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Sample records for bone marrow mononuclear

  1. Bone marrow mononuclears from murine tibia after spaceflight on biosatellite

    NASA Astrophysics Data System (ADS)

    Andreeva, Elena; Roe, Maria; Buravkova, Ludmila; Andrianova, Irina; Goncharova, Elena; Gornostaeva, Alexandra

    Elucidation of the space flight effects on the adult stem and progenitor cells is an important goal in space biology and medicine. A unique opportunity for this is provided by project "BION -M1". The purpose of this study was to evaluate the effects of a 30-day flight on biosatellite "BION - M1" and the subsequent 7-day recovery on the quantity, viability, immunophenotype of mononuclears from murine tibia bone marrow. Also the in vitro characterization of functional capacity of multipotent mesenchymal stromal cells (MSCs) was scheduled. Under the project, the S57black/6 mice were divided into groups: spaceflight/vivarium control, recovery after spaceflight/ vivarium control to recovery. Bone marrow mononuclears were isolated from the tibia and immunophenotyped using antibodies against CD45, CD34, CD90 on a flow cytometer Epics XL (Beckman Coulter). A part of the each pool was frozen for subsequent estimation of hematopoietic colony-forming units (CFU), the rest was used for the evaluation of fibroblast CFU (CFUf) number, MSC proliferative activity and osteogenic potency. The cell number in the flight group was significantly lower than in the vivarium control group. There were no differences in this parameter between flight and control groups after 7 days of recovery. The mononuclears viability was more than 95 percent in all examined groups. Flow cytometric analysis showed no differences in the bone marrow cell immunophenotype (CD45, CD34, CD90.1 (Thy1)), but the flight animals had more large-sized CD45+mononuclears, than the control groups of mice. There was no difference in the CFUf number between groups. After 7 days in vitro the MSC number in flight group was twice higher than in vivarium group, after 10 days - 4 times higher. These data may indicate a higher proliferative activity of MSCs after spaceflight. MSCs showed the same and high alkaline phosphatase activity, both in flight and in the control groups, suggesting no effect of spaceflight factors on early

  2. Bone marrow and bone marrow derived mononuclear stem cells therapy for the chronically ischemic myocardium

    SciTech Connect

    Waksman, Ron; Baffour, Richard

    2003-09-01

    Bone marrow stem cells have been shown to differentiate into various phenotypes including cardiomyocytes, vascular endothelial cells and smooth muscle. Bone marrow stem cells are mobilized and home in to areas of injured myocardium where they are involved in tissue repair. In addition, bone marrow secretes multiple growth factors, which are essential for angiogenesis and arteriogenesis. In some patients, these processes are not enough to avert clinical symptoms of ischemic disease. Therefore, in vivo administration of an adequate number of stem cells would be a significant therapeutic advance. Unfractionated bone marrow derived mononuclear stem cells, which contain both hematopoietic and nonhematopoietic cells may be more appropriate for cell therapy. Studies in animal models suggest that implantation of different types of stem cells improve angiogenesis and arteriogenesis, tissue perfusion as well as left ventricular function. Several unanswered questions remain. For example, the optimal delivery approach, dosage and timing of the administration of cell therapy as well as durability of improvements need to be studied. Early clinical studies have demonstrated safety and feasibility of various cell therapies in ischemic disease. Randomized, double blind and placebo-controlled clinical trials need to be completed to determine the effectiveness of stem cell.

  3. Autologous bone marrow mononuclear cells transplant in patients with critical leg ischemia: preliminary clinical results.

    PubMed

    Li, Min; Zhou, Hua; Jin, Xing; Wang, Mo; Zhang, Shiyi; Xu, Lei

    2013-10-01

    Stem cell transplant can induce vasculogenesis and improve the blood supply to an ischemic region, offering hope for chronic lower extremity ischemic diseases. Bone marrow mononuclear cells are one of the sources for stem cell transplants. We sought to observe the safety and efficacy of autologous bone marrow mononuclear cells transplant for treating critical limb ischemia. Eligible patients were randomized 1:1 to receive placebo (0.9% NaCl) or 1 × 107 piece/mL bone marrow mononuclear cell transplant. For 6 months, patients' skin ulcers, ankle-brachial index, and rest pain were examined and recorded before and after treatment. Six months after the bone marrow mononuclear cells transplant, clinical symptoms like rest pain and skin ulcers gradually abated (P < .05). Ankle-brachial index also increased after the transplant (P < .01). Autologous bone marrow mononuclear cells transplant for treatment of patients with chronic limb ischemia is safe, effective, and feasible.

  4. Treatment of Adult Severe Traumatic Brain Injury Using Autologous Bone Marrow Mononuclear Cells

    DTIC Science & Technology

    2014-12-01

    AD_________________ Award Number: W81XWH-11-1-0460 TITLE: TREATMENT OF ADULT SEVERE TRAUMATIC BRAIN INJURY USING AUTOLOGOUS BONE MARROW ...AUTOLOGOUS BONE MARROW MONONUCLEAR CELLS” 5a. CONTRACT NUMBER 5b. GRANT NUMBER: W81XWH-11-1-0460 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Charles S. Cox...Our primary hypothesis is that bone marrow mononuclear cell (BMMNC) autologous transplantation after TBI is safe. Our secondary hypothesis is that

  5. Characterization of bone marrow mononuclear cells on biomaterials for bone tissue engineering in vitro.

    PubMed

    Henrich, Dirk; Verboket, René; Schaible, Alexander; Kontradowitz, Kerstin; Oppermann, Elsie; Brune, Jan C; Nau, Christoph; Meier, Simon; Bonig, Halvard; Marzi, Ingo; Seebach, Caroline

