasing protein (BPI), induced significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow. In contrast, BPI was not found to have any effect when analyzed using static marrow cultures, even though it has been previously shown to accelerate recovery from radiation-induced toxicity in vivo. These findings demonstrate the potential value of the bone marrow-on-a-chip for modeling blood cell production, monitoring responses to hematopoiesis-modulating drugs, and testing radiation countermeasures in vitro.

Skeletal dosimetry in the MAX06 and the FAX06 phantoms for external exposure to photons based on vertebral 3D-microCT images

NASA Astrophysics Data System (ADS)

Kramer, R.; Khoury, H. J.; Vieira, J. W.; Kawrakow, I.

2006-12-01

3D-microCT images of vertebral bodies from three different individuals have been segmented into trabecular bone, bone marrow and bone surface cells (BSC), and then introduced into the spongiosa voxels of the MAX06 and the FAX06 phantoms, in order to calculate the equivalent dose to the red bone marrow (RBM) and the BSC in the marrow cavities of trabecular bone with the EGSnrc Monte Carlo code from whole-body exposure to external photon radiation. The MAX06 and the FAX06 phantoms consist of about 150 million 1.2 mm cubic voxels each, a part of which are spongiosa voxels surrounded by cortical bone. In order to use the segmented 3D-microCT images for skeletal dosimetry, spongiosa voxels in the MAX06 and the FAX06 phantom were replaced at runtime by so-called micro matrices representing segmented trabecular bone, marrow and BSC in 17.65, 30 and 60 µm cubic voxels. The 3D-microCT image-based RBM and BSC equivalent doses for external exposure to photons presented here for the first time for complete human skeletons are in agreement with the results calculated with the three correction factor method and the fluence-to-dose response functions for the same phantoms taking into account the conceptual differences between the different methods. Additionally the microCT image-based results have been compared with corresponding data from earlier studies for other human phantoms. This article is dedicated to Prof. Dr Guenter Drexler from the Laboratório de Ciências Radiológicas, State University of Rio de Janeiro, on the occasion of his 70th birthday.

BK virus associated pronounced hemorrhagic cystoureteritis after bone marrow transplantation.

PubMed

Haab, Alexander C; Keller, Isabelle S; Padevit, Christian; John, Hubert

2015-10-01

Ureteral stenosis due to reactivation of the BK virus (BKV) in a state of immunodeficiency is very rare. More common is the appearance of a hemorrhagic cystitis. This report not only shows bilateral ureteral stenosis after bone marrow transplantation, but also presents severe complications as chronic pelvic pain and impaired kidney function as well as irreparable damage to the whole urinary tract leading to nephroureterectomy, subtrigonal cystectomy and orthotopic ileal neobladder. Finally renal transplantation was required. To our knowledge this is the first case in the literature where such a severe course of BKV associated hemorrhagic cystoureteritis is described.

Determination of the Fate and Function of Innate Lymphoid Cells Following Adoptive Transfer of Innate Lymphoid Cell Precursors.

PubMed

O'Sullivan, Timothy E; Sun, Joseph C

2018-01-01

Innate lymphoid cells are a heterogeneous family of tissue-resident and circulating lymphocytes that play an important role in host immunity. Recent studies have profiled the developmental pathways of mature ILCs and have identified ILC progenitors in the bone marrow through the use of transcription factor reporter mice. Here we describe methodology to identify and isolate bone marrow CHILP and ILC2 progenitor (ILC2P) cells based on cell surface marker expression for adoptive transfer into lymphopenic mice to track the fate of developing ILCs.

Pearson disease in an infant presenting with severe hypoplastic anemia, normal pancreatic function, and progressive liver failure.

PubMed

Shapira, Adi; Konopnicki, Muriel; Hammad-Saied, Mohammed; Shabad, Evelyn

2014-07-01

Pearson disease is a rare, usually fatal, mitochondrial disorder affecting primarily the bone marrow and the exocrine pancreas. We report a previously healthy 10-week-old girl who presented with profound macrocytic anemia followed by pancytopenia, synthetic liver dysfunction with liver steatosis, and metabolic acidosis with high lactate levels. She had no pancreatic involvement. Multiple cytoplasmic vacuoles in myelocytes and monocytes were seen upon microscopic evaluation of the bone marrow. Genetic analysis of the mitochondrial genome revealed a 5 kbp deletion, thus establishing the diagnosis of Pearson disease.

Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders.

PubMed

Malouf, Reem; Ashraf, Asma; Hadjinicolaou, Andreas V; Doree, Carolyn; Hopewell, Sally; Estcourt, Lise J

2018-05-14

Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries. To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders. We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017. We included RCTs, non-RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster-RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant. We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes. We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs. We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.

Flow cytometry in the bone marrow evaluation of follicular and diffuse large B-cell lymphomas.

PubMed

Palacio, C; Acebedo, G; Navarrete, M; Ruiz-Marcellán, C; Sanchez, C; Blanco, A; López, A

2001-09-01

Bone marrow biopsies are routinely performed in the staging of patients with lymphoma. Despite the lack of evidence for its usefulness, many institutions include flow cytometry (FC) of bone-marrow aspirates in an attempt to increase sensitivity and specificity. The aim of this study is to evaluate the usefulness of FC for the assessment of bone-marrow involvement by lymphoma in follicular (FL) and diffuse large B-cell lymphomas (DLBCL). Seventy-nine bone marrow biopsies from 65 patients diagnosed with FL or DLBCL were examined to compare histology and FC for the assessment of bone-marrow involvement by lymphoma. Bone marrow histology showed involvement (BM+) in 16 cases (20.3%), lack of infiltration (BM(-)) in 52 cases (65.8%) and undetermined or undiagnosed for involvement (BMu) in 11 cases (13.9%). FC was positive for involvement in 28 cases (35.4%) and negative in 51 cases (64.6%). 65 cases (95%) showed concordance between the results of morphology and FC (BM(+)/FC(+) or BM(-)/FC(-)). No BM(+)/FC(-) cases were observed. 3 cases showed discrepant results (BM(-)/FC(+)). In these 3 cases the molecular studies (PCR) demonstrated clonal rearrangement of the heavy immunoglobulin chain (IgH) and/or bcl2-IgH in agreement with the flow results. Among the 11 cases with BMu, all but 2 were FC(+) and concordance with the PCR results was seen in 9 cases (81.9%). We conclude that FC is just as sensitive or perhaps slightly more sensitive than histology in the detection of bone marrow involvement in FL and DLBCL. FC studies may be warranted in those cases in which the morphology is not diagnosed. The clinical relevance of the small clonal B-cell population in patients without histologic bone marrow involvement (BM(-)/FC(+) cases) remains an open question.

SU-F-R-55: Early Detection of Treatment Induced Bone Marrow Injury During Chemoradiation Therapy Using Quantitative CT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, X; Song, Y; Erickson, B

Purpose: Acute hematologic toxicity associated with bone marrow injury is a common complication of chemoradiation therapy (CRT) for pelvic malignancies. In this work, we investigate the feasibility of using quantitative CT to detect bone marrow injury during CRT. Methods: Daily CTs were acquired during routine CT-guided radiation therapy using a CT-on-rails for 15 cervical cancer patients. All patients treated with a radiation dose of 45.0 to 50.4 Gy in 1.8 Gy/fraction along with chemotherapy. For each patient, the contours of bone marrow were generated in L4, L5 and sacrum on the first daily CT and then populated to other dailymore » CTs by rigid registration using MIM (MIM Software Inc., Cleveland, OH) with manual editing if possible. A series of CT texture parameters, including Hunsfield Unit (HU) histogram, mean HU, entropy, energy, in bone marrow contours were calculated using MATLAB on each daily CT and were correlated with the completed blood counts (CBC) collected weekly for each patient. The correlations were analyzed with Pearson correlation tests. Results: For all patient data analyzed, mean HU in bone marrow decreased during CRT delivery. From the first to the last fraction the average mean HU reduction is 58.1 ± 13.6 HU (P<0.01). This decrease can be observed as early as after first 5 fractions and is strongly associated with the changes of most CBC quantities, such as the reductions of white and blood cell counts (r=0.97, P=0.001). The reduction of HU is spatially varied. Conclusion: Chemoradiation induced bone marrow injury can be detected during the delivery of CRT using quantitative CT. Chemoradiation results in reductions in mean HU, which are strongly associated with the change in the pretrial blood cell counts. Early detection of bone marrow injury with commonly available CT opens a door to improve bone marrow sparing, reducing risk of hematologic toxicity.« less

Busulfan Injection

MedlinePlus

... marrow and cancer cells in preparation for a bone marrow transplant. Busulfan is in a class of medications called ... days (for a total of 16 doses) before bone marrow transplant.Busulfan injection may cause seizures during therapy with ...

Yeast-2-Hybrid data file showing progranulin interactions in human fetal brain and bone marrow libraries.

PubMed

Tegeder, Irmgard

2016-12-01

Progranulin deficiency in humans is associated with neurodegeneration. Its mechanisms are not yet fully understood. We performed a Yeast-2-Hybrid screen using human full-length progranulin as bait to assess the interactions of progranulin. Progranulin was screened against human fetal brain and human bone marrow libraries using the standard Matchmaker technology (Clontech). This article contains the full Y2H data table, including blast results and sequences, a sorted table according to selection criteria for likely positive, putatively positive, likely false and false preys, and tables showing the gene ontology terms associated with the likely and putative preys of the brain and bone marrow libraries. The interactions with autophagy proteins were confirmed and functionally analyzed in "Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy" (C. Altmann, S. Hardt, C. Fischer, J. Heidler, H.Y. Lim, A. Haussler, B. Albuquerque, B. Zimmer, C. Moser, C. Behrends, F. Koentgen, I. Wittig, M.H. Schmidt, A.M. Clement, T. Deller, I. Tegeder, 2016) [1].

Adenosine A(3) receptor agonist acts as a homeostatic regulator of bone marrow hematopoiesis.

PubMed

Hofer, Michal; Pospísil, Milan; Znojil, Vladimír; Holá, Jirina; Vacek, Antonín; Streitová, Denisa

2007-07-01

The present study was performed to define the optimum conditions of the stimulatory action of the adenosine A(3) receptor agonist, N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), on bone marrow hematopoiesis in mice. Effects of 2-day treatment with IB-MECA given at single doses of 200nmol/kg twice daily were investigated in normal mice and in mice whose femoral bone marrow cells were either depleted or regenerating after pretreatment with the cytotoxic drug 5-fluorouracil. Morphological criteria were used to determine the proliferation state of the granulocytic and erythroid cell systems. Significant negative correlation between the control proliferation state and the increase of cell proliferation after IB-MECA treatment irrespective of the cell lineage investigated was found. The results suggest the homeostatic character of the induced stimulatory effects and the need to respect the functional state of the target tissue when investigating effects of adenosine receptor agonists under in vivo conditions.

Profilin 1 is essential for retention and metabolism of mouse hematopoietic stem cells in bone marrow

PubMed Central

Zheng, Junke; Lu, Zhigang; Kocabas, Fatih; Böttcher, Ralph T.; Costell, Mercedes; Kang, Xunlei; Liu, Xiaoye; DeBerardinis, Ralph J.; Wang, Qianming; Chen, Guo-Qiang

2014-01-01

How stem cells interact with the microenvironment to regulate their cell fates and metabolism is largely unknown. Here we demonstrated that the deletion of the cytoskeleton-modulating protein profilin 1 (pfn1) in hematopoietic stem cell (HSCs) led to bone marrow failure, loss of quiescence, and mobilization and apoptosis of HSCs in vivo. A switch from glycolysis to mitochondrial respiration with increased reactive oxygen species (ROS) level was also observed in HSCs on pfn1 deletion. Importantly, treatment of pfn1-deficient mice with the antioxidant N-acetyl-l-cysteine reversed the ROS level and loss of quiescence of HSCs, suggesting that the metabolism is mechanistically linked to the cell cycle quiescence of stem cells. The actin-binding and proline-binding activities of pfn1 are required for its function in HSCs. Our study provided evidence that pfn1 at least partially acts through the axis of pfn1/Gα13/EGR1 to regulate stem cell retention and metabolism in the bone marrow. PMID:24385538

An Unexpected Complication of Bone Marrow Aspiration and Trephine Biopsy: Arteriovenous Fistula

PubMed Central

Berber, Ilhami; Erkurt, Mehmet Ali; Kuku, Irfan; Kaya, Emin; Kutlu, Ramazan; Koroglu, Mustafa; Yigit, Ali; Unlu, Serkan

2014-01-01

Objective To report a case of arteriovenous fistula (AVF) following bone marrow aspiration and trephine biopsy. Clinical Presentation and Intervention A 76-year-old man was diagnosed with acute myeloblastic leukemia. Pain and hematoma were detected in his left leg and hip 4 days after bone marrow aspiration and trephine biopsy. A pelvic arteriography was performed, and a diagnosis of AVF was made. Conclusion This case shows that clinicians should be aware of AVF, especially in cases with refractory bleeding after bone marrow aspiration and trephine biopsy despite normal blood coagulation parameters. PMID:24481007

Bone marrow transplant – children - discharge

MedlinePlus

Transplant - bone marrow - children - discharge; Stem cell transplant - children - discharge; Hematopoietic stem cell transplant -children - discharge; Reduced intensity, non-myeloablative transplant - children - discharge; Mini transplant - children - discharge; Allogenic bone ...

Comparison of methodologies in determining bone marrow fat percentage under different environmental conditions.

PubMed

Murden, David; Hunnam, Jaimie; De Groef, Bert; Rawlin, Grant; McCowan, Christina

2017-01-01

The use of bone marrow fat percentage has been recommended in assessing body condition at the time of death in wild and domestic ruminants, but few studies have looked at the effects of time and exposure on animal bone marrow. We investigated the utility of bone marrow fat extraction as a tool for establishing antemortem body condition in postmortem specimens from sheep and cattle, particularly after exposure to high heat, and compared different techniques of fat extraction for this purpose. Femora were collected from healthy and "skinny" sheep and cattle. The bones were either frozen or subjected to 40°C heat; heated bones were either wrapped in plastic to minimize desiccation or were left unwrapped. Marrow fat percentage was determined at different time intervals by oven-drying, or by solvent extraction using hexane in manual equipment or a Soxhlet apparatus. Extraction was performed, where possible, on both wet and dried tissue. Multiple samples were tested from each bone. Bone marrow fat analysis using a manual, hexane-based extraction technique was found to be a moderately sensitive method of assessing antemortem body condition of cattle up to 6 d after death. Multiple replicates should be analyzed where possible. Samples from "skinny" sheep showed a different response to heat from those of "healthy" sheep; "skinny" samples were so reduced in quantity by day 6 (the first sampling day) that no individual testing could be performed. Further work is required to understand the response of sheep marrow.

CHIP regulates bone mass by targeting multiple TRAF family members in bone marrow stromal cells.

PubMed

Wang, Tingyu; Li, Shan; Yi, Dan; Zhou, Guang-Qian; Chang, Zhijie; Ma, Peter X; Xiao, Guozhi; Chen, Di

2018-01-01

Carboxyl terminus of Hsp70-interacting protein (CHIP or STUB1) is an E3 ligase and regulates the stability of several proteins which are involved in different cellular functions. Our previous studies demonstrated that Chip deficient mice display bone loss phenotype due to increased osteoclast formation through enhancing TRAF6 activity in osteoclasts. In this study we provide novel evidence about the function of CHIP. We found that osteoblast differentiation and bone formation were also decreased in Chip KO mice. In bone marrow stromal (BMS) cells derived from Chip -/- mice, expression of a panel of osteoblast marker genes was significantly decreased. ALP activity and mineralized bone matrix formation were also reduced in Chip- deficient BMS cells. We also found that in addition to the regulation of TRAF6, CHIP also inhibits TNFα-induced NF-κB signaling through promoting TRAF2 and TRAF5 degradation. Specific deletion of Chip in BMS cells downregulated expression of osteoblast marker genes which could be reversed by the addition of NF-κB inhibitor. These results demonstrate that the osteopenic phenotype observed in Chip -/- mice was due to the combination of increased osteoclast formation and decreased osteoblast differentiation. Taken together, our findings indicate a significant role of CHIP in bone remodeling.

Global MicroRNA Profiling in Human Bone Marrow Skeletal-Stromal or Mesenchymal-Stem Cells Identified Candidates for Bone Regeneration.

PubMed

Chang, Chi-Chih; Venø, Morten T; Chen, Li; Ditzel, Nicholas; Le, Dang Q S; Dillschneider, Philipp; Kassem, Moustapha; Kjems, Jørgen

2018-02-07

Bone remodeling and regeneration are highly regulated multistep processes involving posttranscriptional regulation by microRNAs (miRNAs). Here, we performed a global profiling of differentially expressed miRNAs in bone-marrow-derived skeletal cells (BMSCs; also known as stromal or mesenchymal stem cells) during in vitro osteoblast differentiation. We functionally validated the regulatory effects of several miRNAs on osteoblast differentiation and identified 15 miRNAs, most significantly miR-222 and miR-423, as regulators of osteoblastogenesis. In addition, we tested the possible targeting of miRNAs for enhancing bone tissue regeneration. Scaffolds functionalized with miRNA nano-carriers enhanced osteoblastogenesis in 3D culture and retained this ability at least 2 weeks after storage. Additionally, anti-miR-222 enhanced in vivo ectopic bone formation through targeting the cell-cycle inhibitor CDKN1B (cyclin-dependent kinase inhibitor 1B). A number of additional miRNAs exerted additive osteoinductive effects on BMSC differentiation, suggesting that pools of miRNAs delivered locally from an implanted scaffold can provide a promising approach for enhanced bone regeneration. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model

PubMed Central

Bhatta, Anil; Sangani, Rajnikumar; Kolhe, Ravindra; Toque, Haroldo A.; Cain, Michael; Wong, Abby; Howie, Nicole; Shinde, Rahul; Elsalanty, Mohammed; Yao, Lin; Chutkan, Norman; Hunter, Monty; Caldwell, Ruth B.; Isales, Carlos; Caldwell, R. William; Fulzele, Sadanand

2016-01-01

A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of L-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of L-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases. PMID:26704078

Prostaglandin E2 Increased Rat Cortical Bone Mass When Administered Immediately Following Ovariectomy

NASA Technical Reports Server (NTRS)

Ke, Hua Zhu; Jee, Webster S.S.; Zeng, Qing Qiang; Li, Mei; Lin, Bai Yun

1993-01-01

To investigate the effects of ovariectomy and the simultaneous administration of prostaglandin E2 (PGE2) on rat tibial shaft cortical bone histomorphometry, thirty-five 3 month-old female Sprague-Dawley rats were either ovariectomized (OVX), or sham ovariectomy (sham-OVX). The OVX rats were divided into three groups and treated with 0, 1 and 6 mg PGE2/kg/day for 90 days. The double fluorescent labeled undecalcified tibial shaft cross sections (proximal to the tibiofibular junction) of all the subjects were used for histomorphometry analysis. No differences in cross-sectional area and cortical bone area were found between sham-OVX and OVX controls, but OVX increased marrow area, intracortical porosity area and endocortical eroded perimeter. Periosteal and endocortical bone formation rates decreased with aging yet OVX prevented these changes. These OVX-induced increases in marrow area and endocortical eroded perimeter were prevented by 1 mg PGE2/kg/day treatment and added bone to periosteal and endocortical surfaces and to the marrow cavity. At the 6 mg/kg/day dose level, PGE2-treated OVX rats increased total tissue area, cortical bone area, marrow trabmular bone area, minimal cortical width and intracortical porosity area, and decreased marrow area compared to basal, sham-OVX and OVX controls. In addition, periosteal bone formation was elevated in the 6 mg PGE2/kg/day-treated OVX rats compared to OVX controls. Endocortical eroded perimeter increased from basal and sham-OVX control levels, but decreased from OVX control levels in the 6 mg PGE2/kg/day-treated OVX rats. Our study confirmed that ovariectomy does not cause osteopenia in tibial shaft cortical bone in rats, but it does stimulate endocortical bone resorption and enlarges marrow area. The new findings from the present study demonstrate that PGE2 prevents the OVX-induced increases in endocortical bone resorption and marrow area and adds additional bone to periosteal and endocortical surfaces and to marrow cavity to increase total bone mass in the tibial shaft of OVX rats when given immediately following ovafiectomy.