    2015-01-01

    Bone marrow mononuclear cells (BMCs) are suitable for bone tissue engineering. Comparative data regarding the needs of BMC for the adhesion on biomaterials and biocompatibility to various biomaterials are lacking to a large extent. Therefore, we evaluated whether a surface coating would enhance BMC adhesion and analyze the biocompatibility of three different kinds of biomaterials. BMCs were purified from human bone marrow aspirate samples. Beta tricalcium phosphate (β-TCP, without coating or coated with fibronectin or human plasma), demineralized bone matrix (DBM), and bovine cancellous bone (BS) were assessed. Seeding efficacy on β-TCP was 95% regardless of the surface coating. BMC demonstrated a significantly increased initial adhesion on DBM and β-TCP compared to BS. On day 14, metabolic activity was significantly increased in BMC seeded on DBM in comparison to BMC seeded on BS. Likewise increased VEGF-synthesis was observed on day 2 in BMC seeded on DBM when compared to BMC seeded on BS. The seeding efficacy of BMC on uncoated biomaterials is generally high although there are differences between these biomaterials. Beta-TCP and DBM were similar and both superior to BS, suggesting either as suitable materials for spatial restriction of BMC used for regenerative medicine purposes in vivo.

  6. Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children.

    PubMed

    Liao, George P; Harting, Matthew T; Hetz, Robert A; Walker, Peter A; Shah, Shinil K; Corkins, Christopher J; Hughes, Travis G; Jimenez, Fernando; Kosmach, Steven C; Day, Mary-Clare; Tsao, KuoJen; Lee, Dean A; Worth, Laura L; Baumgartner, James E; Cox, Charles S

    2015-03-01

    The devastating effect of traumatic brain injury is exacerbated by an acute secondary neuroinflammatory response, clinically manifest as elevated intracranial pressure due to cerebral edema. The treatment effect of cell-based therapies in the acute post-traumatic brain injury period has not been clinically studied although preclinical data demonstrate that bone marrow-derived mononuclear cell infusion down-regulates the inflammatory response. Our study evaluates whether pediatric traumatic brain injury patients receiving IV autologous bone marrow-derived mononuclear cells within 48 hours of injury experienced a reduction in therapeutic intensity directed toward managing elevated intracranial pressure relative to matched controls. The study was a retrospective cohort design comparing pediatric patients in a phase I clinical trial treated with IV autologous bone marrow-derived mononuclear cells (n = 10) to a control group of age- and severity-matched children (n = 19). The study setting was at Children's Memorial Hermann Hospital, an American College of Surgeons Level 1 Pediatric Trauma Center and teaching hospital for the University of Texas Health Science Center at Houston from 2000 to 2008. Study patients were 5-14 years with postresuscitation Glasgow Coma Scale scores of 5-8. The treatment group received 6 million autologous bone marrow-derived mononuclear cells/kg body weight IV within 48 hours of injury. The control group was treated in an identical fashion, per standard of care, guided by our traumatic brain injury management protocol, derived from American Association of Neurological Surgeons guidelines. The primary measure was the Pediatric Intensity Level of Therapy scale used to quantify treatment of elevated intracranial pressure. Secondary measures included the Pediatric Logistic Organ Dysfunction score and days of intracranial pressure monitoring as a surrogate for length of neurointensive care. A repeated-measure mixed model with marginal linear

  7. Use of autologous bone marrow mononuclear cells and cultured bone marrow stromal cells in dogs with orthopaedic lesions.

    PubMed

    Crovace, A; Favia, A; Lacitignola, L; Di Comite, M S; Staffieri, F; Francioso, E

    2008-09-01

    The aim of the study is to evaluate the clinical application in veterinary orthopedics of bone marrow mononuclear cells (BMMNCs) and cultured bone marrow stromal cells (cBMSCs) for the treatment of some orthopaedic lesions in the dog. The authors carried out a clinical study on 14 dogs of different breed, age and size with the following lesions: 1 bone cyst of the glenoid rime; 2 nonunion of the tibia; 3 nonunion of the femur; 2 lengthening of the radius; 1 large bone defect of the distal radius;1 nonunion with carpus valgus; 4 Legg-Calvé-Perthés disease. In 9 cases the BMMCNs were used in combination with a three dimensional resorbable osteogenic scaffold the chemical composition and size of which facilitates the ingrowth of bone. In these cases the BMMNCs were suspended in an adequate amount of fibrin glue and then distribuited uniformly on a Tricalcium-Phosphate (TCP) scaffold onto which were also added some drops of thrombin. In 1 case of nonunion of the tibia and in 3 cases of Legg-Calvè-Perthés (LCP) disease the cultured BMSCs were used instead because of the small size of the dogs and of the little amount of aspirated bone marrow. X-ray examinations were performed immediately after the surgery. Clinical, ultrasounds and X-ray examinations were performed after 20 days and then every month. Until now the treated dogs have shown very good clinical and X-ray results. One of the objectives of the study was to use the BMMNCs in clinical application in orthopaedic lesions in the dog. The advantages of using the cells immediately after the bone marrow is collected, are that the surgery can be performed the same day, the cells do not need to be expanded in vitro, they preserve their osteogenic potential to form bone and promote the proper integration of the implant with the bone and lastly, the technique is easier and the costs are lower.

  8. Morphological Analysis of Biocompatibility of Autologous Bone Marrow Mononuclear Cells with Synthetic Polyethylene Terephthalate Scaffold.