Diagnostic and management dilemma of a pancreas-kidney transplant recipient with aplastic anaemia.

PubMed

Viecelli, Andrea; Hessamodini, Hannah; Augustson, Bradley; Lim, Wai Hon

2014-09-25

We report a case of a 57-year-old woman with type I diabetes who had received a simultaneous pancreas-kidney (SPK) transplant maintained on tacrolimus, mycophenolic acid (MPA) and prednisolone. Her renal allograft failed 6 years post-transplant but she continued to have a normal functioning pancreatic allograft. Over the course of 5 years, she developed progressive bone marrow failure with repeat bone marrow aspirates demonstrating an evolution from erythroid hypoplasia to hypocellular marrow and eventual aplastic anaemia despite discontinuation of MPA and reduction of tacrolimus. She was transfusion-dependent and had frequent admissions for sepsis. Despite treatment with antithymocyte globulin and cyclosporine for aplastic anaemia, she developed fatal invasive pulmonary aspergillosis within 3 weeks of treatment. Even though the cause of aplastic anaemia is likely multifactorial, this case highlights the difficulty in balancing the need for versus the risk of ongoing immunosuppression in a SPK transplant recipient who continues to have normal pancreatic graft function. 2014 BMJ Publishing Group Ltd.

IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia.

PubMed

Kuett, Alexander; Rieger, Christina; Perathoner, Deborah; Herold, Tobias; Wagner, Michaela; Sironi, Silvia; Sotlar, Karl; Horny, Hans-Peter; Deniffel, Christian; Drolle, Heidrun; Fiegl, Michael

2015-12-17

The bone marrow microenvironment is physiologically hypoxic with areas being as low as 1% O2, e.g. the stem cell niche. Acute myeloid leukaemia (AML) blasts misuse these bone marrow niches for protection by the local microenvironment, but also might create their own microenvironment. Here we identify IL-8 as a hypoxia-regulated cytokine in both AML cell lines and primary AML samples that is induced within 48 hours of severe hypoxia (1% O2). IL-8 lacked effects on AML cells but induced migration in mesenchymal stromal cells (MSC), an integral part of the bone marrow. Accordingly, MSC were significantly increased in AML bone marrow as compared to healthy bone marrow. Interestingly, mononuclear cells obtained from healthy bone marrow displayed both significantly lower endogenous and hypoxia-induced production of IL-8. IL-8 mRNA expression in AML blasts from 533 patients differed between genetic subgroups with significantly lower expression of IL-8 in acute promyelocytic leukaemia (APL), while in non APL-AML patients with FLT ITD had the highest IL-8 expression. In this subgroup, high IL-8 expression was also prognostically unfavourable. In conclusion, hypoxia as encountered in the bone marrow specifically increases IL-8 expression of AML, which in turn impacts niche formation. High IL-8 expression might be correlated with poor prognosis in certain AML subsets.

Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood.

PubMed

Taskinen, M; Saarinen-Pihkala, U M; Hovi, L; Lipsanen-Nyman, M

2000-09-16

This follow-up study aimed to assess the frequency of late effects on glucose and lipid metabolism after bone-marrow transplantation in childhood. 23 long-term survivors (median age 20 years) were studied 3-18 years after bone-marrow transplantation and compared with 23 healthy controls matched for age and sex and with 13 patients in remission from leukaemia. 12 (52%) of the 23 bone-marrow transplantation patients had insulin resistance, including impaired glucose tolerance in six and type 2 diabetes in four. The core signs of the metabolic syndrome (hyperinsulinaemia and hypertriglyceridaemia combined), were found in nine (39%) of the bone-marrow transplantation patients compared with one (8%) of the 13 leukaemia patients and none of the healthy controls (p=0.0015). The frequency of insulin resistance increased with the time since bone-marrow transplantation. Abdominal obesity, but not overweight, was common among the patients with insulin resistance. Long-term survivors of bone-marrow transplantation are at substantial risk of insulin resistance, impaired glucose tolerance, and type 2 diabetes even at normal weight and young age. They also develop typical signs of the metabolic syndrome. We advocate measurement of serum lipids, fasting blood glucose, and serum insulin for the follow-up of all patients who undergo transplants in childhood, to be continued regularly and possibly life-long.

Soluble factor(s) from bone marrow cells can rescue lethally irradiated mice by protecting endogenous hematopoietic stem cells.

PubMed

Zhao, Yi; Zhan, Yuxia; Burke, Kathleen A; Anderson, W French

2005-04-01

Ionizing radiation-induced myeloablation can be rescued via bone marrow transplantation (BMT) or administration of cytokines if given within 2 hours after radiation exposure. There is no evidence for the existence of soluble factors that can rescue an animal after a lethal dose of radiation when administered several hours postradiation. We established a system that could test the possibility for the existence of soluble factors that could be used more than 2 hours postirradiation to rescue animals. Animals with an implanted TheraCyte immunoisolation device (TID) received lethal-dose radiation and then normal bone marrow Lin- cells were loaded into the device (thereby preventing direct interaction between donor and recipient cells). Animal survival was evaluated and stem cell activity was tested with secondary bone marrow transplantation and flow cytometry analysis. Donor cell gene expression of five antiapoptotic cytokines was examined. Bone marrow Lin- cells rescued lethally irradiated animals via soluble factor(s). Bone marrow cells from the rescued animals can rescue and repopulate secondary lethally irradiated animals. Within the first 6 hours post-lethal-dose radiation, there is no significant change of gene expression of the known radioprotective factors TPO, SCF, IL-3, Flt-3 ligand, and SDF-1. Hematopoietic stem cells can be protected in lethally irradiated animals by soluble factors produced by bone marrow Lin- cells.

The Molecular Prevalence of Viral Infections in Transplant Candidates with Bone Marrow Suppression, Shiraz, Southern Iran, 2010

PubMed Central

Mohammadi, B.; Yaghobi, R.; Dehghani, M.; Behzad Behbahani, A.

2013-01-01

Background: Transient bone marrow suppression, characterized by acute inability of the bone marrow to produce circulating blood cells, may strongly relate to the pathogenesis of some viral infections. Objective: To study the prevalence of some DNA and RNA viruses in patients with transient bone marrow suppression. Methods: EDTA-treated blood samples were collected from 27 patients with clinically- and laboratory-confirmed transient bone marrow suppression. The genomic DNA of hepatitis B virus, adenovirus, polyomavirus BK, and parvovirus B19, and genomic RNA of hepatitis C and G viruses were extracted and amplified by sensitive and specific in-house simple and nested PCR and RT-PCR protocols, respectively. The risk factors that might be related to the studied viral infections were analyzed. Results: Hepatitis B virus infection was diagnosed in 9 (33%) of 27 patients; adenovirus infection in 2 (7%); and parvovirus B19 infection in 7 (26%) of 27 patients. The genomic DNA of polyomovirus BK was not detected in any patients. Both hepatitis C and G viruses were found in 3 (11%) of 27 patients. Conclusion: Diagnosis of the high prevalence of hepatitis B virus, and parvovirus B19 in patients with transient bone marrow suppression, reflects the importance of these viral infections in introducing bone marrow suppression. This hypothesis should be confirmed in further studies. PMID:25013658

The interrelationship between bone and fat: from cellular see-saw to endocrine reciprocity.

PubMed

Sadie-Van Gijsen, H; Crowther, N J; Hough, F S; Ferris, W F

2013-07-01

The number of mature osteoblasts and marrow adipocytes in bone is influenced by the differentiation of the common mesenchymal progenitor cell towards one phenotype and away from the other. Consequently, factors which promote adipogenesis not only lead to fatty marrow but also inhibit osteoblastogenesis, resulting in decreased osteoblast numbers, diminished bone formation and, potentially, inadequate bone mass and osteoporosis. In addition to osteoblast and bone adipocyte numbers being influenced by this skewing of progenitor cell differentiation towards one phenotype, mature osteoblasts and adipocytes secrete factors which may evoke changes in the cell fate and function of each other. This review examines the endogenous factors, such as PPAR-γ2, Wnt, IGF-1, GH, FGF-2, oestrogen, the GP130 signalling cytokines, vitamin D and glucocorticoids, which regulate the selection between osteoblastogenesis and adipogenesis and the interrelationship between fat and bone. The role of adipokines on bone, such as adiponectin and leptin, as well as adipose-derived oestrogen, is reviewed and the role of bone as an energy regulating endocrine organ is discussed.

Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

PubMed Central

Meng, Jingru; Ma, Xue; Wang, Ning; Jia, Min; Bi, Long; Wang, Yunying; Li, Mingkai; Zhang, Huinan; Xue, Xiaoyan; Hou, Zheng; Zhou, Ying; Yu, Zhibin; He, Gonghao; Luo, Xiaoxing

2016-01-01

Summary Glucagon-like peptide 1 (GLP-1) plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4) promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs), but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis. PMID:26947974

Custom-shaping system for bone regeneration by seeding marrow stromal cells onto a web-like biodegradable hybrid sheet.

PubMed

Tsuchiya, Kohei; Mori, Taisuke; Chen, Guoping; Ushida, Takashi; Tateishi, Tetsuya; Matsuno, Takeo; Sakamoto, Michiie; Umezawa, Akihiro

2004-05-01

New bone for the repair or the restoration of the function of traumatized, damaged, or lost bone is a major clinical need, and bone tissue engineering has been heralded as an alternative strategy for regenerating bone. A novel web-like structured biodegradable hybrid sheet has been developed for bone tissue engineering by preparing knitted poly(DL-lactic-co-glycolic acid) sheets (PLGA sheets) with collagen microsponges in their openings. The PLGA skeleton facilitates the formation of the hybrid sheets into desired shapes, and the collagen microsponges in the pores of the PLGA sheet promote cell adhesion and uniform cell distribution throughout the sheet. A large number of osteoblasts established from marrow stroma adhere to the scaffolds and generate the desired-shaped bone in combination with these novel sheets. These results indicate that the web-like structured novel sheet shows promise for use as a tool for custom-shaped bone regeneration in basic research on osteogenesis and for the development of therapeutic applications. Copyright 2004 Springer-Verlag

A study of bone marrow and subcutaneous fatty acid composition in subjects of varying bone mineral density.

PubMed

Griffith, James F; Yeung, David K W; Ahuja, Anil T; Choy, Carol W Y; Mei, Wong Yin; Lam, Sherlock S L; Lam, T P; Chen, Zhen-Yu; Leung, Ping C

2009-06-01

Osteoporosis is associated with an increase in marrow fat. Fats, particularly polyunsaturated fats, either in co-cultures or diet, have been shown to significantly influence bone remodeling. Whether the increase in marrow fat seen in osteoporosis is also associated with a change in fatty acid composition is not known. This study was undertaken to investigate the fatty acid composition in subjects of varying bone mineral density (BMD). Samples of marrow fat and subcutaneous fat from 126 subjects (98 females, 34 males, mean age 69.7+/-10.5 years) undergoing orthopedic surgery were analyzed for fatty acid composition by gas chromatography. These results were correlated with BMD assessed by DXA. A total of 22 fatty acids were identified in marrow and subcutaneous fat. Significant differences in fatty acid composition existed between marrow and subcutaneous fat as well as between marrow fat samples obtained from the proximal femur and proximal tibia. Other than cis-7-hexadecenoic acid [C16:1 (n=9)] and docosanoic acid [C22:0], no difference in marrow fatty acid composition was evident between subject groups of varying BMD (normal, low bone mass, and osteoporosis). In conclusion, there exists a wide range of individual fatty acids in marrow fat. Marrow fatty acid composition differs from that of subcutaneous fat and varies between predominantly erythropoetic and fatty marrow sites. Other than cis-7-hexadecenoic acid [C16:1 (n=9)] and docosanoic acid [C22:0], no difference in marrow fatty acid composition was evident between subjects of varying BMD.

Experiment K305: Quantitative analysis of selected bone parameters. Supplement 2: Bone elongation rate and bone mass in metaphysis of long bones

NASA Technical Reports Server (NTRS)

Jee, W. S. S.; Kimmel, D. B.; Smith, C.; Dell, R. B.

1981-01-01

The proximal humeral metaphysis of rats from time periods recovery plus zero days (R+0), recovery plus six days (R+6), and recovery plus twenty nine days (R+29) was analyzed. The volume of calcified cartilage and bone in flight and synchronous controls was reduced in groups R+0 and R+6, but was normal in group R+29. The number of functional bone cells (osteoblasts and osteoclasts) was decreased in proportion to the amount of bone in the early groups, and was normal in the last group. The fatty marrow volume was increased only in flight animals of groups R+0 and R+6, but was normal in the R+29 group. Accumulation of excess fatty marrow was seen only in flight animals. The decreased amount of bone and calcified cartilage is believed to be the result of a temporarily slowed or arrested production of calcified cartilage as a substrate for bone formation. This would have resulted from slowed bone elongation during flight and synchronous control conditions. Bone elongation returned to normal by twenty nine days after return.

Mechanisms of "kidney governing bones" theory in traditional Chinese medicine.

PubMed

Ju, Dahong; Liu, Meijie; Zhao, Hongyan; Wang, Jun

2014-09-01

Studies conducted by our group on the mechanism of "kidney governing bones" theory in traditional Chinese medicine (TCM) are reviewed in this paper. Conclusions can be summarized as follows. (1) Neuroendocrine-immune network (NIN)-osteoclast regulatory pathway OPG-RANKL-RANK is one of the mechanisms of "kidney governing bones." Although kidney-reinforcing therapy is regarded as one of the holistic regulatory mechanisms of the body, characteristic holistic regulation in TCM can be reflected through nonselective regulation of the NIN during kidney reinforcement therapy, which can be used to treat osteoporosis through microadjustments in the microenvironment of the bone marrow. (2) Marrow exhaustion in TCM, which is the state wherein lipocytes in the bone marrow increase whereas other cells decrease, serves as the pathogenesis of osteoporosis brought about by failure of the "kidney governing bones." (3) The kidney in TCM can be regarded as a complex system comprising multiple functional units in the body, including the unit "governing bones." Kidney deficiency refers to a deficiency in only one or more units of the kidney system and not the whole system itself, which explains the kidney-reinforcing effect of many herbs; some herbs can treat osteoporosis, but some cannot. Although both classified as kidney-reinforcing agents, the former can resolve failure of the "kidney governing bones" unit while the latter regulates the failure of other units in the kidney system. Despite the current understanding on "kidney governing bones" theory, the mechanism of "kidney governing bones" remains complicated and unresolved. Thus, further studies in this area are warranted.

Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation.

PubMed

Araujo, John C; Poblenz, Ann; Corn, Paul; Parikh, Nila U; Starbuck, Michael W; Thompson, Jerry T; Lee, Francis; Logothetis, Christopher J; Darnay, Bryant G

2009-11-01

Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC(50) of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts, and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases.

Hematologic evaluation of employees with leukopenia. Naval Weapons Center, China Lake, California.

PubMed

Luiken, G A; Marsh, W L; Heath, V C; Long, H L; Weatherly, T L; Seal, G M

1988-12-01

Evaluation of 86 employees with a history of leukopenia at the Naval Weapons Center (NWC), China Lake, California, was done by exposure questionnaires, medical histories, physical examinations, peripheral blood smear, and bone marrow evaluations, including morphologic examination, stem cell culture, and cytogenetics. Forty-eight subjects were found to be leukopenic at the time of the study, and two subjects were found to have hairy cell leukemia. All subjects had positive exposure histories and were healthy at the time of the study. Review of peripheral smears identified the patients with marrow abnormalities. Bone marrow cultures revealed several patients with possible marrow suppression. Chromosome studies were not diagnostic. Five-year follow-up health questionnaires revealed no significant health problems; the two workers with hairy cell leukemia are alive and fully functional. Leukopenia in itself does not appear to be a risk factor for poor health, and it is unknown whether or not it may be a useful screening tool to identify workers at risk in toxic environments. Careful evaluation of blood cell counts and peripheral smears should be sufficient to identify people with potential marrow abnormalities.

Leukemic Cells "Gas Up" Leaky Bone Marrow Blood Vessels.

PubMed

Itkin, Tomer; Rafii, Shahin

2017-09-11

In this issue of Cancer Cell, Passaro et al. demonstrate how leukemia through aberrant induction of reactive oxygen species and nitric oxide production trigger marrow vessel leakiness, instigating pro-leukemic function. Disrupted tumor blood vessels promote exhaustion of non-malignant stem and progenitor cells and may facilitate leukemia relapse following chemotherapeutic treatment. Copyright © 2017. Published by Elsevier Inc.

The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis

PubMed Central

Havens, AM; Jung, Y; Sun, YX; Wang, J; Shah, RB; Bühring, HJ; Pienta, KJ; Taichman, RS

2006-01-01

Background The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow. Results Using prostate cancer cell lines, it was demonstrated that CXCL12 induced both the expression of CD164 mRNA and protein. Functional studies demonstrated that blocking CD164 on prostate cancer cell lines reduced the ability of these cells to adhere to human bone marrow endothelial cells, and invade into extracellular matrices. Human tissue microarrays stained for CD164 demonstrated a positive correlation with prostate-specific antigen levels, while its expression was negatively correlated with the expression of androgen receptor. Conclusion Our findings suggest that CD164 may participate in the localization of prostate cancer cells to the marrow and is further evidence that tumor metastasis and hematopoietic stem cell trafficking may involve similar processes. PMID:16859559

A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy

NASA Astrophysics Data System (ADS)

Hobbs, Robert F.; Song, Hong; Watchman, Christopher J.; Bolch, Wesley E.; Aksnes, Anne-Kirsti; Ramdahl, Thomas; Flux, Glenn D.; Sgouros, George

2012-05-01

Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e. the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 to 20 Gy. The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the absorbed fraction method of dose calculation.

THE EFFECTS OF EXPERIMENTAL PLETHORA ON BLOOD PRODUCTION.

PubMed

Robertson, O H

1917-08-01

With the purpose of determining whether a diminished activity of the bone marrow could be brought about experimentally, plethora was produced in rabbits by means of repeated small transfusions of blood. Counts of the number of reticulated red cells in the circulating blood were made during the course of the experiments as an index to changes in the activity of the bone marrow. With the development of plethora, the number of reticulated cells in the blood decreased. In the majority of the plethoric animals, this diminution was extreme, and in some instances, reticulated cells practically disappeared from the blood. A comparison of the red bone marrow of these animals with that of normal controls revealed a marked reduction in the content of reticulated cells. After a number of transfusions, there occurred in some of the plethoric rabbits a sudden and marked drop in hemoglobin. The hemoglobin continued to fall until a severe grade of anemia was reached. This was followed by an extremely rapid regeneration accompanied by a striking rise in color index. During regeneration, the reticulated cells were enormously increased in number. Taken together, these facts show that the bone marrow is markedly influenced by plethora. The diminished number of reticulated cells observed, both in the circulating blood and in the marrow, would make it appear that a decided decrease in blood production occurs. The reduction in the number of these cells cannot be due to changes in the constitution of the red cells put out by the bone marrow, as a result of an increased quantity of hemoglobin in the body, because during regeneration from the above mentioned anemia, when the color index was very high, reticulated cells were still present in large numbers. That the activity of the bone marrow does actually diminish during plethora is further evidenced by the occurrence of the anemia. The most reasonable explanation of this phenomenon is that the recipient develops an immunity against the blood of the donors, which results in the destruction of the strange cells that are in circulation. In keeping with this conception is the appearance of isoagglutinins for the donors' red cells in the blood of the recipient, at about the time of the beginning fall in hemoglobin. The occurrence of anemia as a result of the destruction of the alien blood only would seem to be due to the circumstance that, during the period of plethora, blood production is greatly diminished; as a consequence, the blood cells proper to the recipient are gradually reduced in number and replaced by alien cells until the latter come to constitute the bulk of the animal's blood. In those rabbits developing anemia, the initial drop of hemoglobin from the plethoric level to the normal was constantly accompanied by a marked rise in the number of reticulated cells. This brought up a subsidiary problem for study. With the idea that the stimulation of the bone marrow might be due to the presence of an increased quantity of broken down blood, rabbits, were injected intravenously with large amounts of laked blood cells. The procedure had no evident effect on the blood picture. It was then found that simple blood removal from a plethoric animal which brought back the hemoglobin to the normal level, or even to a point somewhat above, sufficed to cause a marked increase in the number of reticulated cells. Although these findings are not conclusive, they suggest an explanation for the increased bone marrow activity accompanying the initial drop of hemoglobin in the plethoric rabbits; namely, that the organism had in some way adapted itself during the period of plethora to the presence of a greater amount of blood and that the result of blood loss in such an organism was a relative but not absolute anemia. The finding that the activity of the bone marrow can be depressed by the introduction of a large quantity of blood into the circulation accounts for the diminished bone marrow activity which sometimes occurs after transfusion in pernicious anemia. In such cases there is a marked drop in the number of reticulated cells and other evidence of bone marrow depression; the patient shows no benefit from transfusion or may grow rapidly worse. The cause of this depression is best explained on the basis that in severe instances of the disease where exhaustion of the bone marrow is imminent, the stimulus of the anemia is only just sufficient to keep the marrow functioning. A sudden lowering of this stimulus is brought about by the introduction of a large quantity of blood into the circulation, and the result is a fall in the activity of the bone marrow. It follows from this that in pernicious anemia with a feebly reacting bone marrow as indicated by the number of reticulated red cells, small transfusions are preferable to large ones.

β3-Adrenergic Regulation of EPC Features Through Manipulation of the Bone Marrow MSC Niche.

PubMed

Vafaei, Rana; Nassiri, Seyed Mahdi; Siavashi, Vahid

2017-12-01

Mesenchymal stem cells (MSCs) reside in a specific niche in the bone marrow, however, biological features of this niche are still not fully understood. Given the interactions of MSCs with endothelial cells in different tissues, bone marrow MSC niche may influence the biological features of endothelial progenitor cells (EPCs). To understand the role of the sympathetic nervous system in regulation of the MSC niche, we examined whether the manipulation of the MSC niche via β3-adrenergic signals will affect EPC features. A selective β3 agonist (BRL37344) or a β3 antagonist (SR59230A) was administered in mice for 2 weeks to determine the potential effects of these regimens on the population of CD133 + stem cells in the bone marrow. Then, bone marrow-derived MSCs and EPCs were harvested and expanded from the mice to examine the effect of changes in the MSC niche on EPC features. Improved MSC colony forming potency with increased bone marrow stromal cell-derived factor 1 (SDF-1) (also known as C-X-C motif chemokine 12 [CXCL12]) expression was shown as a result of intensification of the bone marrow adrenergic signals through BRL37344 injection. On the other hand, the blockage of these signals limited the expression level of SDF-1 and resulted in bone marrow enrichment of CD133 + cells. Manipulation of the MSC niche and decreased SDF-1 expression via SR59230A injection also prompted EPCs to form more colonies with augmented proliferation and differentiation capacity. Overall, our results indicate that the β3-adrenergic signals regulate the MSC niche, thereby resulting in modulation of EPC biological features. J. Cell. Biochem. 118: 4753-4761, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Restoration of prostaglandin E2-producing splenic macrophages in sup 89 Sr-treated mice with bone marrow from Corynebacterium parvum primed donors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shibata, Y.

1989-05-01

Administration of Corynebacterium parvum (CP), 56 mg/kg ip to CBA/J mice effected the induction of prostaglandin E2 (PGE2) producing macrophages (M phi) in the bone marrow and the spleen. Maximal release of PGE2 from M phi cultured in vitro with calcium ionophore A23187 for 2 h was reached by marrow M phi removed on 5 days after CP (450 ng/mg cell protein), and by splenic M phi 9 days after CP (400 ng/mg). Neither M phi population, however, yielded more than 6.0 ng/mg leukotriene C4. To assess ontogenic relationships mice were depleted of bone marrow and blood monocytes by ivmore » injection of the bone-seeking isotope, 89Sr. CP was given at several points before or after bone marrow cell depletion. PGE2 production by splenic M phi harvested on day 9 after CP was profoundly impaired when CP was administered either concurrently with or 3 days after 89Sr. When CP was administered 1, 3, 5, and 7 days before 89Sr, however, the induction of PGE2-producing M phi in the spleen was unaffected. To determine whether bone marrow cells from CP-injected donors can restore PGE2-producing splenic M phi (PGSM) in 89Sr-mice, recipient mice which had and had not received CP 3 days after 89Sr were transfused with 5 x 10(6) syngeneic bone marrow cells from donor mice prepared at varying intervals after CP administration. The results clearly indicate the capacity of bone marrow cells harvested on either day 1 or 2 following CP to restore PGSM in CP-primed, but not unprimed, recipients.« less

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis.

PubMed

Gleitz, Hélène Fe; Kramann, Rafael; Schneider, Rebekka K

2018-06-01

Bone marrow fibrosis is the continuous replacement of blood-forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1 + and leptin receptor + mesenchymal stromal cells are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation or pharmacological inhibition of Gli1 + mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet-derived growth factor (PDGF) receptor-α (PDGFRA) gene (Pdgfra) and inhibition of PDGFRA by imatinib in leptin receptor + stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the haematopoietic stem cell niche that govern the mesenchymal stromal cell-to-myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non-malignant conditions, and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the haematopoietic niche and as myofibroblast precursors, and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Clinical Utility of Dual-Energy CT Analysis of Bone Marrow Edema in Acute Wrist Fractures.

PubMed

Ali, Ismail T; Wong, William D; Liang, Teresa; Khosa, Faisal; Mian, Memoona; Jalal, Sabeena; Nicolaou, Savvas

2018-04-01

The purpose of this study is to determine the utility of dual-energy CT (DECT) for assessing carpal fractures and to obtain an attenuation value cutoff (in Hounsfield units) to identify bone marrow edema due to an acute carpal fracture. In this retrospective study, 24 patients who presented with wrist fractures from September 3, 2014, through March 9, 2015, underwent imaging with DECT (80 and 140 kVp). Using the three-material decomposition algorithm specific for virtual noncalcium to construct images, two radiologists identified carpal fractures and associated bone marrow edema. Readers noted the attenuation at areas with and without bone marrow edema. The cutoff value was obtained by ROC analysis and was internally validated on 13 separate patients with suspected wrist fractures. A p < 0.05 was considered statistically significant. CT attenuation was significantly higher in areas of bone marrow edema than in areas without it (p < 0.0001, t test). A cutoff of 5.90 HU allows detection of bone marrow edema associated with acute wrist fractures with 100% sensitivity and 99.5% specificity, compared with visual DECT interpretation. In the 13 validation cases, the cutoff of 5.90 HU identified bone marrow edema with 100% accuracy, compared with visual interpretation. Kappa values were 0.83 between the two readings by reader 1, and 0.73 and 0.96 comparing the two readings of reader 1 with the reading by reader 2. DECT is a useful tool for identifying bone marrow edema in the setting of acute wrist fractures, providing an alternative to MRI. A cutoff value of 5.90 HU can be used for accurate diagnosis and exclusion of carpal fractures.

Marrow changes in anorexia nervosa masking the presence of stress fractures on MR imaging.

PubMed

Tins, Bernhard; Cassar-Pullicino, Victor

2006-11-01

Patients with anorexia nervosa (AN) usually have abnormal bone and bone marrow metabolism resulting in osteopenia and serous bone marrow change. There is an increased risk of stress/insufficiency fractures and these can be the first presentation of AN. This case report describes a patient with previously undiagnosed AN who presented with foot pain. The serous bone marrow changes of AN were found to mask the MR imaging features of stress fractures, as both had low T1w and high T2w and STIR signal intensities. Contrast enhancement was not helpful but actually masked fractures. Scintigraphy was helpful. The radiologist might be the first clinician to raise the possibility of AN and should be aware of the difficulties in diagnosing stress fractures in bones with underlying serous bone marrow change. In this severe case of AN even the heel fat pad and the fat pad in Kager's triangle had undergone serous change.

Inflammatory bowel disease causes reversible suppression of osteoblast and chondrocyte function in mice.

PubMed

Harris, Laura; Senagore, Patricia; Young, Vincent B; McCabe, Laura R

2009-05-01

Decreased bone density and stature can occur in pediatric patients with inflammatory bowel disease (IBD). Little is known about how IBD broadly impacts the skeleton. To evaluate the influence of an acute episode of IBD on growing bone, 4-wk-old mice were administered 5% dextran sodium sulfate (DSS) for 5 days to induce colitis and their recovery was monitored. During active disease and early recovery, trabecular bone mineral density, bone volume, and thickness were decreased. Cortical bone thickness, outer perimeter, and density were also decreased, whereas inner perimeter and marrow area were increased. These changes appear to maintain bone strength since measures of moments of inertia were similar between DSS-treated and control mice. Histological (static and dynamic), serum, and RNA analyses indicate that a decrease in osteoblast maturation and function account for changes in bone density. Unlike some conditions of bone loss, marrow adiposity did not increase. Similar to reports in humans, bone length decreased and correlated with decreases in growth plate thickness and chondrocyte marker expression. During disease recovery, mice experienced a growth spurt that led to their achieving final body weights and bone length, density, and gene expression similar to healthy controls. Increased TNF-alpha and decreased IGF-I serum levels were observed with active disease and returned to normal with recovery. Changes in serum TNF-alpha (increased) and IGF-I (decreased) paralleled changes in bone parameters and returned to normal values with recovery, suggesting a potential role in the skeletal response.

Bone Marrow Adipose Tissue: To Be or Not To Be a Typical Adipose Tissue?

PubMed Central

Hardouin, Pierre; Rharass, Tareck; Lucas, Stéphanie

2016-01-01

Bone marrow adipose tissue (BMAT) emerges as a distinct fat depot whose importance has been proved in the bone–fat interaction. Indeed, it is well recognized that adipokines and free fatty acids released by adipocytes can directly or indirectly interfere with cells of bone remodeling or hematopoiesis. In pathological states, such as osteoporosis, each of adipose tissues – subcutaneous white adipose tissue (WAT), visceral WAT, brown adipose tissue (BAT), and BMAT – is differently associated with bone mineral density (BMD) variations. However, compared with the other fat depots, BMAT displays striking features that makes it a substantial actor in bone alterations. BMAT quantity is well associated with BMD loss in aging, menopause, and other metabolic conditions, such as anorexia nervosa. Consequently, BMAT is sensed as a relevant marker of a compromised bone integrity. However, analyses of BMAT development in metabolic diseases (obesity and diabetes) are scarce and should be, thus, more systematically addressed to better apprehend the bone modifications in that pathophysiological contexts. Moreover, bone marrow (BM) adipogenesis occurs throughout the whole life at different rates. Following an ordered spatiotemporal expansion, BMAT has turned to be a heterogeneous fat depot whose adipocytes diverge in their phenotype and their response to stimuli according to their location in bone and BM. In vitro, in vivo, and clinical studies point to a detrimental role of BM adipocytes (BMAs) throughout the release of paracrine factors that modulate osteoblast and/or osteoclast formation and function. However, the anatomical dissemination and the difficulties to access BMAs still hamper our understanding of the relative contribution of BMAT secretions compared with those of peripheral adipose tissues. A further characterization of the phenotype and the functional regulation of BMAs are ever more required. Based on currently available data and comparison with other fat tissues, this review addresses the originality of the BMAT with regard to its development, anatomy, metabolic properties, and response to physiological cues. PMID:27445987

SU-F-J-222: Using PET Imaging to Evaluate Proliferation and Blood Flow in Irradiated and Non-Irradiated Bone Marrow 1 Year After Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuire, S; Ponto, L; Menda, Y

Purpose: To compare proliferation and blood flow in pelvic and thoracic bone marrow 1 year after pelvic chemoradiation. Methods: Sixteen pelvic cancer patients were enrolled in an IRB-approved protocol to acquire FLT PET images during radiation therapy simulation (baseline) and 1 year after chemoradiation therapy. Three subjects also had optional O-15 water PET images acquired 1 year after chemoradiation therapy. Baseline FLT PET images were used to create IMRT plans to spare pelvic bone marrow identified as regions with FLT SUV ≥ 2 without compromising PTV coverage or OAR sparing. Marrow VOIs were defined using a 50% maximum pixel valuemore » threshold on baseline FLT PET images (VIEW, PMOD version 3.5) in the sacrum and thoracic spine representing irradiated and non-irradiated regions, respectively. FLT PET and O-15 water PET images acquired 1 year after therapy were co-registered to baseline images (FUSION PMOD) and the same VOIs were used to measure proliferation (FLT SUV) and blood flow (O-15 water uptake). Separate image-based input functions were used for blood flow quantitation in each VOI. Results: Mean 1 year FLT SUV in sacral and thoracic VOIs for were 1.1 ± 0.4 and 6.5 ± 1.7, respectively for N = 16 subjects and were 1.2 ± 0.2 and 5.6 ± 1.6, respectively for N = 3 subjects who also underwent O-15 water imaging. Blood flow measures in equivalent sacral and thoracic marrow regions (N = 3) were 21.3 ± 8.7 and 18.3 ± 4.9 mL/min/100mL respectively. Conclusion: Decreased bone marrow proliferation measured by FLT SUV does not appear to correspond to decreased blood flow as measured by O-15 water PET imaging. Based on this small sample at a single time point, reduced blood supply does not explain reductions in bone marrow proliferative activity 1 year after chemoradiation therapy.« less

[Search for non-relative donor by the Russian register of bone marrow donors].

PubMed

Zaretskaia, Iu M; Khamaganova, E G; Aleshchenko, S M; Murashova, L A

2002-01-01

To select maximally HLA compatible donor for hematological patients who need transplantation of bone marrow from non-relative donor. 75 patients with hematological malignancy were observed. All of them have indications to non-relative transplantation of the bone marrow. Methods of polymerase chain reaction with sequence-specific primers and classic microlymphocytotoxic test were used. Typing of HLA antigens of class I and alleles of class II loci enabled search for non-relative donor for transplantation of bone marrow in accordance with the requirements of the European Federation of Immunogenetics. Most of the patients (86.6%) had at least one potential HLA-A, -B, -DR compatible donor. Half of the patients had potential donors typed at the allele level by class II loci. This diminishes time of HLA compatible donor selection. DNA typing enables the search for the non-relative donors meeting modern requirements. This allowed 5 non-relative bone marrow transplantations.

Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis.

PubMed

Wahlin, Staffan; Aschan, Johan; Björnstedt, Mikael; Broomé, Ulrika; Harper, Pauline

2007-01-01

We report the case of a middle-age patient presenting with severe progressive protoporphyric cholestasis. To halt further progression of liver disease, medical treatment was given aimed at different mechanisms possibly causing cholestasis in erythropoietic protoporphyria. Within eighty days, liver biochemistry completely normalized and liver histology markedly improved. Bone marrow transplantation was performed to prevent relapse of cholestatic liver disease by correcting the main site of protoporphyrin overproduction. Thirty-three months after cholestatic presentation and ten months after bone marrow transplantation, liver and porphyrin biochemistry remains normal. The patient is in excellent condition and photosensitivity is absent. The theoretical role of each treatment used to successfully reverse cholestasis and the role of bone marrow transplantation in erythropoietic protoporphyria are discussed. Medical treatment can resolve hepatic abnormalities in protoporphyric cholestasis. Bone marrow transplantation achieves phenotypic reversal and may offer protection from future protoporphyric liver disease.

The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis

PubMed Central

Zhang, Weiwei; Ran, Qian; Xiang, Yang; Zhong, Jiang F.; Li, Shengwen Calvin

2018-01-01

Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation. PMID:29765406

New factors controlling the balance between osteoblastogenesis and adipogenesis.

PubMed

Abdallah, Basem M; Kassem, Moustapha

2012-02-01

The majority of conditions associated with bone loss, including aging, are accompanied by increased marrow adiposity possibly due to shifting of the balance between osteoblast and adipocyte differentiation in bone marrow stromal (skeletal) stem cells (MSC). In order to study the relationship between osteoblastogenesis and adipogenesis in bone marrow, we have characterized cellular models of multipotent MSC as well as pre-osteoblastic and pre-adipocytic cell populations. Using these models, we identified two secreted factors in the bone marrow microenviroment: secreted frizzled-related protein 1 (sFRP-1) and delta-like1 (preadipocyte factor 1) (Dlk1/Pref-1). Both exert regulatory effects on osteoblastogenesis and adipogenesis. Our studies suggest a model for lineage fate determination of MSC that is regulated through secreted factors in the bone marrow microenvironment that mediate a cross-talk between lineage committed cell populations in addition to controlling differentiation choices of multipotent MSC. Copyright © 2011 Elsevier Inc. All rights reserved.

Expression of Essential B Cell Development Genes in Horses with Common Variable Immunodeficiency

PubMed Central

Tallmadge, R.L.; Such, K.A.; Miller, K.C.; Matychak, M.B.; Felippe, M.J.B.

2012-01-01

Common variable immunodeficiency (CVID) is a heterogeneous disorder of B cell differentiation or function with inadequate antibody production. Our laboratory studies a natural form of CVID in horses characterized by late-onset B cell lymphopenia due to impaired B cell production in the bone marrow. This study was undertaken to assess the status of B cell differentiation in the bone marrow of CVID-affected horses by measuring the expression of genes essential for early B cell commitment and development. Standard RT-PCR revealed that most of the transcription factors and key signaling molecules that directly regulate B cell differentiation in the bone marrow and precede PAX5 are expressed in the affected horses. Yet, the expression of PAX5 and relevant target genes was variable. Quantitative RT-PCR analysis confirmed that the mRNA expression of E2A, PAX5, CD19, and IGHD was significantly reduced in equine CVID patients when compared to healthy horses (p < 0.05). In addition, the PAX5/EBF1 and PAX5/B220 ratios were significantly reduced in CVID patients (p < 0.01). Immunohistochemical analysis confirmed the absence of PAX5-BSAP expression in the bone marrow of affected horses. Our data suggest that B cell development seems to be impaired at the transition between pre-pro-B cells and pro-B cells in equine CVID patients. PMID:22464097

Bone marrow adipocytes: a neglected target tissue for growth hormone.