    PubMed

    Gilevich, I V; Polyakov, I S; Porkhanov, V A; Chekhonin, V P

    2017-07-01

    We studied the properties of a tissue-engineered trachea consisting of a polyethylene terephthalate scaffold populated with autologous bone marrow mononuclear cells. The tissue-engineered constructs were obtained before surgery, during the postoperative period, and during autopsy. Cytomorphological analysis during the postoperative period showed the presence of mesenchymal stem cells on the inner surface of the implant on day 3 after surgery and cells of the respiratory epithelium on day 10-14. In autopsy samples, single epithelial cells, endothelial cells, and basal cells were found. Biocompatibility of the tissue-engineered trachea with autologous mononuclear cells of the patient was demonstrated.

  9. Treatment with at Homeopathic Complex Medication Modulates Mononuclear Bone Marrow Cell Differentiation

    PubMed Central

    Cesar, Beatriz; Abud, Ana Paula R.; de Oliveira, Carolina C.; Cardoso, Francolino; Bernardi, Raffaello Popa Di; Guimarães, Fernando S. F.; Gabardo, Juarez; de Freitas Buchi, Dorly

    2011-01-01

    A homeopathic complex medication (HCM), with immunomodulatory properties, is recommended for patients with depressed immune systems. Previous studies demonstrated that the medication induces an increase in leukocyte number. The bone marrow microenvironment is composed of growth factors, stromal cells, an extracellular matrix and progenitor cells that differentiate into mature blood cells. Mice were our biological model used in this research. We now report in vivo immunophenotyping of total bone marrow cells and ex vivo effects of the medication on mononuclear cell differentiation at different times. Cells were examined by light microscopy and cytokine levels were measured in vitro. After in vivo treatment with HCM, a pool of cells from the new marrow microenvironment was analyzed by flow cytometry to detect any trend in cell alteration. The results showed decreases, mainly, in CD11b and TER-119 markers compared with controls. Mononuclear cells were used to analyze the effects of ex vivo HCM treatment and the number of cells showing ring nuclei, niche cells and activated macrophages increased in culture, even in the absence of macrophage colony-stimulating factor. Cytokines favoring stromal cell survival and differentiation in culture were induced in vitro. Thus, we observe that HCM is immunomodulatory, either alone or in association with other products. PMID:19736221

  10. Cell therapy with bone marrow mononuclear cells in elastase-induced pulmonary emphysema.

    PubMed

    Longhini-Dos-Santos, Nathalia; Barbosa-de-Oliveira, Valter Abraão; Kozma, Rodrigo Heras; Faria, Carolina Arruda de; Stessuk, Talita; Frei, Fernando; Ribeiro-Paes, João Tadeu

    2013-04-01

    Emphysema is characterized by destruction of alveolar walls with loss of gas exchange surface and consequent progressive dyspnea. This study aimed to evaluate the efficiency of cell therapy with bone marrow mononuclear cells (BMMC) in an animal model of elastase-induced pulmonary emphysema. Emphysema was induced in C57Bl/J6 female mice by intranasal instillation of elastase. After 21 days, the mice received bone marrow mononuclear cells from EGFP male mice with C57Bl/J6 background. The groups were assessed by comparison and statistically significant differences (p < 0.05) were observed among the groups treated with BMMC and evaluated after 7, 14 and 21 days. Analysis of the mean linear intercept (Lm) values for the different groups allowed to observe that the group treated with BMMC and evaluated after 21 days showed the most significant result. The group that received no treatment showed a statistically significant difference when compared to other groups, except the group treated and evaluated after 21 days, evidencing the efficacy of cell therapy with BMMC in pulmonary emphysema.

  11. Autologous bone marrow mononuclear cell transplantation in Duchenne muscular dystrophy - a case report.

    PubMed

    Sharma, Alok; Sane, Hemangi; Paranjape, Amruta; Bhagawanani, Khushboo; Gokulchandran, Nandini; Badhe, Prerna

    2014-01-01

    Male, 9 FINAL DIAGNOSIS: Duchenne muscular dystrophy Symptoms: Hyporeflexia • hypotonia • weaknes of lower limbs - Clinical Procedure: - Specialty: Neurology. Congenital defects/diseases. Duchenne muscular dystrophy (DMD) is a fatal, genetic, progressive, degenerating muscle disorder. Current treatment options are palliative. Newer options of cellular therapy promise to alter the disease process. Preclinical studies have successfully tested myogenic, neurogenic potential and dystrophin expression of bone marrow mononuclear cells. We treated a 9-year-old boy suffering from DMD with serial autologous bone marrow mononuclear cell transplantations followed by multidisciplinary rehabilitation. Brooke-Vignos score was 10 and he was wheelchair-bound. Over 36 months, gradual progressive improvement was noticed in muscle strength, ambulation with assistive devices, fine motor movements, Brooke-Vignos score, and functional independence measure score. Nine months after the transplantation, electromyography findings showed development of new normal motor unit potentials of the vastus medialis muscle. Magnetic resonance imaging scan of musculoskeletal systems showed no increase in fatty infiltration. This case report provides early investigative findings or the restorative effects of cellular therapy in DMD.

  12. Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.