PubMed

Gevers, Evelien F; Loveridge, Nigel; Robinson, Iain C A F

2002-10-01

Bone marrow (BM) contains numerous adipocytes. These share a common precursor with osteoblasts and chondrocytes, but their function is unknown. It is unclear what regulates the differentiation of these three different cell types, though their subsequent metabolic activity is under hormonal regulation. GH and estrogen stimulate bone growth and mineralization, by direct effects on chondrocytes and osteoblasts. GH also stimulates lipolysis in subcutaneous and visceral adipocytes. However, adipocytes in BM have largely been ignored as potential targets for GH or estrogen action. We have addressed this by measuring BM adipocyte number, perimeter and area as well as bone area and osteoblast activity in GH-deficient dwarf (dw/dw), normal, or ovariectomized (Ovx) rats, with or without GH, IGF-1, PTH, or estrogen treatment or high fat feeding. Marrow adipocyte numbers were increased 5-fold (P < 0.001) in dw/dw rats, and cell size was also increased by 20%. These values returned toward normal in dw/dw rats given GH but not when given IGF-1. Cancellous bone area and osteoblast number were significantly (P < 0.005) lower in dw/dw rats, though alkaline phosphatase (ALP) activity in individual osteoblasts was unchanged. GH treatment increased % osteoblast covered bone surface without affecting individual cell ALP activity. Ovariectomy in normal or dw/dw rats had no affect on marrow adipocyte number nor size, although estrogen treatment in ovariectomized (Ovx) normal rats did increase adipocyte number. Ovx decreased tibial cancellous bone area in normal rats (64%; P < 0.05) and decreased osteoblast ALP-activity (P < 0.01) but did not affect the percentage of osteoblast-covered bone surface. Estrogen replacement reversed these changes. While treatment with PTH by continuous sc infusion decreased cancellous bone (P < 0.05) and high fat feeding increased the size of BM adipocytes (P < 0.01), they did not affect BM adipocyte number. These results suggest that GH has a specific action on BM adipocytes that is not simply due to altered bone or fat metabolism. We conclude that the marrow adipocyte lineage is an important and specific target for GH action. The inverse relationship between adipocyte number and osteoblast covered bone surface, together with the well-known effects of GH on epiphysial chondrocytes leads us to propose that GH plays two important roles on cells of all three lineages. During differentiation, it regulates the numbers of each cell type that are maintained from the common precursor lineage. Subsequently it has cell-specific effects on the metabolic activities of the differentiated cells. In the case of marrow adipocytes, GH-dependent lipolysis could provide an important hormonally regulated local high energy source in bone.

p53-Based Strategy for Protection of Bone Marrow From Y-90 Ibritumomab Tiuxetan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, Hang, E-mail: suh3@uthscsa.edu; Ganapathy, Suthakar; Li, Xiaolei

Purpose: The main drawbacks of radioimmunotherapy have been severe hematological toxicity and potential development of myelodysplastic syndrome and secondary leukemia. Activation of p53 follows a major pathway by which normal tissues respond to DNA-damaging agents, such as chemotherapy and radiation therapy, that result in injuries and pathological consequences. This pathway is separate from the tumor suppressor pathway of p53. We have previously reported that use of low-dose arsenic (LDA) temporarily and reversibly suppresses p53 activation, thereby ameliorating normal tissue toxicity from exposure to 5-fluorouracil and X rays. We have also demonstrated that LDA-mediated protection requires functional p53 and thus ismore » selective to normal tissues, as essentially every cancer cell has dysfunctional p53. Here we tested the protective efficacy of LDA for bone marrow tissue against radioimmunotherapy through animal experiments. Methods and Materials: Mice were subjected to LDA pretreatment for 3 days, followed by treatment with Y-90 ibritumomab tiuxetan. Both dose course (10, 25, 50, 100, and 200 μCi) and time course (6, 24, and 72 hours and 1 and 2 weeks) experiments were performed. The response of bone marrow cells to LDA was determined by examining the expression of NFκB, Glut1, and Glut3. Staining with hematoxylin and eosin, γ-H2AX, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to examine morphology, DNA damage response, and apoptotic cell populations. Results: Elevated levels of NFκB, Glut1, and Glut3 were observed in bone marrow cells after LDA treatment. Bone marrow damage levels induced by Y-90 ibritumomab tiuxetan were greatly reduced by LDA pretreatment. Consistent with this observation, significantly less DNA damage and fewer apoptotic cells were accumulated after Y-90 ibritumomab tiuxetan treatment in LDA-pretreated mice. Furthermore, in the mouse xenograft model implanted with human Karpas-422 lymphoma cells, LDA pretreatment did not have any detectable effect on either tumor growth or Y-90 ibritumomab tiuxetan (200 μCi)-induced tumor suppression. Conclusions: LDA pretreatment protected bone marrow without compromising tumor control caused by Y-90 ibritumomab tiuxetan.« less

Mesenchymal Stem Cells From Bone Marrow, Adipose Tissue, and Lung Tissue Differentially Mitigate Lung and Distal Organ Damage in Experimental Acute Respiratory Distress Syndrome.

PubMed

Silva, Johnatas D; Lopes-Pacheco, Miquéias; Paz, Ana H R; Cruz, Fernanda F; Melo, Elga B; de Oliveira, Milena V; Xisto, Débora G; Capelozzi, Vera L; Morales, Marcelo M; Pelosi, Paolo; Cirne-Lima, Elizabeth; Rocco, Patricia R M

2018-02-01

Mesenchymal stem cells-based therapies have shown promising effects in experimental acute respiratory distress syndrome. Different mesenchymal stem cells sources may result in diverse effects in respiratory diseases; however, there is no information regarding the best source of mesenchymal stem cells to treat pulmonary acute respiratory distress syndrome. We tested the hypothesis that mesenchymal stem cells derived from bone marrow, adipose tissue, and lung tissue would lead to different beneficial effects on lung and distal organ damage in experimental pulmonary acute respiratory distress syndrome. Animal study and primary cell culture. Laboratory investigation. Seventy-five Wistar rats. Wistar rats received saline (control) or Escherichia coli lipopolysaccharide (acute respiratory distress syndrome) intratracheally. On day 2, acute respiratory distress syndrome animals were further randomized to receive saline or bone marrow, adipose tissue, or lung tissue mesenchymal stem cells (1 × 10 cells) IV. Lung mechanics, histology, and protein levels of inflammatory mediators and growth factors were analyzed 5 days after mesenchymal stem cells administration. RAW 264.7 cells (a macrophage cell line) were incubated with lipopolysaccharide followed by coculture or not with bone marrow, adipose tissue, and lung tissue mesenchymal stem cells (10 cells/mL medium). Regardless of mesenchymal stem cells source, cells administration improved lung function and reduced alveolar collapse, tissue cellularity, collagen, and elastic fiber content in lung tissue, as well as decreased apoptotic cell counts in liver. Bone marrow and adipose tissue mesenchymal stem cells administration also reduced levels of tumor necrosis factor-α, interleukin-1β, keratinocyte-derived chemokine, transforming growth factor-β, and vascular endothelial growth factor, as well as apoptotic cell counts in lung and kidney, while increasing expression of keratinocyte growth factor in lung tissue. Additionally, mesenchymal stem cells differently modulated the secretion of biomarkers by macrophages depending on their source. Mesenchymal stem cells from different sources led to variable responses in lungs and distal organs. Bone marrow and adipose tissue mesenchymal stem cells yielded greater beneficial effects than lung tissue mesenchymal stem cells. These findings may be regarded as promising in clinical trials.

Unsaturation level decreased in bone marrow fat of postmenopausal women with low bone density using high resolution magic angle spinning (HRMAS) 1H NMR spectroscopy.

PubMed

Li, Xiaojuan; Shet, Keerthi; Xu, Kaipin; Rodríguez, Juan Pablo; Pino, Ana María; Kurhanewicz, John; Schwartz, Ann; Rosen, Clifford J

2017-12-01

There are increasing evidences suggesting bone marrow adiposity tissue (MAT) plays a critical role in affecting both bone quantity and quality. However, very limited studies that have investigated the association between the composition of MAT and bone mineral density (BMD). The goal of this study was to quantify MAT unsaturation profile of marrow samples from post-menopausal women using ex vivo high-resolution magic angle spinning (HRMAS) proton nuclear magnetic resonance ( 1 H NMR) spectroscopy, and to investigate the relationship between MAT composition and BMD. Bone marrow samples were obtained by iliac crest aspiration during surgical procedures from 24 postmenopausal women (65-89years) who had hip surgery due to bone fracture or arthroplasty. Marrow fat composition parameters, in particular, unsaturation level (UL), mono-unsaturation level (MUL) and saturation level (SL), were quantified using HRMAS 1 H NMR spectroscopy. The patients were classified into three groups based on the DXA BMD T-scores: controls, osteopenia and osteoporosis. Marrow fat composition was compared between these three groups as well as between subjects with and without factures using ANOCOVA, adjusted for age. Subjects with lower BMD (n=17) had significantly lower MUL (P=0.003) and UL (P=0.039), and significantly higher SL (P=0.039) compared to controls (n=7). When separating lower BMD into osteopenia (n=9) and osteoporosis (n=8) groups, subjects with osteopenia had significantly lower MUL (P=0.002) and UL (P=0.010), and significantly higher SL (P=0.010) compared to healthy controls. No significant difference was observed between subjects with osteopenia and osteoporosis. Using HRMAS 1 H NMR, significantly lower unsaturation and significantly higher saturation levels were observed in the marrow fat of subjects with lower BMD. HRMAS 1 H NMR was shown to be a powerful tool for identifying novel MR markers of marrow fat composition that are associated with bone quality and potentially fracture, and other bone pathologies and changes after treatment. A better understanding of the relationship between bone marrow composition and bone quality in humans may identify novel treatment targets, and provide guidance on novel interventions and therapeutic strategies for bone preservation. Copyright © 2017 Elsevier Inc. All rights reserved.

Prominent gelatinous bone marrow transformation presenting prior to myelodysplastic syndrome: a case report with review of the literature.

PubMed

Nakanishi, Ryota; Ishida, Mitsuaki; Hodohara, Keiko; Yoshida, Takashi; Yoshii, Miyuki; Okuno, Hiroko; Horinouchi, Akiko; Iwai, Muneo; Yoshida, Keiko; Kagotani, Akiko; Okabe, Hidetoshi

2013-01-01

Gelatinous bone marrow transformation (GMT) is a rare disorder characterized by the presence of fat cell atrophy, loss of hematopoietic cells, and deposition of extracellular gelatinous materials. GMT is not a specific disease, but is strongly associated with malnutrition and drugs. Albeit extremely rare, GMT has been reported in patients with myeloproliferative disorders. Herein, we report the second documented case of hypoplastic myelodysplastic syndrome (MDS) accompanying GMT. A 73-year-old Japanese male with excellent nutrition status and no history of alcohol or drug intake was detected with pancytopenia. The initial bone marrow aspirate specimen reveled hypocellular marrow without dysplastic signs in the myeloid cells. Bone marrow biopsy demonstrated hypocellular bone marrow with prominent GMT. He received blood transfusions, however, pancytopenia continued to progress. The second bone marrow aspirate specimen showed dysplastic changes, such as pseudo-Pelger-Huët cells, hypogranular or agranular granulocytes, and megakaryocytes with multiple small nuclei. Cytogenetic study demonstrated deletion of chromosome 7. Therefore, an ultimate diagnosis of hypoplastic MDS accompanying GMT was made. Only a limited number of cases of myeloproliferative disorders with GMT have been reported. Our analysis of these cases revealed that chromosome 7 abnormality is frequently observed in this condition. Moreover, findings from the current case suggested that myeloproliferative disorders including MDS must be included in the differential diagnostic considerations of GMT patients, who have no history of malnutrition or drugs, and careful examination of the bone marrow smear specimen and cytogenetic analysis are necessary for early detection of underlying myeloproliferative disorders.

Bone marrow induced osteogenesis in hydroxyapatite and calcium carbonate implants.

PubMed

Vuola, J; Göransson, H; Böhling, T; Asko-Seljavaara, S

1996-09-01

In this experimental study, blocks of natural coral (calcium carbonate) and its structurally similar derivate in the form of hydroxyapatite (calcium phosphate) were implanted in rat latissimus dorsi muscle with autogenous bone marrow to compare their bone-forming capability. A block without marrow placed in the opposite latissimus muscle served as a control. The animals were killed at 3, 6 and 12 weeks and, in the hydroxyapatite group, also at 24 weeks. The sections were analysed histologically and histomorphometrically. Bone was found only in implants containing bone marrow. Bone formation was significantly (p < 0.05) higher in coral than in hydroxyapatite implants at 3 weeks (10.8% versus 4.8%) and at 12 weeks (13.7% versus 6.3%, bone/total original block area). At 12 weeks all the coral implants had lost their original structure, and the cross-sectional area of the block had diminished to 40% of the original area.

Bone marrow necrosis secondary to imatinib usage, mimicking spinal metastasis on magnetic resonance imaging and FDG-PET/CT.

PubMed

Aras, Yavuz; Akcakaya, Mehmet Osman; Unal, Seher N; Bilgic, Bilge; Unal, Omer Faruk

2012-01-01

Imatinib mesylate has become the treatment of choice for gastrointestinal stromal tumors (GISTs) and has made a revolutionary impact on survival rates. Bone marrow necrosis is a very rare adverse event in malignant GIST. Bone metastases are also rarely encountered in the setting of this disease. The authors report on a patient with malignant GIST who developed a bone lesion, mimicking spinal metastasis on both MR imaging and FDG-PET/CT. Corpectomy and anterior fusion was performed, but the pathology report was consistent with bone marrow necrosis. Radiological and clinical similarities made the distinction between metastasis and bone marrow necrosis challenging for the treating physicians. Instead of radical surgical excision, more conservative methods such as percutaneous or endoscopic bone biopsies may be more useful for pathological confirmation, even though investigations such as MR imaging and FDG-PET/CT indicate metastatic disease.

Interventions for treating simple bone cysts in the long bones of children.

PubMed

Zhao, Jia-Guo; Wang, Jia; Huang, Wan-Jie; Zhang, Peng; Ding, Ning; Shang, Jian

2017-02-04

Simple bone cysts, also known as a unicameral bone cysts or solitary bone cysts, are the most common type of benign bone lesion in growing children. Cysts may lead to repeated pathological fracture (fracture that occurs in an area of bone weakened by a disease process). Occasionally, these fractures may result in symptomatic malunion. The main goals of treatment are to decrease the risk of pathological fracture, enhance cyst healing and resolve pain. Despite the numerous treatment methods that have been used for simple bone cysts in long bones of children, there is no consensus on the best procedure. This is an update of a Cochrane review first published in 2014. To assess the effects (benefits and harms) of interventions for treating simple bone cysts in the long bones of children, including adolescents.We intended the following main comparisons: invasive (e.g. injections, curettage, surgical fixation) versus non-invasive interventions (e.g. observation, plaster cast, restricted activity); different categories of invasive interventions (i.e. injections, curettage, drilling holes and decompression, surgical fixation and continued decompression); different variations of each category of invasive intervention (e.g. different injection substances: autologous bone marrow versus steroid). We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the China National Knowledge Infrastructure Platform, trial registers, conference proceedings and reference lists. Date of last search: April 2016. Randomised and quasi-randomised controlled trials evaluating methods for treating simple bone cysts in the long bones of children. Two review authors independently screened search results and performed study selection. We resolved differences in opinion between review authors by discussion and by consulting a third review author. Two review authors independently assessed risk of bias and data extraction. We summarised data using risk ratios (RRs) or mean differences (MDs), as appropriate, and 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the overall quality of the evidence. In this update in 2017, we did not identify any new randomised controlled trials (RCT) for inclusion. We identified one ongoing trial that we are likely to include in a future update. Accordingly, our results are unchanged. The only included trial is a multicentre RCT conducted at 24 locations in North America and India that compared bone marrow injection with steroid (methylprednisolone acetate) injection for treating simple bone cysts. Up to three injections were planned for participants in each group. The trial involved 90 children (mean age 9.5 years) and presented results for 77 children at two-year follow-up. Although the trial had secure allocation concealment, it was at high risk of performance bias and from major imbalances in baseline characteristics. Reflecting these study limitations, we downgraded the quality of evidence by two levels to 'low' for most outcomes, meaning that we are unsure about the estimates of effect. For outcomes where there was serious imprecision, we downgraded the quality of evidence by a further level to 'very low'.The trial provided very low quality evidence that fewer children in the bone marrow injection group had radiographically assessed healing of bone cysts at two years than in the steroid injection group (9/39 versus 16/38; RR 0.55 favouring steroid injection, 95% CI 0.28 to 1.09). However, the result was uncertain and may be compatible with no difference or small benefit favouring bone marrow injection. Based on an illustrative success rate of 421 children with healed bone cysts per 1000 children treated with steroid injections, this equates to 189 fewer (95% CI 303 fewer to 38 more) children with healed bone cysts per 1000 children treated with bone marrow injections. There was low quality evidence of a lack of difference between the two interventions at two years in functional outcome, based on the Activity Scale for Kids function score (0 to 100; higher scores equate to better outcome: MD -0.90; 95% CI -4.26 to 2.46) or in pain assessed using the Oucher pain score. There was very low quality evidence of a lack of differences between the two interventions for adverse events: subsequent pathological fracture (9/39 versus 11/38; RR 0.80, 95% CI 0.37 to 1.70) or superficial infection (two cases in the bone marrow group). Recurrence of bone cyst, unacceptable malunion, return to normal activities, and participant satisfaction were not reported. The available evidence is insufficient to determine the relative effects of bone marrow versus steroid injections, although the bone marrow injections are more invasive. Noteably, the rate of radiographically assessed healing of the bone cyst at two years was well under 50% for both interventions. Overall, there is a lack of evidence to determine the best method for treating simple bone cysts in the long bones of children. Further RCTs of sufficient size and quality are needed to guide clinical practice.

A fatal case of bone marrow embolism of unknown cause masquerading clinically as dengue shock syndrome.

PubMed

Selvi, Subramanian Kalaivani; Kar, Rakhee; Vadivelan, Mehalingam; Subrahmanyam, Dharanipragada Krishna Suri

2012-01-01

Bone marrow fat embolism usually occurs following multiple bone fractures, intraosseous surgical procedures, following vigorous cardiac resuscitation, ecclampsia, sickle cell anemia, malignancies, etc. We present a case of 70-year-old male who presented with fever, cough with expectoration, respiratory distress, altered sensorium, hypotension and thrombocytopenia, and diagnosed to have dengue shock syndrome and expired within 1 day of admission. Postmortem lung biopsy revealed bone marrow fat embolism.

Analysis of bone marrow plasma cells in patients with solitary bone plasmacytoma.

PubMed

Bhaskar, Archana; Gupta, Ritu; Sharma, Atul; Kumar, Lalit; Jain, Paresh

Local radiotherapy is the treatment of choice for solitary bone plasmacytoma (SBP) and the role of adjuvant systemic chemotherapy in preventing progression to multiple myeloma (MM) is controversial. The purpose of this study was to examine the presence of systemic disease in the form of neoplastic plasma cells (PC) in bone marrow of patients with SBP. Flow cytometric immunophenotyping of PC was carried out on bone marrow aspirate of 7 patients using monoclonal antibodies: CD19 FITC, CD45 FITC, CD20 FITC, CD52 PE, CD117 PE, CD56 PE, CD38 PerCP-Cy5.5, CD138 APC, anti-kappa (κ) FITC and anti-lambda (λ) PE. The neoplastic as well as normal PC were identified in bone marrow aspirate of all the patients at the time of diagnosis; the neoplastic PC ranged from 0.1%to 0.7% of all BM cells and 33.5% to 89.7% of total BMPC. The κ:λ ratio was normal in all the samples ranging from 0.5% to 1.6%. The present work shows the presence of systemic disease in the form of neoplastic PC in bone marrow of patients with SBP. Prospective studies would be required to study if the levels of neoplastic PC in the bone marrow may help us identify patients who are likely to progress to overt MM and benefit from systemic chemotherapy.

Membrane estrogen receptor alpha is an important modulator of bone marrow C-Kit+ cells mediated cardiac repair after myocardial infarction

PubMed Central

Su, Feng; Zhang, Wentian; Liu, Jianfang

2015-01-01

It has been validated that c-kit positive (c-kit+) cells in infarcted myocardium are from bone marrow (BM). Given the recent study that in the heart, estrogen receptor alpha (ERα) is involved in adaptive mechanisms by supporting cardiomyocytes survival via post-infarct cardiac c-kit+ cells, we tested a novel hypothesis that membrane ERα (mERа) supports survival of BM c-kit+ cells and enhance protective paracrine function for cardiac repair. Our data showed that myocardial infarction (MI) leads to an increase in c-kit+ first in bone marrow and then specifically within the infarcted myocardium. Also up-regulated mERа in post-infarct BM c-kit+ cells was found in day 3 post MI. In vitro co-culture system, mERа+ enhances the beneficial effects of BM c-kit+ cells by increasing their viability and reducing apoptosis. Post-infarct c-kit+ mERа+ cells population expresses predominant ERα and holds self-renewal as well as cardiac differentiation potentials after MI. In vivo, BM c-kit+ cells reduced infarct size, fibrosis and improved cardiac function. In conclusion, BM c-kit+ mERа+ exerted significantly cardiac protection after MI. A potential important implication of this study is that the manipulation of BM c-kit+ stem cells with ERа-dependent fashion may be helpful in recovering functional performance after cardiac tissue injury. PMID:26191121

78 FR 60810 - Change to the Definition of “Human Organ” Under Section 301 of the National Organ Transplant Act...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-02

... hematopoietic stem cells (HSCs) within peripheral blood in the definition of ``bone marrow.'' This would clarify... of whether they were recovered directly from bone marrow (by aspiration) or from peripheral blood (by... consideration.'' ``Human organ'' is defined to include ``bone marrow * * * or any subpart thereof'' or any organ...

[Endogenous pyrogen formation by bone marrow cells].

PubMed

Efremov, O M; Sorokin, A V; El'kina, O A

1978-01-01

The cells of the rabbit bone marrow produced endogenous pyrogen in response to stimulation with bacterial lipopolysaccharide. Incubation of the cells in medium No 199 containing a 15% homologous serum is optimal for the release of pyrogen. It is supposed that the cells of the bone marrow take part in the formation of endgenous pyrogen and in the mechanism of pyrexia in the organism.

[Regulatory problems regarding bone marrow transplantation from non-consanguinous donors].

PubMed

Moratti, A

1999-01-01

The paper reports the normative rules and the Italian Ministry of Health administrative instructions concerning the bone marrow unrelated donor (MUD) search in the Italian Bone Marrow Donor Registry (IBMDR) and in international registries from the preliminary activation to a MUD bone marrow transplant (BMT), when a volunteer donor, perfectly compatible with a recipient lacking a HLA identical sibling, is found. The article describes all the expenses pertinent to the different stages of search and the documents necessary to obtain the reimbursement of these expenses. A very recent Ministry Decree establishing that all the search costs will be charged to the competent local sanitary authority is added.

Molecular cloning and chromosomal mapping of bone marrow stromal cell surface gene, BST2, that may be involved in pre-B-cell growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishikawa, Jun; Kaisho, Tsuneyasu; Tomizawa, Hitoshi

1995-04-10

Bone marrow stromal cells regulate B-cell growth and development through their surface molecules and cytokines. In this study, we generated a mAb, RS38, that recognized a novel human membrane protein, BST-2, expressed on bone marrow stromal cell lines and synovial cell lines. We cloned a cDNA encoding BST-2 from a rheumatoid arthritis-derived synovial cell line. BST-2 is a 30- to 36-kDa type II transmembrane protein, consisting of 180 amino acids. The BST-2 gene (HGMW-approved symbol BST2) is located on chromosome 19p13.2. BST-2 is expressed not only on certain bone marrow stromal cell lines but also on various normal tissues, althoughmore » its expression pattern is different from that of another bone marrow stromal cell surface molecule, BST-1. BST-2 surface expression on fibroblast cell lines facilitated the stromal cell-dependent growth of a murine bone marrow-derived pre-B-cell line, DW34. The results suggest that BST-2 may be involved in pre-B-cell growth. 45 refs., 7 figs., 2 tabs.« less

PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells

PubMed Central

Gur-Cohen, Shiri; Itkin, Tomer; Chakrabarty, Sagarika; Graf, Claudine; Kollet, Orit; Ludin, Aya; Golan, Karin; Kalinkovich, Alexander; Ledergor, Guy; Wong, Eitan; Niemeyer, Elisabeth; Porat, Ziv; Erez, Ayelet; Sagi, Irit; Esmon, Charles T; Ruf, Wolfram; Lapidot, Tsvee

2016-01-01

Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation-related also control retention of EPCR+ LT-HSCs in the bone marrow and their recruitment to the blood via two different protease activated receptor 1 (PAR1)-mediated pathways. Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to TACE-mediated EPCR shedding, enhanced CXCL12-CXCR4-induced motility, and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with protein C that retain EPCR+ LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing VLA4 affinity and adhesion. Inhibition of NO production by activated protein C (aPC)-EPCR-PAR1 signaling reduces progenitor cell egress, increases NOlow bone marrow EPCR+ LT-HSCs retention and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR that control NO production to balance maintenance and recruitment of bone marrow EPCR+ LT-HSCs with clinical relevance. PMID:26457757

Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo.

PubMed

Massberg, Steffen; Konrad, Ildiko; Schürzinger, Katrin; Lorenz, Michael; Schneider, Simon; Zohlnhoefer, Dietlind; Hoppe, Katharina; Schiemann, Matthias; Kennerknecht, Elisabeth; Sauer, Susanne; Schulz, Christian; Kerstan, Sandra; Rudelius, Martina; Seidl, Stefan; Sorge, Falko; Langer, Harald; Peluso, Mario; Goyal, Pankaj; Vestweber, Dietmar; Emambokus, Nikla R; Busch, Dirk H; Frampton, Jon; Gawaz, Meinrad

2006-05-15

The accumulation of smooth muscle and endothelial cells is essential for remodeling and repair of injured blood vessel walls. Bone marrow-derived progenitor cells have been implicated in vascular repair and remodeling; however, the mechanisms underlying their recruitment to the site of injury remain elusive. Here, using real-time in vivo fluorescence microscopy, we show that platelets provide the critical signal that recruits CD34+ bone marrow cells and c-Kit+ Sca-1+ Lin- bone marrow-derived progenitor cells to sites of vascular injury. Correspondingly, specific inhibition of platelet adhesion virtually abrogated the accumulation of both CD34+ and c-Kit+ Sca-1+ Lin- bone marrow-derived progenitor cells at sites of endothelial disruption. Binding of bone marrow cells to platelets involves both P-selectin and GPIIb integrin on platelets. Unexpectedly, we found that activated platelets secrete the chemokine SDF-1alpha, thereby supporting further primary adhesion and migration of progenitor cells. These findings establish the platelet as a major player in the initiation of vascular remodeling, a process of fundamental importance for vascular repair and pathological remodeling after vascular injury.

Investigation into Variation of Endogenous Metabolites in Bone Marrow Cells and Plasma in C3H/He Mice Exposed to Benzene

PubMed Central

Sun, Rongli; Zhang, Juan; Yin, Lihong; Pu, Yuepu

2014-01-01

Benzene is identified as a carcinogen. Continued exposure of benzene may eventually lead to damage to the bone marrow, accompanied by pancytopenia, aplastic anemia or leukemia. This paper explores the variations of endogenous metabolites to provide possible clues for the molecular mechanism of benzene-induced hematotoxicity. Liquid chromatography coupled with time of flight-mass spectrometry (LC-TOF-MS) and principal component analysis (PCA) was applied to investigate the variation of endogenous metabolites in bone marrow cells and plasma of male C3H/He mice. The mice were injected subcutaneously with benzene (0, 300, 600 mg/day) once daily for seven days. The body weights, relative organ weights, blood parameters and bone marrow smears were also analyzed. The results indicated that benzene caused disturbances in the metabolism of oxidation of fatty acids and essential amino acids (lysine, phenylalanine and tyrosine) in bone marrow cells. Moreover, fatty acid oxidation was also disturbed in plasma and thus might be a common disturbed metabolic pathway induced by benzene in multiple organs. This study aims to investigate the underlying molecular mechanisms involved in benzene hematotoxicity, especially in bone marrow cells. PMID:24658442

CELLS INVOLVED IN THE IMMUNE RESPONSE

PubMed Central

Singhal, Sharwan K.; Richter, Maxwell

1968-01-01

Cell suspensions of immune rabbit lymph nodes and spleen were capable of undergoing blastogenesis and mitosis and of incorporating tritiated thymidine when maintained in culture with the specific antigen in vitro. They did not respond to other, non-cross-reacting antigens. The blastogenic response obtained with immune lymph node cells could be correlated with the antibody synthesizing capacity of fragment cultures prepared from the same lymph nodes. Cell suspensions of immune bone marrow responded to non-cross-reacting antigens only whereas cell suspensions of immune thymus, sacculus rotundus, and appendix did not respond when exposed to any of the antigens tested. On the other hand, neither fragments nor cell suspensions prepared from lymph nodes, spleen, and thymus of normal, unimmunized rabbits responded with antibody formation and blastogenesis when exposed to any of the antigens. However, normal bone marrow cells responded with marked blastogenesis and tritiated thymidine uptake. The specificity of this in vitro bone marrow response was demonstrated by the fact that the injection of a protein antigen in vivo resulted in the loss of reactivity by the marrow cell to that particular antigen but not to the other, non-cross-reacting antigens. Furthermore, bone marrow cells of tolerant rabbits failed to respond to the specific antigen in vitro. It was also demonstrated that normal bone marrow cells incubated with antigen are capable of forming antibody which could be detected by the fluorescent antibody technique. This response of the bone marrow cells has been localized to the lymphocyte-rich fraction of the bone marrow. It is concluded that the bone marrow lymphocyte, by virtue of its capacity to react with blastogenesis and mitosis and with antibody formation upon initial exposure to the antigen, a capacity not possessed by lymphocytes of the other lymphoid organs, has a preeminent role in the sequence of cellular events culminating in antibody formation. PMID:4176224

Bone marrow biopsy

MedlinePlus

... aspiration removes a small amount of marrow in liquid form for examination. ... and a syringe is used to withdraw the liquid bone marrow. If this is done, the needle will be removed and repositioned. Or, another needle may be used for the biopsy.

Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function.

PubMed

Nam, Sorim; Kang, Kyeongah; Cha, Jae Seon; Kim, Jung Woo; Lee, Hee Gu; Kim, Yonghwan; Yang, Young; Lee, Myeong-Sok; Lim, Jong-Seok

2016-12-01

Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6G high Ly6C low Gr1 high CD11b + ) and MO-MDSCs (Ly6G - Ly6C high Gr-1 int CD11b + ) have an immune suppressive function. Interferon regulatory factor 4 (IRF4) has a role in the negative regulation of TLR signaling and is associated with lymphoid cell development. However, the roles of IRF4 in myeloid cell differentiation are unclear. In this study, we found that IRF4 expression was remarkably suppressed during the development of MDSCs in the tumor microenvironment. Both the mRNA and protein levels of IRF4 in MDSCs were gradually reduced, depending on the development of tumors in the 4T1 model. siRNA-mediated knockdown of IRF4 in bone marrow cells promoted the differentiation of PMN-MDSCs. Similarly, IRF4 inhibition in bone marrow cells using simvastatin, which has been known to inhibit IRF4 expression, increased PMN-MDSC numbers. In contrast, IRF4 overexpression in bone marrow cells inhibited the total numbers of MDSCs, especially PMN-MDSCs. Notably, treatment with IL-4, an upstream regulator of IRF4, induced IRF4 expression in the bone marrow cells, and consequently, IL-4-induced IRF4 expression resulted in a decrease in PMN-MDSC numbers. Finally, we confirmed that IRF4 expression in MDSCs can modulate their activity to inhibit T cell proliferation through IL-10 production and ROS generation, and myeloid-specific deletion of IRF4 leads to the increase of MDSC differentiation. Our present findings indicate that IRF4 reduction induced by tumor formation can increase the number of MDSCs, and increases in the IRF4 expression in MDSCs may infringe on the immune-suppressive function of MDSCs. © Society for Leukocyte Biology.

Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model.

PubMed

Nahon, Joya E; Hoekstra, Menno; Havik, Stefan R; Van Santbrink, Peter J; Dallinga-Thie, Geesje M; Kuivenhoven, Jan-Albert; Geerling, Janine J; Van Eck, Miranda

2018-05-05

Proteoglycan 4 (Prg4) has a high structural similarity with the established atherosclerosis-modulating proteoglycan versican, but its role in atherogenesis is still unknown. Therefore, the impact of Prg4 deficiency on macrophage function in vitro and atherosclerosis susceptibility in vivo was investigated. The presence and localization of Prg4 was studied in atherosclerotic lesions. Furthermore, the effect of Prg4 deficiency on macrophage foam cell formation, cholesterol efflux and lipopolysaccharide (LPS) response was determined. Finally, susceptibility for atherosclerotic lesion formation was investigated in bone marrow-specific Prg4 knockout (KO) mice. Prg4 mRNA expression was induced 91-fold (p<0.001) in murine initial atherosclerotic lesions and Prg4 protein co-localized with human lesional macrophages. Murine Prg4 KO macrophages showed increased foam cell formation (+2.1-fold, p<0.01). In parallel, the expression of the cholesterol efflux genes ATP-binding cassette transporter A1 and scavenger receptor type B1 was lower (-35%, p<0.05;-40%, p<0.05) in Prg4 KO macrophages. This translated into an impaired cholesterol efflux to high-density lipoprotein (-13%, p<0.001) and apolipoprotein A1 (-8%, p<0.05). Furthermore, Prg4 KO macrophages showed an impaired LPS-induced rise in TNFα secretion as compared to wild-type controls (-31%, p<0.001), indicating a reduced inflammatory response. Combined, these pro- and anti-atherogenic effects did not translate into a significant difference in atherosclerotic lesion formation upon bone marrow-specific deletion of Prg4 in low-density lipoprotein receptor KO mice. Prg4 is present in macrophages in both murine and human atherosclerotic lesions and critically influences macrophage function, but deletion of Prg4 in bone marrow-derived cells does not affect atherosclerotic lesion development. Copyright © 2018 Elsevier B.V. All rights reserved.

WE-E-BRE-01: An Image-Based Skeletal Dosimetry Model for the ICRP Reference Adult Female - Internal Electron Sources

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Reilly, S; Maynard, M; Marshall, E

Purpose: Limitations seen in previous skeletal dosimetry models, which are still employed in commonly used software today, include the lack of consideration of electron escape and cross-fire from cortical bone, the modeling of infinite spongiosa, the disregard of the effect of varying cellularity on active marrow self-irradiation, and the lack of use of the more recent ICRP definition of a 50 micron surrogate tissue region for the osteoprogenitor cells - shallow marrow. These limitations were addressed in the present dosimetry model. Methods: Electron transport was completed to determine specific absorbed fractions to active marrow and shallow marrow of the skeletalmore » regions of the adult female. The bone macrostructure was obtained from the whole-body hybrid computational phantom of the UF series of reference phantoms, while the bone microstructure was derived from microCT images of skeletal region samples taken from a 45 year-old female cadaver. The target tissue regions were active marrow and shallow marrow. The source tissues were active marrow, inactive marrow, trabecular bone volume, trabecular bone surfaces, cortical bone volume and cortical bone surfaces. The marrow cellularity was varied from 10 to 100 percent for active marrow self-irradiation. A total of 33 discrete electron energies, ranging from 1 keV to 10 MeV, were either simulated or modeled analytically. Results: The method of combining macro- and microstructure absorbed fractions calculated using MCNPX electron transport was found to yield results similar to those determined with the PIRT model for the UF adult male in the Hough et al. study. Conclusion: The calculated skeletal averaged absorbed fractions for each source-target combination were found to follow similar trends of more recent dosimetry models (image-based models) and did not follow current models used in nuclear medicine dosimetry at high energies (due to that models use of an infinite expanse of trabecular spongiosa)« less

Bone stress injury of the ankle in professional ballet dancers seen on MRI

PubMed Central

Elias, Ilan; Zoga, Adam C; Raikin, Steven M; Peterson, Judith R; Besser, Marcus P; Morrison, William B; Schweitzer, Mark E

2008-01-01

Background Ballet Dancers have been shown to have a relatively high incidence of stress fractures of the foot and ankle. It was our objective to examine MR imaging patterns of bone marrow edema (BME) in the ankles of high performance professional ballet dancers, to evaluate clinical relevance. Methods MR Imaging was performed on 12 ankles of 11 active professional ballet dancers (6 female, 5 male; mean age 24 years, range 19 to 32). Individuals were imaged on a 0.2 T or 1.5 T MRI units. Images were evaluated by two musculoskeletal radiologists and one orthopaedic surgeon in consensus for location and pattern of bone marrow edema. In order to control for recognized sources of bone marrow edema, images were also reviewed for presence of osseous, ligamentous, tendinous and cartilage injuries. Statistical analysis was performed to assess the strength of the correlation between bone marrow edema and ankle pain. Results Bone marrow edema was seen only in the talus, and was a common finding, observed in nine of the twelve ankles imaged (75%) and was associated with pain in all cases. On fluid-sensitive sequences, bone marrow edema was ill-defined and centered in the talar neck or body, although in three cases it extended to the talar dome. No apparent gender predilection was noted. No occult stress fracture could be diagnosed. A moderately strong correlation (phi = 0.77, p= 0.0054) was found between edema and pain in the study population. Conclusion Bone marrow edema seems to be a specific MRI finding in the talus of professional ballet dancers, likely related to biomechanical stress reactions, due to their frequently performed unique maneuvers. Clinically, this condition may indicate a sign of a bone stress injury of the ankle. PMID:18371230

Similarities and Differences between Porcine Mandibular and Limb Bone Marrow Mesenchymal Stem Cells

PubMed Central

Lloyd, Brandon; Tee, Boon Ching; Headley, Colwyn; Emam, Hany; Mallery, Susan; Sun, Zongyang

2017-01-01

Objective Research has shown promise of using bone marrow mesenchymal stem cells (BMSCs) for craniofacial bone regeneration; yet little is known about the differences of BMSCs from limb and craniofacial bones. This study compared pig mandibular and tibia BMSCs for their in vitro proliferation, osteogenic differentiation properties and gene expression. Design Bone marrow was aspirated from the tibia and mandible of 3–4 month-old pigs (n=4), followed by BMSC isolation, culture-expansion and characterization by flow cytometry. Proliferation rates were assessed using population doubling times. Osteogenic differentiation was evaluated by alkaline phosphatase activity. Affymetrix porcine microarray was used to compare gene expressions of tibial and mandibular BMSCs, followed by real-time RT-PCR evaluation of certain genes. Results Our results showed that BMSCs from both locations expressed MSC markers but not hematopoietic markers. The proliferation and osteogenic differentiation potential of mandibular BMSCs were significantly stronger than those of tibial BMSCs. Microarray analysis identified 404 highly abundant genes, out of which 334 genes were matched between the two locations and annotated into the same functional groups including osteogenesis and angiogenesis, while 70 genes were mismatched and annotated into different functional groups. In addition, 48 genes were differentially expressed by at least 1.5-fold difference between the two locations, including higher expression of cranial neural crest-related gene BMP-4 in mandibular BMSCs, which was confirmed by real-time RT-PCR. Conclusions Altogether, these data indicate that despite strong similarities in gene expression between mandibular and tibial BMSCs, mandibular BMSCs express some genes differently than tibial BMSCs and have a phenotypic profile that may make them advantageous for craniofacial bone regeneration. PMID:28135571

ω-3 Fatty Acids Reduce Chemotherapy-Induced Hematological Toxicity by Bone Marrow Stimulation in Mice.