    PubMed

    Cox, Charles S; Hetz, Robert A; Liao, George P; Aertker, Benjamin M; Ewing-Cobbs, Linda; Juranek, Jenifer; Savitz, Sean I; Jackson, Margaret L; Romanowska-Pawliczek, Anna M; Triolo, Fabio; Dash, Pramod K; Pedroza, Claudia; Lee, Dean A; Worth, Laura; Aisiku, Imoigele P; Choi, Huimahn A; Holcomb, John B; Kitagawa, Ryan S

    2017-04-01

    Preclinical studies using bone marrow derived cells to treat traumatic brain injury have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe traumatic brain injury demonstrated safety and potentially a central nervous system structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Adults with severe traumatic brain injury (Glasgow Coma Scale 5-8) and without signs of irreversible brain injury were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6, 9, 12 ×10(6) cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest-related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included magnetic resonance imaging-based measurements of supratentorial and corpus callosal volumes as well as diffusion tensor imaging-based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months postinjury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pretreatment, posttreatment, and at 1 and 6 month follow-up. There were no serious adverse events. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest

  13. Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Stem Cells in Subacute Ischemic Stroke Patients.

    PubMed

    Ghali, Azza Abass; Yousef, Mohamed Khalil; Ragab, Osama AbdAllah; ElZamarany, Enas Arafa

    2016-01-01

    Based on many preclinical and small clinical trials, stem cells can help stroke patient with the possibility of replacing the cells and supporting the remaining cells. The aim of this study was to evaluate the safety and feasibility of bone marrow mononuclear (BMMN) stem cell transplantation in subacute ischemic stroke patients. Thirty-nine (n = 39) patients with subacute ischemic cerebral infarct due to large artery occlusion in the middle cerebral artery (MCA) territory were recruited. They were distributed into two groups: first group (n = 21) served as an experimental group, which received intra-arterial (IA) mononuclear stem cells (bone marrow-derived mononuclear cell), while the other group (n = 18) served as a control group. All the patients were evaluated clinically by National Institutes of Health Stroke Scale, modified Rankin Scale, Barthel Index, modified and standardized Arabic version of the Comprehensive Aphasia Test, and radiological for 12 months. The stem cell-treated group showed better improvement, but it was not significant when compared with the non-treated group. The volume of infarction changes at the end of the study was non-significant between both the groups. There was no, or minimal, adverse reactions in stem cell-treated group. The study results suggest that autologous BMMN stem cell IA transplantation in subacute MCA ischemic stroke patients is safe with very minimal hazards, but no significant improvement of motor, language disturbance, or infarction volume was detected in stem cell-treated group compared with the non-treated group.

  14. Supernatant of Bone Marrow Mesenchymal Stromal Cells Induces Peripheral Blood Mononuclear Cells Possessing Mesenchymal Features

    PubMed Central

    Hu, Gang; Xu, Jun-jun; Deng, Zhi-hong; Feng, Jie; Jin, Yan

    2011-01-01

    Increasing evidence shows that some cells from peripheral blood fibroblast-like mononuclear cells have the capacity to differentiate into mesenchymal lineages. However, the insufficiency of these cells in the circulation challenges the cell isolation and subsequently limits the clinical application of these cells. In the present study, the peripheral blood mononuclear cells (pbMNCs) were isolated from wound animals and treated with the supernatant of bone marrow mesenchymal stromal cells (bmMSCs). Results showed these pbMNCs were fibroblast-like, had stromal morphology, were negative for CD34 and CD45, but positive for Vimentin and Collagen I, and had the multipotency to differentiate into adipocytes and osteoblasts. We named these induced peripheral blood-derived mesenchymal stromal cells (ipbMSCs). Skin grafts in combination with ipbMSCs and collagen I were applied for wound healing, and results revealed ipbMSC exhibited similar potency and effectiveness in the promotion of wound healing to the bmMSCs. Hereafter, we speculate that the mixture of growth factors and chemokines secreted by bmMSCs may play an important roles in the induction of the proliferation and mesenchymal differentiation of mononuclear cells. Our results are clinically relevant because it provide a new method for the acquisition of MSCs which can be used as a candidate for the wound repair. PMID:21494428

  15. [Preliminary study on autologous bone marrow mononuclear cells transplantation for lower limb chronic venous ulcer].

    PubMed

    Huang, Wen; Wang, Liwei; Tan, Bin; Zhang, Guozhen; Zhao, Yu; Ren, Guosheng

    2011-05-01

    To investigate the effectiveness of autologous bone marrow mononuclear cells transplantation on lower limb chronic venous ulcer. Between May 2009 and September 2010, 17 patients with lower limb chronic venous ulcer were treated with autologous bone marrow mononuclear cells transplantation (transplantation group) and 10 patients treated without cells transplantation served as control group. In the transplantation group, there were 9 males and 8 females with age of (33.3 +/- 6.1) years, including 11 cases of simple great saphenous vein varicosity and 6 cases of chronic venous insufficiency; the area of ulcer was (4.39 +/- 2.46) cm2; and the duration of ulcer ranged from 3 months to 6 years. In the control group, there were 4 males and 6 females with age of (39.2 +/- 10.3) years, including 7 cases of simple great saphenous vein varicosity and 3 cases of chronic venous insufficiency; and the area of ulcer was (5.51 +/- 2.63) cm2; and the duration of ulcer ranged from 3 months to 2 years. All patients in both groups were classified as C6 according to clinical etiology anatomy pathophysiology (CEAP) classification. No significant difference was found in the general data between 2 groups (P > 0.05). The healing process of ulcer was observed. The granulation tissue was harvested for HE staining before operation and at 3 days after operation in the transplantation group. The microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression of ulcer granulation tissue were observed. In the transplantation group, ulcer healing was accelerated; complete healing was observed in 15 cases, partial healing in 1 case, and no healing in 1 case with the median healing time of 22 days. However, in the control group, the healing process was slower; complete healing of ulcer was observed in 7 cases and no healing in 3 cases with the median healing time of 57.5 days. There was significant difference in the healing time between 2 groups (Z = 0.001 4, P = 0.0027). HE

  16. Nature of mononuclear cells positive for acid phosphatase activity in bone marrow of patients with renal osteodystrophy.