PubMed

Murakami, Kohei; Miyata, Hiroshi; Miyazaki, Yasuhiro; Makino, Tomoki; Takahashi, Tsuyoshi; Kurokawa, Yukinori; Yamasaki, Makoto; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro

2017-07-01

ω-3 Fatty acids exert several benefits during chemotherapy, such as preventing intestinal mucosal damage and improving response to chemotherapy. However, little is known about the effect of ω-3 fatty acids on chemotherapy-induced hematological toxicities. Mice that had consumed either an ω-3-rich or an ω-3-poor diet for 2 weeks were intraperitoneally administered cisplatin. The resultant changes in blood cell count, bone marrow cell count, and cytokine levels in bone marrow supernatant were analyzed. The effect of ω-3 fatty acids on human peripheral blood mononuclear cells (PBMCs) exposed to cisplatin was also examined. Although peripheral blood cell counts decreased after cisplatin treatment in both groups of mice, the decrease in white blood cell count was significantly lower in mice that consumed the ω-3-rich diet. The decrease in bone marrow cells after cisplatin treatment was also reduced in mice that consumed the ω-3-rich diet. Levels of stem cell factor (SCF) and fibroblast growth factor 1 (FGF-1) were significantly higher in bone marrow supernatants from mice that consumed the ω-3-rich diet. The rate of apoptosis in PBMCs (after exposure to cisplatin) cultured in medium containing ω-3 fatty acids was significantly lower than in PBMCs cultured in control medium. ω-3-Rich diets reduced chemotherapy-induced leukopenia in mice. This may be the result of increased numbers of bone marrow cells due to higher levels of SCF and FGF-1 in the bone marrow.

Osteoblasts Protect AML Cells from SDF-1-Induced Apoptosis

PubMed Central

Kremer, Kimberly N.; Dudakovic, Amel; McGee-Lawrence, Meghan E.; Philips, Rachael L.; Hess, Allan D.; Smith, B. Douglas; van Wijnen, Andre J.; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; Hedin, Karen E.

2014-01-01

The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF-1 naturally present in that location. In co-culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF-1-induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W-20-17, mediated this protection via a cell contact-independent mechanism. In contrast, bone marrow-derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4-dependent mechanism and failed to protect AML cells from exogenously added SDF-1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF-1-driven apoptotic pathway of CXCR4-expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF-1-induced apoptosis of AML cells residing within the bone marrow microenvironment. PMID:24851270

Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women.

PubMed

Bredella, Miriam A; Gerweck, Anu V; Barber, Lauren A; Breggia, Anne; Rosen, Clifford J; Torriani, Martin; Miller, Karen K

2014-05-01

Abdominal adiposity is associated with low BMD and decreased growth hormone (GH) secretion, an important regulator of bone homeostasis. The purpose of our study was to determine the effects of a short course of GH on markers of bone turnover and bone marrow fat in premenopausal women with abdominal adiposity. In a 6-month, randomized, double-blind, placebo-controlled trial we studied 79 abdominally obese premenopausal women (21-45 y) who underwent daily sc injections of GH vs. placebo. Main outcome measures were body composition by DXA and CT, bone marrow fat by proton MR spectroscopy, P1NP, CTX, 25(OH)D, hsCRP, undercarboxylated osteocalcin (ucOC), preadipocyte factor 1 (Pref 1), apolipoprotein B (ApoB), and IGF-1. GH increased IGF-1, P1NP, 25(OH)D, ucOC, bone marrow fat and lean mass, and decreased abdominal fat, hsCRP, and ApoB compared with placebo (p<0.05). There was a trend toward an increase in CTX and Pref-1. Among all participants, a 6-month increase in IGF-1 correlated with 6-month increase in P1NP (p=0.0005), suggesting that subjects with the greatest increases in IGF-1 experienced the greatest increases in bone formation. A six-month decrease in abdominal fat, hsCRP, and ApoB inversely predicted 6-month change in P1NP, and 6-month increase in lean mass and 25(OH)D positively predicted 6-month change in P1NP (p≤0.05), suggesting that subjects with greatest decreases in abdominal fat, inflammation and ApoB, and the greatest increases in lean mass and 25(OH)D experienced the greatest increases in bone formation. A six-month increase in bone marrow fat correlated with 6-month increase in P1NP (trend), suggesting that subjects with the greatest increases in bone formation experienced the greatest increases in bone marrow fat. Forward stepwise regression analysis indicated that increase in lean mass and decrease in abdominal fat were positive predictors of P1NP. When IGF-1 was added to the model, it became the only predictor of P1NP. GH replacement in abdominally obese premenopausal women for 6 months increased bone turnover and bone marrow fat. Reductions in abdominal fat, and inflammation, and increases in IGF-1, lean mass and vitamin D were associated with increased bone formation. The increase in bone marrow fat may reflect changes in energy demand from increased bone turnover. Copyright © 2014 Elsevier Inc. All rights reserved.

Mechanical and biological properties of the micro-/nano-grain functionally graded hydroxyapatite bioceramics for bone tissue engineering.

PubMed

Zhou, Changchun; Deng, Congying; Chen, Xuening; Zhao, Xiufen; Chen, Ying; Fan, Yujiang; Zhang, Xingdong

2015-08-01

Functionally graded materials (FGM) open the promising approach for bone tissue repair. In this study, a novel functionally graded hydroxyapatite (HA) bioceramic with micrograin and nanograin structure was fabricated. Its mechanical properties were tailored by composition of micrograin and nanograin. The dynamic mechanical analysis (DMA) indicated that the graded HA ceramics had similar mechanical property compared to natural bones. Their cytocompatibility was evaluated via fluorescent microscopy and MTT colorimetric assay. The viability and proliferation of rabbit bone marrow mesenchymal stem cells (BMSCs) on ceramics indicated that this functionally graded HA ceramic had better cytocompatibility than conventional HA ceramic. This study demonstrated that functionally graded HA ceramics create suitable structures to satisfy both the mechanical and biological requirements of bone tissues. Copyright © 2015 Elsevier Ltd. All rights reserved.

Osteogenic Performance of Donor-Matched Human Adipose and Bone Marrow Mesenchymal Cells Under Dynamic Culture

PubMed Central

Wu, Wei; Le, Andrew V.; Mendez, Julio J.; Chang, Julie; Niklason, Laura E.

2015-01-01

Adipose-derived mesenchymal cells (ACs) and bone marrow-derived mesenchymal cells (BMCs) have been widely used for bone regeneration and can be seeded on a variety of rigid scaffolds. However, to date, a direct comparison of mesenchymal cells (MC) harvested from different tissues from the same donor and cultured in identical osteogenic conditions has not been investigated. Indeed, it is unclear whether marrow-derived or fat-derived MC possess intrinsic differences in bone-forming capabilities, since within-patient comparisons have not been previously done. This study aims at comparing ACs and BMCs from three donors ranging in age from neonatal to adult. Matched cells from each donor were studied in three distinct bioreactor settings, to determine the best method to create a viable osseous engineered construct. Human ACs and BMCs were isolated from each donor, cultured, and seeded on decellularized porcine bone (DCB) constructs. The constructs were then subjected to either static or dynamic (stirring or perfusion) bioreactor culture conditions for 7–21 days. Afterward, the constructs were analyzed for cell adhesion and distribution and osteogenic differentiation. ACs demonstrated higher seeding efficiency than BMCs. However, static and dynamic culture significantly increased BMCs proliferation more than ACs. In all conditions, BMCs demonstrated stronger osteogenic activity as compared with ACs, through higher alkaline phosphatase activity and gene expression for various bony markers. Conversely, ACs expressed more collagen I, which is a nonspecific matrix molecule in most connective tissues. Overall, dynamic bioreactor culture conditions enhanced osteogenic gene expression in both ACs and BMCs. Scaffolds seeded with BMCs in dynamic stirring culture conditions exhibit the greatest osteogenic proliferation and function in vitro, proving that marrow-derived MC have superior bone-forming potential as compared with adipose-derived cells. PMID:25668104

Short-term physical activity intervention decreases femoral bone marrow adipose tissue in young children: a pilot study

PubMed Central

Casazza, K; Hanks, LJ; Hidalgo, B; Hu, HH; Affuso, O

2011-01-01

Mechanical stimulation is necessary for maximization of geometrical properties of bone mineralization contributing to long-term strength. The amount of mineralization in bones has been reciprocally related to volume of bone marrow adipose tissue and this relationship is suggested to be an independent predictor of fracture. Physical activity represents an extrinsic factor that impacts both mineralization and marrow volume exerting permissive capacity of the growing skeleton to achieve its full genetic potential. Because geometry- and shape-determining processes primarily manifest during the linear growth period, the accelerated structural changes accompanying early childhood (ages 3 to 6 y) may have profound impact on lifelong bone health. The objective of this pilot study was to determine if a short-term physical activity intervention in young children would result in augmentation of geometric properties of bone. Three days per week the intervention group (n=10) participated in 30 minutes of moderate intensity physical activity, such as jumping, hopping and running, and stretching activities, whereas controls (n=10) underwent usual activities during the 10-week intervention period. Femoral bone marrow adipose tissue volume and total body composition were assessed by magnetic resonance imaging and dual-energy X-ray absorptiometry, respectively, at baseline and after ten weeks. Although after 10-weeks, intergroup differences were not observed, a significant decrease in femoral marrow adipose tissue volume was observed in those participating in physical activity intervention. Our findings suggest physical activity may improve bone quality via antagonistic effects on femoral bone marrow adipose tissue and possibly long-term agonistic effects on bone mineralization. PMID:21939791

Determining the best treatment for simple bone cyst: a decision analysis.

PubMed

Lee, Seung Yeol; Chung, Chin Youb; Lee, Kyoung Min; Sung, Ki Hyuk; Won, Sung Hun; Choi, In Ho; Cho, Tae-Joon; Yoo, Won Joon; Yeo, Ji Hyun; Park, Moon Seok

2014-03-01

The treatment of simple bone cysts (SBC) in children varies significantly among physicians. This study examined which procedure is better for the treatment of SBC, using a decision analysis based on current published evidence. A decision tree focused on five treatment modalities of SBC (observation, steroid injection, autologous bone marrow injection, decompression, and curettage with bone graft) were created. Each treatment modality was further branched, according to the presence and severity of complications. The probabilities of all cases were obtained by literature review. A roll back tool was utilized to determine the most preferred treatment modality. One-way sensitivity analysis was performed to determine the threshold value of the treatment modalities. Two-way sensitivity analysis was utilized to examine the joint impact of changes in probabilities of two parameters. The decision model favored autologous bone marrow injection. The expected value of autologous bone marrow injection was 0.9445, while those of observation, steroid injection, decompression, and curettage and bone graft were 0.9318, 0.9400, 0.9395, and 0.9342, respectively. One-way sensitivity analysis showed that autologous bone marrow injection was better than that of decompression for the expected value when the rate of pathologic fracture, or positive symptoms of SBC after autologous bone marrow injection, was lower than 20.4%. In our study, autologous bone marrow injection was found to be the best choice of treatment of SBC. However, the results were sensitive to the rate of pathologic fracture after treatment of SBC. Physicians should consider the possibility of pathologic fracture when they determine a treatment method for SBC.

The clinical impact of staging bone marrow examination on treatment decisions and prognostic assessment of lymphoma patients.

PubMed

Painter, Dan; Smith, Alexandra; de Tute, Ruth; Crouch, Simon; Roman, Eve; Jack, Andrew

2015-07-01

This study investigates the value of performing a staging bone marrow in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and classical hodgkin lymphoma (CHL). The results of 3112 staging bone marrow examinations were assessed for impact on prognostic assessment and critical treatment decisions. The detection of marrow involvement altered the disease-specific prognostic index for 4·3% of DLBCL, 6·2% of FL and 0·6% of CHL but marrow involvement in DLBCL was an independent prognostic factor. Knowing the marrow status potentially changed treatment in 92 patients, detection of these patients would have required 854 examinations to be performed. © 2015 John Wiley & Sons Ltd.

[Progesterone Promotes Human Bone Marrow Mesenchymal Stem Cells to Synthesize Fibronectin via ERK Pathway].

PubMed

Wu, Zhen-Yong; Chen, Jing-Li; Huang, Shu; Zhang, Hui; Wang, Fang; Wang, Yan; Bi, Xiao-Yun; Guo, Zi-Kuan

2015-12-01

To investigate whether the progesterone can promote fibronection (FN) synthesis by human bone marrow mesenchymal stem cells (MSCs) and to explore the potential underlying mechanism. The human bone marrow MSCs were cultured in a serum-free medium with progesterone for 72 hours, the MTT test was performed to observe the proliferation status and adhension ability of the treated cells. Western blot was used to detect the content of FN in MSDs with GAPDH as the internal reference, the phosphorylation of ERK1/2, as well as the FN content in MSC treated by PD98059, a specific inhibitor of ERK1/2. The progesterone at a range of certain doses not effect on the proliferation of human bone marrow MSCs. Progesterone (25 µg/L) treatment enhanced the FN expression and adherent ability of marrow MSCs. Progesterone could induce prompt phosphorylation of ERK 1/2 and its promoting effects on FN synthesis was reversed by PD98059. The progesterone can promote FN synthesis by human bone marrow MSCs via ERK 1/2 pathway, and it might be used to culture MSCs in serum-free medium.

TNF-α signaling in Fanconi anemia

PubMed Central

Du, Wei; Erden, Ozlem; Pang, Qishen

2013-01-01

Tumor necrosis factor-alpha (TNF-α is a major pro-inflammatory cytokine involved in systemic inflammation and the acute phase reaction. Dysregulation of TNF production has been implicated in a variety of human diseases including Fanconi anemia (FA). FA is a genomic instability syndrome characterized by progressive bone marrow failure and cancer susceptibility. The patients with FA are often found overproducing TNF-α, which may directly affect hematopoietic stem cell (HSC) function by impairing HSC survival, homing and proliferation, or indirectly change the bone marrow microenvironment critical for HSC homeostasis and function, therefore contribute to disease progression in FA. In this brief review, we discuss the link between TNF-α signaling and FA pathway with emphasis on the implication of inflammation in the pathophysiology and abnormal hematopoiesis in FA. PMID:23890415

TNF-α signaling in Fanconi anemia.

PubMed

Du, Wei; Erden, Ozlem; Pang, Qishen

2014-01-01

Tumor necrosis factor-alpha (TNF-α) is a major pro-inflammatory cytokine involved in systemic inflammation and the acute phase reaction. Dysregulation of TNF production has been implicated in a variety of human diseases including Fanconi anemia (FA). FA is a genomic instability syndrome characterized by progressive bone marrow failure and cancer susceptibility. The patients with FA are often found overproducing TNF-α, which may directly affect hematopoietic stem cell (HSC) function by impairing HSC survival, homing and proliferation, or indirectly change the bone marrow microenvironment critical for HSC homeostasis and function, therefore contributing to disease progression in FA. In this brief review, we discuss the link between TNF-α signaling and FA pathway with emphasis on the implication of inflammation in the pathophysiology and abnormal hematopoiesis in FA. © 2013.

Mastocytosis: magnetic resonance imaging patterns of marrow disease.

PubMed

Avila, N A; Ling, A; Metcalfe, D D; Worobec, A S

1998-03-01

To report the bone marrow MRI findings of patients with mastocytosis and correlate them with clinical, pathologic, and radiographic features. Eighteen patients with mastocytosis had T1-weighted spin echo and short tau inversion recovery MRI of the pelvis at 0.5 T. In each patient the MR pattern of marrow disease was classified according to intensity and uniformity and was correlated with the clinical category of mastocytosis, bone marrow biopsy results, and radiographic findings. Two patients had normal MRI scans and normal bone marrow biopsies. One patient had a normal MRI scan and a marrow biopsy consistent with mastocytosis. Fifteen patients had abnormal MRI scans and abnormal marrow biopsies. There were several different MR patterns of marrow involvement; none was specifically associated with any given clinical category of mastocytosis. Fifteen of the 18 patients had radiographs of the pelvis; of those, 13 with abnormal MRI scans and abnormal marrow biopsies had the following radiographic findings: normal (nine); sclerosis (three); diffuse osteopenia (one). While radiographs are very insensitive for the detection of marrow abnormalities in mastocytosis, MRI is very sensitive and may display several different patterns of marrow involvement.

Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.

PubMed

Bär, Christian; Povedano, Juan Manuel; Serrano, Rosa; Benitez-Buelga, Carlos; Popkes, Miriam; Formentini, Ivan; Bobadilla, Maria; Bosch, Fatima; Blasco, Maria A

2016-04-07

Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres. © 2016 by The American Society of Hematology.

Alternative RNA Splicing of CSF3R in Promoting Myelodysplastic Syndromes

DTIC Science & Technology

2017-01-01

Myelodysplastic Syndromes, Bone Marrow Failure, Granulopoiesis, RNA splicing 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES...major distinguishing feature of myelodysplastic syndromes (MDS), the most common form of acquired bone marrow failure, is the presence of recurrent...model by expressing alternative splice form in the context of Csf3r-/- mice. KEYWORDS: Myelodysplastic Syndromes, Bone Marrow Failure

Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

DTIC Science & Technology

2017-12-01

using isogenic (mutant/complemented) human cell line pairs from patients with Fanconi anemia (FA), a heritable human bone marrow failure (BMF) syndrome ...small molecules could be therapeutically useful in reducing the risk of BMF in diseases such as Fanconi anemia, and perhaps after radiation exposure...damage-repair, DNA damage response, Fanconi anemia and associated bone marrow failure syndromes and environmental and molecular toxicology will all be

Bone Marrow Lipids in Rats Exposed to Total-Body Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Snyder, Fred; Cress, Edgar A.

1963-05-01

ABS>Thin-layer chromatography was used to demonstrate that bone marrow lipids of rats were primarily triglycerides; gas-liquid chromatography of the fraction revealed that palmitic and oleic acids account for more than 80% of the fatty acids. Minor lipid components present in the control and irradiated marrow are glyceryl ethers, cholesterol, fatty acids, and phospholipids. Cholesterol esters were not found. Total-body irradiation (800 r) increases the femur marrow triglyceride fraction approximately six times by 1 week after irradiation, and it remains elevated for many weeks. The relationship between dose and increase in marrow triglycerides appears to fit the equation y = bxmore » a. The water and lipid content of bone marrow bear a reciprocal relation to each other, while both water and residue are significantly reduced in the irradiated femur marrow.« less

Peripheral-blood stem cells versus bone marrow from unrelated donors.

PubMed

Anasetti, Claudio; Logan, Brent R; Lee, Stephanie J; Waller, Edmund K; Weisdorf, Daniel J; Wingard, John R; Cutler, Corey S; Westervelt, Peter; Woolfrey, Ann; Couban, Stephen; Ehninger, Gerhard; Johnston, Laura; Maziarz, Richard T; Pulsipher, Michael A; Porter, David L; Mineishi, Shin; McCarty, John M; Khan, Shakila P; Anderlini, Paolo; Bensinger, William I; Leitman, Susan F; Rowley, Scott D; Bredeson, Christopher; Carter, Shelly L; Horowitz, Mary M; Confer, Dennis L

2012-10-18

Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).

Imaging Radiation-Induced Gastrointestinal, Bone Marrow Injury and Recovery Kinetics Using 18F-FDG PET

PubMed Central

Tang, Tien T.; Rendon, David A.; Zawaski, Janice A.; Afshar, Solmaz F.; Kaffes, Caterina K.; Sabek, Omaima M.

2017-01-01

Positron emission tomography using 18F-Fluro-deoxy-glucose (18F-FDG) is a useful tool to detect regions of inflammation in patients. We utilized this imaging technique to investigate the kinetics of gastrointestinal recovery after radiation exposure and the role of bone marrow in the recovery process. Male Sprague-Dawley rats were either sham irradiated, irradiated with their upper half body shielded (UHBS) at a dose of 7.5 Gy, or whole body irradiated (WBI) with 4 or 7.5 Gy. Animals were imaged using 18F-FDG PET/CT at 5, 10 and 35 days post-radiation exposure. The gastrointestinal tract and bone marrow were analyzed for 18F-FDG uptake. Tissue was collected at all-time points for histological analysis. Following 7.5 Gy irradiation, there was a significant increase in inflammation in the gastrointestinal tract as indicated by the significantly higher 18F-FDG uptake compared to sham. UHBS animals had a significantly higher activity compared to 7.5 Gy WBI at 5 days post-exposure. Animals that received 4 Gy WBI did not show any significant increase in uptake compared to sham. Analysis of the bone marrow showed a significant decrease of uptake in the 7.5 Gy animals 5 days post-irradiation, albeit not observed in the 4 Gy group. Interestingly, as the metabolic activity of the gastrointestinal tract returned to sham levels in UHBS animals it was accompanied by an increase in metabolic activity in the bone marrow. At 35 days post-exposure both gastrointestinal tract and bone marrow 18F-FDG uptake returned to sham levels. 18F-FDG imaging is a tool that can be used to study the inflammatory response of the gastrointestinal tract and changes in bone marrow metabolism caused by radiation exposure. The recovery of the gastrointestinal tract coincides with an increase in bone marrow metabolism in partially shielded animals. These findings further demonstrate the relationship between the gastrointestinal syndrome and bone marrow recovery, and that this interaction can be studied using non-invasive imaging modalities. PMID:28052129

Imaging Radiation-Induced Gastrointestinal, Bone Marrow Injury and Recovery Kinetics Using 18F-FDG PET.

PubMed

Tang, Tien T; Rendon, David A; Zawaski, Janice A; Afshar, Solmaz F; Kaffes, Caterina K; Sabek, Omaima M; Gaber, M Waleed

2017-01-01

Positron emission tomography using 18F-Fluro-deoxy-glucose (18F-FDG) is a useful tool to detect regions of inflammation in patients. We utilized this imaging technique to investigate the kinetics of gastrointestinal recovery after radiation exposure and the role of bone marrow in the recovery process. Male Sprague-Dawley rats were either sham irradiated, irradiated with their upper half body shielded (UHBS) at a dose of 7.5 Gy, or whole body irradiated (WBI) with 4 or 7.5 Gy. Animals were imaged using 18F-FDG PET/CT at 5, 10 and 35 days post-radiation exposure. The gastrointestinal tract and bone marrow were analyzed for 18F-FDG uptake. Tissue was collected at all-time points for histological analysis. Following 7.5 Gy irradiation, there was a significant increase in inflammation in the gastrointestinal tract as indicated by the significantly higher 18F-FDG uptake compared to sham. UHBS animals had a significantly higher activity compared to 7.5 Gy WBI at 5 days post-exposure. Animals that received 4 Gy WBI did not show any significant increase in uptake compared to sham. Analysis of the bone marrow showed a significant decrease of uptake in the 7.5 Gy animals 5 days post-irradiation, albeit not observed in the 4 Gy group. Interestingly, as the metabolic activity of the gastrointestinal tract returned to sham levels in UHBS animals it was accompanied by an increase in metabolic activity in the bone marrow. At 35 days post-exposure both gastrointestinal tract and bone marrow 18F-FDG uptake returned to sham levels. 18F-FDG imaging is a tool that can be used to study the inflammatory response of the gastrointestinal tract and changes in bone marrow metabolism caused by radiation exposure. The recovery of the gastrointestinal tract coincides with an increase in bone marrow metabolism in partially shielded animals. These findings further demonstrate the relationship between the gastrointestinal syndrome and bone marrow recovery, and that this interaction can be studied using non-invasive imaging modalities.

Long-term culture and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized mesenchymal cells.

PubMed

Garba, Abubakar; Acar, Delphine D; Roukaerts, Inge D M; Desmarets, Lowiese M B; Devriendt, Bert; Nauwynck, Hans J

2017-09-01

Mesenchymal cells are multipotent stromal cells with self-renewal, differentiation and immunomodulatory capabilities. We aimed to develop a co-culture model for differentiating hematopoietic cells on top of immortalized mesenchymal cells for studying interactions between hematopoietic and mesenchymal cells, useful for adequately exploring the therapeutic potential of mesenchymal cells. In this study, we investigated the survival, proliferation and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized porcine bone marrow mesenchymal cells for a period of five weeks. Directly after collection, primary porcine bone marrow mesenchymal cells adhered firmly to the bottom of the culture plates and showed a fibroblast-like appearance, one week after isolation. Upon immortalization, porcine bone marrow mesenchymal cells were continuously proliferating. They were positive for simian virus 40 (SV40) large T antigen and the mesenchymal cell markers CD44 and CD55. Isolated red bone marrow cells were added to these immortalized mesenchymal cells. Five weeks post-seeding, 92±6% of the red bone marrow hematopoietic cells were still alive and their number increased 3-fold during five weekly subpassages on top of the immortalized mesenchymal cells. The red bone marrow hematopoietic cells were originally small and round; later, the cells increased in size. Some of them became elongated, while others remained round. Tiny dendrites appeared attaching hematopoietic cells to the underlying immortalized mesenchymal cells. Furthermore, weekly differential-quick staining of the cells indicated the presence of monoblasts, monocytes, macrophages and lymphocytes in the co-cultures. At three weeks of co-culture, flow cytometry analysis showed an increased surface expression of CD172a, CD14, CD163, CD169, CD4 and CD8 up to 37±0.8%, 40±8%, 41±4%, 23±3% and 19±5% of the hematopoietic cells, respectively. In conclusion, continuous mesenchymal cell cultures were successfully established and characterized and they supported the proliferation of red bone marrow hematopoietic cells, which finally differentiated into monocytic cells and CD4 + and CD8 + cells. Copyright © 2017. Published by Elsevier B.V.

An image-based skeletal dosimetry model for the ICRP reference adult female—internal electron sources

NASA Astrophysics Data System (ADS)

O'Reilly, Shannon E.; DeWeese, Lindsay S.; Maynard, Matthew R.; Rajon, Didier A.; Wayson, Michael B.; Marshall, Emily L.; Bolch, Wesley E.

2016-12-01

An image-based skeletal dosimetry model for internal electron sources was created for the ICRP-defined reference adult female. Many previous skeletal dosimetry models, which are still employed in commonly used internal dosimetry software, do not properly account for electron escape from trabecular spongiosa, electron cross-fire from cortical bone, and the impact of marrow cellularity on active marrow self-irradiation. Furthermore, these existing models do not employ the current ICRP definition of a 50 µm bone endosteum (or shallow marrow). Each of these limitations was addressed in the present study. Electron transport was completed to determine specific absorbed fractions to both active and shallow marrow of the skeletal regions of the University of Florida reference adult female. The skeletal macrostructure and microstructure were modeled separately. The bone macrostructure was based on the whole-body hybrid computational phantom of the UF series of reference models, while the bone microstructure was derived from microCT images of skeletal region samples taken from a 45 years-old female cadaver. The active and shallow marrow are typically adopted as surrogate tissue regions for the hematopoietic stem cells and osteoprogenitor cells, respectively. Source tissues included active marrow, inactive marrow, trabecular bone volume, trabecular bone surfaces, cortical bone volume, and cortical bone surfaces. Marrow cellularity was varied from 10 to 100 percent for active marrow self-irradiation. All other sources were run at the defined ICRP Publication 70 cellularity for each bone site. A total of 33 discrete electron energies, ranging from 1 keV to 10 MeV, were either simulated or analytically modeled. The method of combining skeletal macrostructure and microstructure absorbed fractions assessed using MCNPX electron transport was found to yield results similar to those determined with the PIRT model applied to the UF adult male skeletal dosimetry model. Calculated skeletal averaged absorbed fractions for each source-target combination were found to follow similar trends of more recent dosimetry models (image-based models) but did not follow results from skeletal models based upon assumptions of an infinite expanse of trabecular spongiosa.

Restoration of Viral Immunity in Immunodeficient Humans by the Adoptive Transfer of T Cell Clones

NASA Astrophysics Data System (ADS)

Riddell, Stanley R.; Watanabe, Kathe S.; Goodrich, James M.; Li, Cheng R.; Agha, Mounzer E.; Greenberg, Philip D.

1992-07-01

The adoptive transfer of antigen-specific T cells to establish immunity is an effective therapy for viral infections and tumors in animal models. The application of this approach to human disease would require the isolation and in vitro expansion of human antigen-specific T cells and evidence that such T cells persist and function in vivo after transfer. Cytomegalovirus-specific CD8^+ cytotoxic T cell (CTL) clones could be isolated from bone marrow donors, propagated in vitro, and adoptively transferred to immunodeficient bone marrow transplant recipients. No toxicity developed and the clones provided persistent reconstitution of CD8^+ cytomegalovirus-specific CTL responses.

Acute myelogenous leukemia cells with the MLL-ELL translocation convert morphologically and functionally into adherent myofibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tashiro, Haruko; Mizutani-Noguchi, Mitsuho; Shirasaki, Ryosuke

2010-01-01

Bone marrow-myofibroblasts, a major component of bone marrow-stroma, are reported to originate from hematopoietic stem cells. We show in this paper that non-adherent leukemia blasts can change into myofibroblasts. When myeloblasts from two cases of acute myelogenous leukemia with a fusion product comprising mixed lineage leukemia and RNA polymerase II elongation factor, were cultured long term, their morphology changed to that of myofibroblasts with similar molecular characteristics to the parental myeloblasts. The original leukemia blasts, when cultured on the leukemia blast-derived myofibroblasts, grew extensively. Leukemia blasts can create their own microenvironment for proliferation.

Influence of bone marrow on osseointegration in long bones: an experimental study in sheep.

PubMed

Morelli, Fabrizio; Lang, Niklaus P; Bengazi, Franco; Baffone, Davide; Vila Morales, C Dadonim; Botticelli, Daniele

2015-03-01

To evaluate the influence of yellow bone marrow on osseointegration of titanium oral implants using a long bone model. The two tibiae of eight sheep were used as experimental sites. Two osteotomies for implant installation were prepared in each tibia. At the control sites, no further treatments were performed while, at the test sites, bone marrow was removed from the osteotomy site with a curette to an extent that exceeded the implant dimensions. As a result, the apical portion of the implants at the control sites was in contact with bone marrow while, at the test sites, it was in contact with the blood clot. After 2 months, the same procedures were performed in the contralateral side. After another month, the animal was sacrificed. Ground sections were obtained for histological analysis. After 1 month of healing, no differences between test and control sites were found in the apical extension of osseointegration and the percentage of new bone-to-implant contact. However, after 3 months of healing, a higher percentage of new bone-to-implant contact was found at the test compared to the control sites in the marrow compartment. The apical extension of osseointegration, however, was similar to that found at the 1-month healing period both for test and control sites. Osseointegration appeared to be favored by the presence of a blood clot when compared to the presence of yellow fatty bone marrow. Moreover, the contact with cortical bone appeared to be a prerequisite for the osseointegration process in the long bone model. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The mechanical coupling of adult marrow stromal stem cells during cardiac regeneration assessed in a 2-D co-culture model

PubMed Central

Valarmathi, Mani T.; Fuseler, John W.; Goodwin, Richard L.; Davis, Jeffrey M.; Potts, Jay D.

2011-01-01

Postnatal cardiomyocytes undergo terminal differentiation and a restricted number of human cardiomyocytes retain the ability to divide and regenerate in response to ischemic injury. However, whether these neo-cardiomyocytes are derived from endogenous population of resident cardiac stem cells or from the exogenous double assurance population of resident bone marrow-derived stem cells that populate the damaged myocardium is unresolved and under intense investigation. The vital challenge is to ameliorate and/or regenerate the damaged myocardium. This can be achieved by stimulating proliferation of native quiescent cardiomyocytes and/or cardiac stem cell, or by recruiting exogenous autologous or allogeneic cells such as fetal or embryonic cardiomyocyte progenitors or bone marrow-derived stromal stem cells. The prerequisites are that these neo-cardiomyocytes must have the ability to integrate well within the native myocardium and must exhibit functional synchronization. Adult bone marrow stromal cells (BMSCs) have been shown to differentiate into cardiomyocyte-like cells both in vitro and in vivo. As a result, BMSCs may potentially play an essential role in cardiac repair and regeneration, but this concept requires further validation. In this report, we have provided compelling evidence that functioning cardiac tissue can be generated by the interaction of multipotent BMSCs with embryonic cardiac myocytes (ECMs) in two-dimensional (2-D) co-cultures. The differentiating BMSCs were induced to undergo cardiomyogenic differentiation pathway and were able to express unequivocal electromechanical coupling and functional synchronization with ECMs. Our 2-D co-culture system provides a useful in vitro model to elucidate various molecular mechanisms underpinning the integration and orderly maturation and differentiation of BMSCs into neo-cardiomyocytes during myocardial repair and regeneration. PMID:21288568

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

PubMed Central

Corre, Jill; Mahtouk, Karène; Attal, Michel; Gadelorge, Mélanie; Huynh, Anne; Fleury-Cappellesso, Sandrine; Danho, Clotaire; Laharrague, Patrick; Klein, Bernard; Rème, Thierry; Bourin, Philippe

2007-01-01

Recent literature suggested that cell of the microenvironment of solid tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression with Affymetrix arrays and phenotypic and functional study in 3 groups of individuals: patients with MM and those with monoclonal gamopathy of undefined significance (MGUS), and healthy aged-matched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in a MM group. MGUS BMMSCs were interspersed between those 2 groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs 46% were involved in tumor-microenvironment cross-talk. Known soluble factors involved in MM pathophysiologic features, (interleukin (IL)-6, IL-1β, DKK1 and amphiregulin, were revealed and new ones found. In particular, GDF-15 was found to induce dose-dependant growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an over-growth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, BMMSCs from MM patients could create a very efficient niche to support the survival and proliferation of the myeloma stem cells. PMID:17344918

Augmented macrophage differentiation and polarization of tumor-associated macrophages towards M1 subtype in listeria-administered tumor-bearing host.

PubMed

Rai, Rakesh K; Vishvakarma, Naveen K; Mohapatra, Tribhuban M; Singh, Sukh Mahendra

2012-09-01

This study investigates the effect of Listeria administration on differentiation of macrophages from precursor bone marrow cells and functional status of tumor-associated macrophages (TAM). Listeria administration not only resulted in an augmented infiltration of tumor by F4/80 macrophages but also repolarized the functional status of TAM displaying features of some M1 macrophage subtype with upregulated phagocytosis and tumoricidal activity accompanied by altered expression of monocarboxylate transporter-1, toll-like receptor-2, surface markers: CD11c, interleukin-2 receptor, CD62L, and secreted molecules: nitric oxide, interleukin (IL)-1, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor. Declined tumor cell survival and modulated repertoire of cytokines: interferon-γ, IL-6, IL-10, and transforming growth factor-β in tumor microenvironment indicated their role in polarization of TAM towards proinflammatory state. Bone marrow cell of Listeria-administered tumor-bearing mice showed augmented survival, declined expression of p53 upregulated modulator of apoptosis with an upregulated differentiation into activation responsive bone marrow-derived macrophages along with altered expression of macrophage-colony stimulating factor, macrophage-colony stimulating factor receptor, and granulocyte macrophage-colony stimulating factor receptor. These findings indicate that Listeria infection is associated with an augmented differentiation of macrophages accompanied by tumoricidal activation of TAM.

Identification of the active components in Bone Marrow Soup: a mitigator against irradiation-injury to salivary glands.

PubMed

Fang, Dongdong; Hu, Shen; Liu, Younan; Quan, Vu-Hung; Seuntjens, Jan; Tran, Simon D

2015-11-03

In separate studies, an extract of soluble intracellular contents from whole bone marrow cells, named "Bone Marrow (BM) Soup", was reported to either improve cardiac or salivary functions post-myocardial infarction or irradiation (IR), respectively. However, the active components in BM Soup are unknown. To demonstrate that proteins were the active ingredients, we devised a method using proteinase K followed by heating to deactivate proteins and for safe injections into mice. BM Soup and "deactivated BM Soup" were injected into mice that had their salivary glands injured with 15Gy IR. Control mice received either injections of saline or were not IR. Results at week 8 post-IR showed the 'deactivated BM Soup' was no better than injections of saline, while injections of native BM Soup restored saliva flow, protected salivary cells and blood vessels from IR-damage. Protein arrays detected several angiogenesis-related factors (CD26, FGF, HGF, MMP-8, MMP-9, OPN, PF4, SDF-1) and cytokines (IL-1ra, IL-16) in BM Soup. In conclusion, the native proteins (but not the nucleic acids, lipids or carbohydrates) were the therapeutic ingredients in BM Soup for functional salivary restoration following IR. This molecular therapy approach has clinical potential because it is theoretically less tumorigenic and immunogenic than cell therapies.

Mechanism Underlying Linezolid-induced Thrombocytopenia in a Chronic Kidney Failure Mouse Model

PubMed Central

Nishijo, Nao; Tsuji, Yasuhiro; Matsunaga, Kazuhisa; Kutsukake, Masahiko; Okazaki, Fumiyasu; Fukumori, Shiro; Kasai, Hidefumi; Hiraki, Yoichi; Sakamaki, Ippei; Yamamoto, Yoshihiro; Karube, Yoshiharu; To, Hideto

2017-01-01

Objective: To investigate the relationship between renal function and linezolid (LZD)-induced thrombocytopenia and elucidate the underlying mechanism using a chronic renal disease (CRD) mouse model. Materials and Methods: CRD was induced in 5-week-old male Institute of Cancer Research (ICR) mice by 5/6 nephrectomy. After this procedure, LZD (25 and 100 mg/kg) was administered intraperitoneally once every day for 28 days. Platelet counts, white blood cell (WBC) counts, and hematocrit (HCT) levels were measured every 7 days. 2-14C-thymidine (0.185 MBq) was administrated intravenously to LZD-administered mice to evaluate the thymidine uptake ability of bone marrow. Results: Platelet counts were significantly lower in the LZD-administered CRD group than in the LZD-nonadministered groups at 14, 21, and 28 days (P < 0.05); however, these changes were not observed in LZD-administered mice with normal renal function, regardless of the duration of LZD administration. No significant changes were observed in WBC counts or HCT levels in any LZD-administered CRD mouse. Moreover, radioactive levels in bone marrow were not significantly different in each group. Conclusions: These results indicate that LZD-induced decreases in platelet counts were enhanced by renal impairment in vivo, suggesting that LZD-induced thrombocytopenia is not caused by nonimmune-mediated bone marrow suppression. PMID:28405130

Characterization of a 5-fluorouracil-enriched osteoprogenitor population of the murine bone marrow.