    PubMed Central

    Kaye, M; Henderson, J

    1988-01-01

    Fifty two of 63 patients with renal osteodystrophy had one or more mononuclear cells positive for acid phosphatase in the marrow. These cells are also tartrate resistant and non-specific esterase negative, and are believed to be precursors to osteoclasts and other acid phosphatase positive cells resorbing bone on the trabecular surface. Images Figure PMID:3360955

  17. Outcomes of autologous bone marrow mononuclear cells for cerebral palsy: an open label uncontrolled clinical trial.

    PubMed

    Nguyen, Liem Thanh; Nguyen, Anh Tuan; Vu, Chinh Duy; Ngo, Doan V; Bui, Anh V

    2017-04-12

    Stem cell therapy has emerged as a promising method for improving motor function of patients with cerebral palsy. The aim of this study is to assess the safety and effectiveness of autologous bone marrow mononuclear stem cell transplantation in patients with cerebral palsy related to oxygen deprivation. An open label uncontrolled clinical trial was carried out at Vinmec International Hospital. The intervention consisted of two administrations of stem cells, the first at baseline and the second 3 months later. Improvement was monitored at 3 months and 6 months after the first administration of stem cells, using the Gross Motor Function Measure (GMFM) and Modified Ashworth Score which measures muscle tone. No severe complications were recorded during the study. After transplantation, 12 patients encountered fever without infections and 9 patients experienced vomiting which was easily managed with medications. Gross motor function was markedly improved 3 months or 6 months after stem cell transplantation than at baseline. The post-transplantation GMFM-88 total score, each of its domains and the GMFM-66 percentile were all significantly higher (p-value < 0.001). Muscle spasticity also reduced significantly after transplantation (p-value < 0.001). The therapy was equally effective regardless of sex, age and GMFCS level (p-value > 0.05). Autologous bone marrow mononuclear cell transplantation appears to be a safe and effective therapy for patients with cerebral palsy. ClinicalTrials.gov Identifier: NCT02569775 . Retrospectively registered on October 15, 2015.

  18. Autologous bone marrow mononuclear cells in ischemic cerebrovascular accident paves way for neurorestoration: a case report.

    PubMed

    Sharma, Alok; Sane, Hemangi; Nagrajan, Anjana; Gokulchandran, Nandini; Badhe, Prerna; Paranjape, Amruta; Biju, Hema

    2014-01-01

    In response to acute ischemic stroke, large numbers of bone marrow stem cells mobilize spontaneously in peripheral blood that home onto the site of ischemia activating the penumbra. But with chronicity, the numbers of mobilized cells decrease, reducing the degree and rate of recovery. Cellular therapy has been explored as a new avenue to restore the repair process in the chronic stage. A 67-year-old Indian male with a chronic right middle cerebral artery ischemic stroke had residual left hemiparesis despite standard management. Recovery was slow and partial resulting in dependence to carry out activities of daily living. Our aim was to enhance the speed of recovery process by providing an increased number of stem cells to the site of injury. We administered autologous bone marrow mononuclear cells intrathecally alongwith rehabilitation and regular follow up. The striking fact was that the hand functions, which are the most challenging deficits, showed significant recovery. Functional Independence Measure scores and quality of life improved. This could be attributed to the neural tissue restoration. We hypothesize that cell therapy may be safe, novel and appealing treatment for chronic ischemic stroke. Further controlled trials are indicated to advance the concept of Neurorestoration.

  19. Molecular Imaging of Bone Marrow Mononuclear Cell Survival and Homing in Murine Peripheral Artery Disease

    PubMed Central

    van der Bogt, Koen E.A.; Hellingman, Alwine A.; Lijkwan, Maarten A.; Bos, Ernst-Jan; de Vries, Margreet R.; Fischbein, Michael P.; Quax, Paul H.; Robbins, Robert C.; Hamming, Jaap F.; Wu, Joseph C.

    2013-01-01

    Introduction Bone marrow mononuclear cell (MNC) therapy is a promising treatment for peripheral artery disease (PAD). This study aims to provide insight into cellular kinetics using molecular imaging following different transplantation methods. Methods and Results MNCs were isolated from F6 transgenic mice (FVB background) that express firefly luciferase (Fluc) and green fluorescence protein (GFP). Male FVB and C57Bl6 mice (n=50) underwent femoral artery ligation and were randomized into 4 groups receiving: (1) single intramuscular (i.m.) injection of 2×106 MNC; (2) four weekly i.m. injections of 5×105 MNC; (3) 2×106 MNCs intravenously (i.v.); and (4) PBS. Cellular kinetics, measured by in vivo bioluminescence imaging (BLI), revealed near-complete donor cell death 4 weeks after i.m. transplantation. Following i.v. transplantation, BLI monitored cells homed in on the injured area in the limb, as well as to the liver, spleen, and bone marrow. Ex vivo BLI showed presence of MNCs in the scar tissue and adductor muscle. However, no significant effects on neovascularisation were observed as monitored by Laser-Doppler-Perfusion-Imaging and histology. Conclusion This is one of the first studies to assess kinetics of transplanted MNCs in PAD using in vivo molecular imaging. MNC survival is short lived and MNCs do not significantly stimulate perfusion in this model. PMID:22239892

  20. Periodontal regeneration by autologous bone marrow mononuclear cells embedded in a novel thermo reversible gelation polymer.

    PubMed

    Sankaranarayanan, Seshadri; Jetty, Nadeem; Gadagi, Jayaprakash S; Preethy, Senthilkumar; Abraham, Samuel J K

    2013-01-01

    Regeneration of bony defects caused by periodontal disease continues to be a challenge for clinicians. Application of stem cells from different tissue sources and scaffolds for regeneration have been reported in animal models but clinical studies with long term follow-ups are limited. Herein we report the three years follow-up of the application of autologous bone marrow mononuclear cells (BMMNCs) embedded in a thermo-reversible gelation polymer (TGP) for periodontal regeneration. A 23-year female patient with advanced periodontitis (class IV gingival recession, probing pocket depth (PPD) of 5 mm and 6 mm in relation to mandibular lateral and central incisors respectively, and clinical attachment level (CAL) of 13 mm) correlated with radiographic evidence of severe horizontal bone loss extending up to the apex of mandibular incisors was selected for the treatment. After debridement, the defect was implanted with BMMNCs impregnated in TGP. Then the clinical parameters and radiographic evaluation were made at periodic intervals of 6, 12, 24 and 36 months. At six months, significant improvement with the clinical parameters (PPD had reduced to 2 mm, clinical attachment level had improved by 6 mm) was observed. At 36 months, the radiograph revealed bone regeneration with improvement in vertical and horizontal bone height. Transplantation of BMMNCs in a novel TGP is safe and results in a relatively significant and stable clinical outcome in horizontal alveolar bony defects.

  1. Transient Canonical Wnt Stimulation Enriches Human Bone Marrow Mononuclear Cell Isolates for Osteoprogenitors

    PubMed Central

    Janeczek, Agnieszka A.; Tare, Rahul S.; Scarpa, Edoardo; Moreno‐Jimenez, Ines; Rowland, Caroline A.; Jenner, Dominic; Newman, Tracey A.; Oreffo, Richard O. C.

    2015-01-01

    Abstract Activation of the canonical Wnt signaling pathway is an attractive anabolic therapeutic strategy for bone. Emerging data suggest that activation of the Wnt signaling pathway promotes bone mineral accrual in osteoporotic patients. The effect of Wnt stimulation in fracture healing is less clear as Wnt signaling has both stimulatory and inhibitory effects on osteogenesis. Here, we tested the hypothesis that transient Wnt stimulation promotes the expansion and osteogenesis of a Wnt‐responsive stem cell population present in human bone marrow. Bone marrow mononuclear cells (BMMNCs) were isolated from patients undergoing hip arthroplasty and exposed to Wnt3A protein. The effect of Wnt pathway stimulation was determined by measuring the frequency of stem cells within the BMMNC populations by fluorescence‐activated cell sorting and colony forming unit fibroblast (CFU‐F) assays, before determining their osteogenic capacity in in vitro differentiation experiments. We found that putative skeletal stem cells in BMMNC isolates exhibited elevated Wnt pathway activity compared with the population as whole. Wnt stimulation resulted in an increase in the frequency of skeletal stem cells marked by the STRO‐1bright/Glycophorin A− phenotype. Osteogenesis was elevated in stromal cell populations arising from BMMNCs transiently stimulated by Wnt3A protein, but sustained stimulation inhibited osteogenesis in a concentration‐dependent manner. These results demonstrate that Wnt stimulation could be used as a therapeutic approach by transient targeting of stem cell populations during early fracture healing, but that inappropriate stimulation may prevent osteogenesis. Stem Cells 2016;34:418–430 PMID:26573091

  2. Therapeutic Time Window and Dose Response of Autologous Bone Marrow Mononuclear Cells for Ischemic Stroke

    PubMed Central

    Yang, Bing; Strong, Roger; Sharma, Sushil; Brenneman, Miranda; Mallikarjunarao, Kasam; Xi, XiaoPei; Grotta, James C.; Aronowski, Jaroslaw; Savitz, Sean I.

    2012-01-01

    Although mononuclear cells (MNCs) from bone marrow are being investigated in phase I clinical trials in stroke patients, dose response, therapeutic time window and biodistribiton have not been well-characterized in animal stroke models. Long Evans rats underwent common carotid artery/middle cerebral artery occlusion (CCA/MCAo) and 24 hrs later were randomized to receive saline IV or a bone marrow aspiration followed by an IV infusion of autologous separated MNCs (1 million, 10 million or 30 million cells/kg). In another experiment, rats underwent CCAo/MCAo and were randomized at 24 hrs, 72 hrs or 7 days after stroke to receive a saline injection or 10 million/kg MNCs. All animals were evaluated on the cylinder and corner tests up to 28 days. MNCs were tracked using Q-dot nanocrystals to monitor biodistribution. Animals treated with MNCs at 10 million and 30 million cells/kg at 24 hrs after stroke had significant reductions in neurological deficits and lesion size compared to saline controls or animals treated with 1 million cells/kg. There was no difference in neurological deficits in the 10 and 30 million cell/kg groups at 28 days. Animals treated with MNCs at 72 hrs but not at 7 days showed a significant reduction in neurological deficits by 28 days. Labeled MNCs were found in the brain, spleen, lung, liver, and kidney at 1 hr and exponentially decreased over the ensuing week. In conclusion, we found a maximum reduction in neurological deficits at 10 and 30 million cells/kg and a therapeutic time window up to 72 hrs after stroke. PMID:21412816