PubMed

Falla, N; Van Vlasselaer; Bierkens, J; Borremans, B; Schoeters, G; Van Gorp, U

1993-12-15

In the presence of beta-glycerophosphate and vitamin C, cultures of normal mouse bone marrow cells form three-dimensional structures that stain positive with the Von Kossa technique and express alkaline phosphatase (ALP), collagen type I, and osteocalcin. Little is known about the characteristics and frequency of the cells that contribute to this phenomenon. Most likely, mature osteoblastic cells do not contribute to the nodule formation because no osteocalcin expressing cells are detected in the flushed marrow by in situ hybridization. Limiting dilution analysis shows that, in normal bone marrow, 1 of 2.2 x 10(5) cells has the potency to form a bone nodule and to express ALP, collagen, and osteocalcin in a temporal fashion. Upon in vivo treatment with 5-fluorouracil (5-FU), this frequency increases 12-fold, eg, 1 in 1.75 x 10(4) cells shows osteogenic activity. In comparison, fibroblast colony forming cells occur at a frequency of 1 of 2.5 x 10(4) or 1 of 5 x 10(3) plated cells in normal or 5-FU-treated marrow, respectively. Using density centrifugation, the majority of the osteoprogenitor cells in 5-FU marrow are found in the low-density (1.066 to 1.067 g/mL) fractions. In addition, these cells bind to nylon wool but not to plastic and aggregate in the presence of wheat germ agglutinin and soybean agglutinin. Scanning and transmission electron microscopy shows that the bone nodules in 5-FU marrow cultures are composed of fibroblastoid cells embedded in a mineralized collagen matrix. In conclusion, our results show that a quiescent cell population in the murine bone marrow with fibroblastoid characteristics contributes to the formation of bone-like nodules in vitro.

Directing bone marrow-derived stromal cell function with mechanics.

PubMed

Potier, E; Noailly, J; Ito, K

2010-03-22

Because bone marrow-derived stromal cells (BMSCs) are able to generate many cell types, they are envisioned as source of regenerative cells to repair numerous tissues, including bone, cartilage, and ligaments. Success of BMSC-based therapies, however, relies on a number of methodological improvements, among which better understanding and control of the BMSC differentiation pathways. Since many years, the biochemical environment is known to govern BMSC differentiation, but more recent evidences show that the biomechanical environment is also directing cell functions. Using in vitro systems that aim to reproduce selected components of the in vivo mechanical environment, it was demonstrated that mechanical loadings can affect BMSC proliferation and improve the osteogenic, chondrogenic, or myogenic phenotype of BMSCs. These effects, however, seem to be modulated by parameters other than mechanics, such as substrate nature or soluble biochemical environment. This paper reviews and discusses recent experimental data showing that despite some knowledge limitation, mechanical stimulation already constitutes an additional and efficient tool to drive BMSC differentiation. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Gastric carcinoma metastatic to the bone marrow: immunoperoxidase identification of KMO-1 antigen in MGG-destained aspirate.

PubMed

Kobayashi, T K; Yakushiji, M

1991-01-01

A case is presented that illustrates the application of the immunoperoxidase technique to the May-Grünwald-Giemsa (MGG)-destained bone marrow aspirate. The cytologic findings in a MGG-stained smear of the bone marrow suggested a metastatic epithelial tumor. Subsequently, a positive reaction to KMO-1, a monoclonal antibody raised against a colon carcinoma cell line, was demonstrated in tumor cells in the MGG-destained smear sample as well as in the paraffin-embedded section of the primary gastric cancer. The demonstration of the cancer-associated antigen in the MGG-destained material may be useful in establishing the diagnosis of metastatic tumor in the bone marrow.

Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels.

PubMed

Cooper, Scott T; Sell, Shawn S; Fahrenkrog, Molly; Wilkinson, Kory; Howard, David R; Bergen, Hannah; Cruz, Estefania; Cash, Steve E; Andrews, Matthew T; Hampton, Marshall

2016-07-01

Mammalian hibernators adapt to prolonged periods of immobility, hypometabolism, hypothermia, and oxidative stress, each capable of reducing bone marrow activity. In this study bone marrow transcriptomes were compared among thirteen-lined ground squirrels collected in July, winter torpor, and winter interbout arousal (IBA). The results were consistent with a suppression of acquired immune responses, and a shift to innate immune responses during hibernation through higher complement expression. Consistent with the increase in adipocytes found in bone marrow of hibernators, expression of genes associated with white adipose tissue are higher during hibernation. Genes that should strengthen the bone by increasing extracellular matrix were higher during hibernation, especially the collagen genes. Finally, expression of heat shock proteins were lower, and cold-response genes were higher, during hibernation. No differential expression of hematopoietic genes involved in erythrocyte or megakaryocyte production was observed. This global view of the changes in the bone marrow transcriptome over both short term (torpor vs. IBA) and long term (torpor vs. July) hypothermia can explain several observations made about circulating blood cells and the structure and strength of the bone during hibernation. Copyright © 2016 the American Physiological Society.

Using [{sup 18}F]Fluorothymidine Imaged With Positron Emission Tomography to Quantify and Reduce Hematologic Toxicity Due to Chemoradiation Therapy for Pelvic Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuire, Sarah M., E-mail: sarah-mcguire@uiowa.edu; Bhatia, Sudershan K.; Sun, Wenqing

Purpose: The purpose of the present prospective clinical trial was to determine the efficacy of [{sup 18}F]fluorothymidine (FLT)-identified active bone marrow sparing for pelvic cancer patients by correlating the FLT uptake change during and after chemoradiation therapy with hematologic toxicity. Methods and Materials: Simulation FLT positron emission tomography (PET) images were used to spare pelvic bone marrow using intensity modulated radiation therapy (IMRT BMS) for 32 patients with pelvic cancer. FLT PET scans taken during chemoradiation therapy after 1 and 2 weeks and 30 days and 1 year after completion of chemoradiation therapy were used to evaluate the acute and chronic dose responsemore » of pelvic bone marrow. Complete blood counts were recorded at each imaging point to correlate the FLT uptake change with systemic hematologic toxicity. Results: IMRT BMS plans significantly reduced the dose to the pelvic regions identified with FLT uptake compared with control IMRT plans (P<.001, paired t test). Radiation doses of 4 Gy caused an ∼50% decrease in FLT uptake in the pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT-identified bone marrow exposed to ≥4 Gy after 1 week developed grade 2 leukopenia sooner than subjects with less marrow exposed to ≥4 Gy (P<.05, Cox regression analysis). Apparent bone marrow recovery at 30 days after therapy was not maintained 1 year after chemotherapy. The FLT uptake in the pelvic bone marrow regions that received >35 Gy was 18.8% ± 1.8% greater at 30 days after therapy than at 1 year after therapy. The white blood cell, platelet, lymphocyte, and neutrophil counts at 1 year after therapy were all lower than the pretherapy levels (P<.05, paired t test). Conclusions: IMRT BMS plans reduced the dose to FLT-identified pelvic bone marrow for pelvic cancer patients. However, reducing hematologic toxicity is challenging owing to the acute radiation sensitivity (∼4 Gy) and chronic suppression of activity in bone marrow receiving radiation doses >35 Gy, as measured by the FLT uptake change correlated with the complete blood cell counts.« less

Following damage, the majority of bone marrow-derived airway cells express an epithelial marker.

PubMed

MacPherson, Heather; Keir, Pamela A; Edwards, Carol J; Webb, Sheila; Dorin, Julia R

2006-12-19

Adult-derived bone marrow stem cells are capable of reconstituting the haematopoietic system. However there is ongoing debate in the literature as to whether bone marrow derived cells have the ability to populate other tissues and express tissue specific markers. The airway has been an organ of major interest and was one of the first where this was demonstrated. We have previously demonstrated that the mouse airway can be repopulated by side population bone marrow transplanted cells. Here we investigate the frequency and phenotypic nature of these bone marrow derived cells. Female mice were engrafted with male whole bone marrow or side population (SP) cells and subjected to detergent-induced damage after 3 months. Donor cells were identified by Y chromosome fluorescence in situ hybridisation and their phenotype was assessed by immunohistochemistry on the same sections. Slides were visualised by a combination of widefield and deconvolved microscopy and whole cells were analysed on cytospin preparations. The frequencies of engraftment of male cells in the airway of mice that show this (9/10), range from 1.0-1.6% with whole marrow and 0.6-1.5% with SP cells. Undamaged controls have only between 0.1 and 0.2% male cells in the trachea. By widefield microscopy analysis we find 60.2% (53/88) of male donor derived cells express cytokeratins as a marker of epithelial cells. These results were reinforced using deconvolved microscopy and scored by two independent investigators. In addition cytospin analysis of cells dissociated from the damaged trachea of engrafted mice also reveals donor derived Y chromosome positive cells that are immunopositive for cytokeratin. Using cytokeratin and the universal haematopoietic marker CD45 immunohistochemistry, we find the donor derived cells fall into four phenotypic classes. We do not detect cytokeratin positive cells in whole bone marrow using cytokeratin immunostaining and we do not detect any cytokeratin mRNA in SP or bone marrow samples by RT-PCR. The appearance of bone marrow derived cells in the tracheal epithelium is enriched by detergent-induced tissue damage and the majority of these cells express an epithelial marker. The cytokeratin positive donor derived cells in the tracheal epithelium are not present in the injected donor cells and must have acquired this novel phenotype in vivo.

Following damage, the majority of bone marrow-derived airway cells express an epithelial marker

PubMed Central

MacPherson, Heather; Keir, Pamela A; Edwards, Carol J; Webb, Sheila; Dorin, Julia R

2006-01-01

Background Adult-derived bone marrow stem cells are capable of reconstituting the haematopoietic system. However there is ongoing debate in the literature as to whether bone marrow derived cells have the ability to populate other tissues and express tissue specific markers. The airway has been an organ of major interest and was one of the first where this was demonstrated. We have previously demonstrated that the mouse airway can be repopulated by side population bone marrow transplanted cells. Here we investigate the frequency and phenotypic nature of these bone marrow derived cells. Methods Female mice were engrafted with male whole bone marrow or side population (SP) cells and subjected to detergent-induced damage after 3 months. Donor cells were identified by Y chromosome fluorescence in situ hybridisation and their phenotype was assessed by immunohistochemistry on the same sections. Slides were visualised by a combination of widefield and deconvolved microscopy and whole cells were analysed on cytospin preparations. Results The frequencies of engraftment of male cells in the airway of mice that show this (9/10), range from 1.0 – 1.6% with whole marrow and 0.6 – 1.5% with SP cells. Undamaged controls have only between 0.1 and 0.2% male cells in the trachea. By widefield microscopy analysis we find 60.2% (53/88) of male donor derived cells express cytokeratins as a marker of epithelial cells. These results were reinforced using deconvolved microscopy and scored by two independent investigators. In addition cytospin analysis of cells dissociated from the damaged trachea of engrafted mice also reveals donor derived Y chromosome positive cells that are immunopositive for cytokeratin. Using cytokeratin and the universal haematopoietic marker CD45 immunohistochemistry, we find the donor derived cells fall into four phenotypic classes. We do not detect cytokeratin positive cells in whole bone marrow using cytokeratin immunostaining and we do not detect any cytokeratin mRNA in SP or bone marrow samples by RT-PCR. Conclusion The appearance of bone marrow derived cells in the tracheal epithelium is enriched by detergent-induced tissue damage and the majority of these cells express an epithelial marker. The cytokeratin positive donor derived cells in the tracheal epithelium are not present in the injected donor cells and must have acquired this novel phenotype in vivo. PMID:17177981

Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro.

PubMed

Redondo, Juliana; Sarkar, Pamela; Kemp, Kevin; Virgo, Paul F; Pawade, Joya; Norton, Aimie; Emery, David C; Guttridge, Martin G; Marks, David I; Wilkins, Alastair; Scolding, Neil J; Rice, Claire M

2017-05-01

Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this study was provided by the Medical Research Council, UK (grant no. MR/K004166/1). The ACTiMuS study is sup-ported by the Silverman Family Foundation, Multiple Sclerosis Trust, Rosetree’s Trust, Catholic Bishops of England and Wales and Friends of Frenchay and SIAMMS-II by the Sir Halley Stewart Trust. C.M.R., P.S., and K.K. received support from the Burden Neurological Institute.

77 FR 12316 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-29

..., mobilizes hematopoietic stem/progenitor cells (HSPCs) from the bone marrow into blood. These mobilized HSPCs... bone marrow. miR126 may also facilitate mobilization of bone-resident cancer cells into the circulation where they could be more easily targeted by cancer therapeutics. This discovery could replace bone...

Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.

PubMed

Engel, Barbara C; Podsakoff, Greg M; Ireland, Joanna L; Smogorzewska, E Monika; Carbonaro, Denise A; Wilson, Kathy; Shah, Ami; Kapoor, Neena; Sweeney, Mirna; Borchert, Mark; Crooks, Gay M; Weinberg, Kenneth I; Parkman, Robertson; Rosenblatt, Howard M; Wu, Shi-Qi; Hershfield, Michael S; Candotti, Fabio; Kohn, Donald B

2007-01-15

A patient with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoietic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells.

Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report

PubMed Central

Engel, Barbara C.; Podsakoff, Greg M.; Ireland, Joanna L.; Smogorzewska, E. Monika; Carbonaro, Denise A.; Wilson, Kathy; Shah, Ami; Kapoor, Neena; Sweeney, Mirna; Borchert, Mark; Crooks, Gay M.; Weinberg, Kenneth I.; Parkman, Robertson; Rosenblatt, Howard M.; Wu, Shi-Qi; Hershfield, Michael S.; Candotti, Fabio; Kohn, Donald B.

2007-01-01

A patient with adenosine deaminase–deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoietic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells. PMID:16973956

Dasatinib inhibits both osteoclast activation and prostate cancer PC-3 cell-induced osteoclast formation

PubMed Central

Araujo, John C.; Poblenz, Ann; Corn, Paul G.; Parikh, Nila U.; Starbuck, Michael W.; Thompson, Jerry T.; Lee, Francis; Logothetis, Christopher J.; Darnay, Bryant G.

2013-01-01

Purpose Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. Results Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC50 of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. Experimental design We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. Conclusion Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases. PMID:19855158

Trained nurses can obtain satisfactory bone marrow aspirates and trephine biopsies.

PubMed Central

Lawson, S; Aston, S; Baker, L; Fegan, C D; Milligan, D W

1999-01-01

AIMS: To assess the feasibility of training nurse practitioners to perform bone marrow aspiration and trephine biopsy, and to compare the quality of these samples with those obtained by medical staff. METHODS: A retrospective audit was undertaken of nurse practitioner and medical staff performance in bone marrow procedures in a busy haematology day unit. RESULTS: Nurse practitioners fared favourably in comparison with medical staff in performing bone marrow trephine biopsies, with mean biopsy lengths of 11 mm and 10.7 mm respectively. However, only 78% of the smears obtained by the nurses were judged technically satisfactory, compared with 91% prepared by doctors. This discrepancy was thought to be due largely to the quality of slide spreading. CONCLUSIONS: With motivated staff and a structured educational and training programme it is possible for nurse practitioners to perform the techniques of bone marrow aspiration and biopsy, and obtain specimens of satisfactory quality, thus improving efficiency of the haematology day unit and increasing quality of patient care. Images PMID:10396248

Notch-dependent T-lineage commitment occurs at extrathymic sites following bone marrow transplantation

PubMed Central

Maillard, Ivan; Schwarz, Benjamin A.; Sambandam, Arivazhagan; Fang, Terry; Shestova, Olga; Xu, Lanwei; Bhandoola, Avinash; Pear, Warren S.

2006-01-01

Early T-lineage progenitors (ETPs) arise after colonization of the thymus by multipotent bone marrow progenitors. ETPs likely serve as physiologic progenitors of T-cell development in adult mice, although alternative T-cell differentiation pathways may exist. While we were investigating mechanisms of T-cell reconstitution after bone marrow transplantation (BMT), we found that efficient donor-derived thymopoiesis occurred before the pool of ETPs had been replenished. Simultaneously, T lineage–restricted progenitors were generated at extrathymic sites, both in the spleen and in peripheral lymph nodes, but not in the bone marrow or liver. The generation of these T lineage–committed cells occurred through a Notch-dependent differentiation process. Multipotent bone marrow progenitors efficiently gave rise to extrathymic T lineage–committed cells, whereas common lymphoid progenitors did not. Our data show plasticity of T-lineage commitment sites in the post-BMT environment and indicate that Notch-driven extrathymic Tlineage commitment from multipotent progenitors may contribute to early T-lineage reconstitution after BMT. PMID:16397133

Denosumab is effective in the treatment of bone marrow oedema syndrome.

PubMed

Rolvien, Tim; Schmidt, Tobias; Butscheidt, Sebastian; Amling, Michael; Barvencik, Florian

2017-04-01

Bone marrow oedema (BMO) syndrome describes a painful condition with increase of interstitial fluid within bone and is often lately diagnosed due to unspecific symptoms. The underlying causes are diverse while it is widely assumed that in cases of BMO local bone resorption is increased. Denosumab, a human monoclonal antibody that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL) inhibits osteoclastic bone resorption and is commonly administered in the treatment of osteoporosis. Besides one previous case report, its clinical effectiveness in the treatment of bone marrow oedema has not been elucidated. We treated 14 patients with primary (idiopathic) bone marrow oedema of the lower extremity with single dose denosumab application. Mean time between onset of pain and therapy was 155days. MRI scans were performed for initial diagnosis, and 6-12 weeks after denosumab injection. Vitamin D and calcium homeostasis were strived to be balanced before initiation of therapy. Furthermore bone status was analysed using Dual-energy X-ray absorptiometry (DXA) and extended bone turnover serum markers. After 6-12 weeks, BMO dissolved partly or completely in 93%, while a complete recovery was observed in 50% of the individuals. Visual analogue scale (VAS) evaluation revealed a significant decrease in pain level. Furthermore, bone turnover decreased significantly after treatment. No adverse reactions were reported. In conclusion, our retrospective analysis shows that denosumab is highly effective in the treatment of bone marrow oedema and therefore represents an alternative treatment option. Copyright © 2017 Elsevier Ltd. All rights reserved.

Innate Immunity Dysregulation in Myelodysplastic Syndromes

DTIC Science & Technology

2014-10-01

the CD34+ enriched MDS bone marrow hematopoietic stem/ progenitor cells . We also demonstrated that interference of the TLR2-JMJD3 innate immunity...able to demonstrate that TLR2 innate immune signaling is excessively activated in MDS bone marrow stem/ progenitor cells and that inhibiting this...evidence that the deregulation of innate immune and inflammatory signaling also 13 affects other cells from the immune system and the bone marrow

Effect of Zoledronate on Oral Wound Healing in Rats

PubMed Central

Yamashita, Junro; Koi, Kiyono; Yang, Dong-Ye; McCauley, Laurie K.

2010-01-01

Purpose Osteonecrosis of the jaw (ONJ) is a growing concern in patients who receive bisphosphonates which target osteoclasts. Since osteoclasts play multifunctional roles in the bone marrow, their suppression likely affects bone homeostasis and alters wound healing of the jaw. The objective was to delineate the impact of osteoclast suppression in the bone marrow and wound healing of the jaw. Experimental Design Zoledronate was administered to senile rats for 14 weeks. A portion of the gingiva was removed to denude the palatal bone. Gene expression in the bone marrow was assessed and histologic sections analyzed to determine the wound healing status. Results Angiogenesis-related genes, CD31 and VEGF-A, were not altered by zoledronate. VEGF-C, which plays a role in lymphangiogenesis, was suppressed. There was a decrease in gene expression of Tcirg1 and MMP-13. Bone denudation caused extensive osteocyte death indicative of bone necrosis. In zoledronate-treated rats, the necrotic bone was retained in the wound while, in controls, osteoclastic resorption of the necrotic bone was prominent. Even though large necrotic bone areas existed in zoledronate-treated rats, overlaying soft tissue healed clinically. Immunohistochemical staining showed rich vascularity in the overlaying soft tissue. Conclusions Zoledronate therapy impacts bone marrow by suppressing genes associated with lymphoangiogenesis and tissue remodeling, such as VEGF-C and MMP-13. Zoledronate was associated with impaired osseous wound healing but had no effect on angiogenic markers in the bone marrow or soft tissue wound healing. Zoledronate selectively blunts healing in bone but does not effect soft tissue healing in the oral cavity. PMID:21149614