  3. Effects of multiple-injection of bone marrow mononuclear cells on spinal cord injury of rats.

    PubMed

    Kanekiyo, Kenji; Nakano, Norihiko; Homma, Tamami; Yamada, Yoshihiro; Tamachi, Masahiro; Suzuki, Yoshihisa; Fukushima, Masanori; Saito, Fukuki; Ide, Chizuka

    2017-03-28

    The effects of multiple-injection of bone marrow mononuclear cells (BMNCs) on spinal cord injury (SCI) were compared with those of single-injection in rats. BMNCs separated by density-gradient centrifugation from a bone marrow perfusate were injected 3 times (once weekly) through the cerebrospinal fluid (CSF) via the 4th ventricle, and the locomotor improvement and tissue recovery, including axonal regeneration, were compared with those of single-injection. While the single-injection group showed a steep elevation of the BBB (Basso-Beattie-Bresnahan) score 1 week after transplantation, the multiple-injection group maintained a similar steep elevation for 2 weeks after transplantation, and the BBB scores of the multiple-injection group remained thereafter at a level around 2-3 points higher than those of the single-injection group until the end of the experiment. There were significant differences between the single- and multiple-injection groups at 3, 4, and 8 weeks after transplantation. The difference of BBB scores at 8 weeks after transplantation suggested that there was a marked difference in the quality of locomotor behaviors between the single-and multiple-injection groups at this stage. An extensive outgrowth of regenerating axons through the astrocyte-devoid areas, and a marked reduction of cavity formation were found in both the single- and multiple-injection groups. There were, however, no significant differences in the density of regenerating axons or volumes of cavities between the single- and multiple-injection groups. These results showed that, although tissue recoveries were similar between single- and multiple-injection, the multiple-injection of BMNCs was more beneficial for locomotor improvement than single-injection for the treatment of SCI. Considering the technically simple and low-cost procedures for the preparation and injection of BMNCs, multiple-injection of BMNCs by lumbar puncture has an advantage over single-injection on clinical

  4. [Bone marrow mononuclear cells from murine tibia after the space flight on biosatellite "Bion-M1"].

    PubMed

    Andreeva, E R; Goncharova, E A; Gornostaeva, A N; Grigor'eva, O V; Buravkova, L B

    2014-01-01

    Cellularity, viability and immunophenotype of mononuclear cells derived from the tibial marrow of C57bL/6 mice were measured after the 30-day "Bion-M1" space flight and subsequent 7-day recovery. Cell number in the flight group was significantly less than in the group of vivarium control. There was no difference in the parameter between the flight and control groups after the recovery. Viability of mononuclear cells was more than 95% in all examined groups. Flow cytometric analysis failed to show differences in bone marrow cell immunophenotype (CD45, CD34, CD90.1 (Thy1); however, the flight animals had more large-sized CD45+ mononuclears than the control groups of mice. These results indicate that spaceflight factors did not have significant damaging effects on the number or immunophenotype of murine bone marrow mononuclears. These observations are consistent with the previously made assumption of a moderate and reversible stress reaction of mammals to space flight.

  5. Bone Marrow Mononuclear Cells Protect Neurons and Modulate Microglia in Cell Culture Models of Ischemic Stroke

    PubMed Central

    Sharma, Sushil; Yang, Bing; Strong, Roger; Xi, Xiao Pei; Brenneman, Miranda; Grotta, James C.; Aronowski, Jaroslaw; Savitz, Sean I.

    2010-01-01

    Background Although several studies have provided evidence for the therapeutic potential of bone marrow-derived mononuclear cells (MNCs) in animal models of stroke, the mechanisms underlying their benefits remain largely unknown. We have determined the neuroprotective potential of MNCs in primary neuronal cultures exposed to various injuries in vitro. Methods Cortical neurons in culture were exposed to oxygen-glucose deprivation, hypoxia, or hydrogen peroxide and cell death was assayed by MTT, caspase-3 activation or TUNEL labelling at 24 hrs. Cultures were randomized to co-treatment with MNC-derived supernatants or media before injury exposure. In separate experiments, macrophage or microglial cultures were exposed to lipopolypolysacharide (LPS) in the presence and absence of MNC-derived supernatants. Neuronal cultures were then exposed to conditioned media derived from activated macrophages or microglia. Cytokines from the supernantants of MNC cultures exposed to normoxia or hypoxia were also estimated by enzyme-linked immunosorbant assay (ELISA). Results MNC-derived supernatants attenuated neuronal death induced by OGD, hypoxia, hydrogen peroxide, and conditioned macrophage/microglial media and contain a number of trophic factors including IL-10, IGF-1, VEGF, and SDF-1. Conclusion MNCs provide broad neuroprotection against a variety of injuries relevant to stroke. PMID:20629187

  6. A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier.

    PubMed

    Sharma, Alok; Sane, Hemangi; Gokulchandran, Nandini; Kulkarni, Pooja; Gandhi, Sushant; Sundaram, Jyothi; Paranjape, Amruta; Shetty, Akshata; Bhagwanani, Khushboo; Biju, Hema; Badhe, Prerna

    2015-01-01

    Cerebral palsy is a nonprogressive heterogeneous group of neurological disorders with a growing rate of prevalence. Recently, cellular therapy is emerging as a potential novel treatment strategy for cerebral palsy. The various mechanisms by which cellular therapy works include neuroprotection, immunomodulation, neurorestoration, and neurogenesis. We conducted an open label, nonrandomized study on 40 cases of cerebral palsy with an aim of evaluating the benefit of cellular therapy in combination with rehabilitation. These cases were administered autologous bone marrow mononuclear cells intrathecally. The follow-up was carried out at 1 week, 3 months, and 6 months after the intervention. Adverse events of the treatment were also monitored in this duration. Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. The results of this study demonstrate that cellular therapy may accelerate the development, reduce disability, and improve the quality of life of patients with cerebral palsy.

  7. Improved Quality of Life in A Case of Cerebral Palsy after Bone Marrow Mononuclear Cell Transplantation.

    PubMed

    Sharma, Alok; Sane, Hemangi; Kulkarni, Pooja; D'sa, Myola; Gokulchandran, Nandini; Badhe, Prerna

    2015-01-01

    Cerebral palsy (CP) is a non progressive, demyelinating disorder that affects a child's development and posture and may be associated with sensation, cognition, communication and perception abnormalities. In CP, cerebral white matter is injured resulting in the loss of oligodendrocytes. This causes damage to the myelin and disruption of nerve conduction. Cell therapy is being explored as an alternate therapeutic strategy as there is no treatment currently available for CP. To study the benefits of this treatment we have administered autologous bone marrow mononuclear cells (BMMNCs) to a 12-year-old CP case. He was clinically re-evaluated after six months and found to demonstrate positive clinical and functional outcomes. His trunk strength, upper limb control, hand functions, walking stability, balance, posture and coordination improved. His ability to perform activities of daily living improved. On repeating the Functional Independence Measure (FIM), the score increased from 90 to 113. A repeat positron emission tomography-computed tomography (PET-CT) scan of the brain six months after intervention showed progression of the mean standard deviation values towards normalization which correlated to the functional changes. At one year, all clinical improvements have remained. This indicated that cell transplantation may improve quality of life and have a potential for treatment of CP.

  8. Paracrine Effects of Bone Marrow Mononuclear Cells in Survival and Cytokine Expression after 90% Partial Hepatectomy

    PubMed Central

    Kieling, Carlos Oscar; Uribe-Cruz, Carolina; López, Mónica Luján; Osvaldt, Alessandro Bersch; da Silveira, Themis Reverbel

    2017-01-01

    Acute liver failure is a complex and fatal disease. Cell-based therapies are a promising alternative therapeutic approach for liver failure due to relatively simple technique and lower cost. The use of semipermeable microcapsules has become an interesting tool for evaluating paracrine effects in vivo. In this study, we aimed to assess the paracrine effects of bone marrow mononuclear cells (BMMC) encapsulated in sodium alginate to treat acute liver failure in an animal model of 90% partial hepatectomy (90% PH). Encapsulated BMMC were able to increase 10-day survival without enhancing liver regeneration markers. Gene expression of Il-6 and Il-10 in the remnant liver was markedly reduced at 6 h after 90% PH in animals receiving encapsulated BMMC compared to controls. This difference, however, was neither reflected by changes in the number of CD68+ cells nor by serum levels of IL6. On the other hand, treated animals presented increased caspase activity and gene expression in the liver. Taken together, these results suggest that BMMC regulate immune response and promote apoptosis in the liver after 90% PH by paracrine factors. These changes ultimately may be related to the higher survival observed in treated animals, suggesting that BMMC may be a promising alternative to treat acute liver failure. PMID:28326105

  9. Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study.

    PubMed

    Sharma, Alok; Gokulchandran, Nandini; Sane, Hemangi; Nagrajan, Anjana; Paranjape, Amruta; Kulkarni, Pooja; Shetty, Akshata; Mishra, Priti; Kali, Mrudula; Biju, Hema; Badhe, Prerna

    2013-01-01

    Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs) intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7). Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT) scan recorded objective changes. Out of 32 patients, a total of 29 (91%) patients improved on total ISAA scores and 20 patients (62%) showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P < 0.001) on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism.

  10. Repair of critical-size bone defects using bone marrow stromal cells: a histomorphometric study in rabbit calvaria. Part I: use of fresh bone marrow or bone marrow mononuclear fraction.

    PubMed

    Pelegrine, André Antonio; Aloise, Antonio Carlos; Zimmermann, Allan; de Mello E Oliveira, Rafael; Ferreira, Lydia Masako

    2014-05-01

    The aim of this study was to compare the bone healing observed after the use of (1) a scaffold enriched with fresh bone marrow, (2) a scaffold enriched with bone marrow mononuclear fraction, and (3) a scaffold alone. Twenty one rabbits were randomly divided into three groups of six animals and 1 group of 3 animals. Bilateral 12-mm diameter defects were created in the animals' parietal bones. In Control Group, the defects were filled with a xenograft alone (n = 6); in Group 1, with a xenograft enriched with fresh bone marrow (n = 6); in Group 2, with a xenograft enriched with bone marrow mononuclear fraction (n = 6) and in Unfilled Group, nothing was grafted (n = 3). In Groups 1, 2, and Control, one of the calvarial defects was randomly covered with a barrier membrane. The rabbits were sacrificed 8 weeks after surgery, and their parietal bones were harvested and analyzed histomorphometrically. The histomorphometric analysis showed no difference between Group 1 and the Control Group regarding non-vital mineralized tissue area, but Group 2 showed a statistically significant higher percentage than the Control Group (P < 0.05) for both situations, with membrane (21.24 ± 3.78% and 13.52 ± 3.00%, respectively) and without membrane (20.91 ± 2.01% and 13.08 ± 1.72%, respectively). Group 2 showed the highest percentage of vital mineralized tissue area, followed by Group 1 and the Control Group (P < 0.05) for both situations, with membrane (28.17 ± 3.19%; 21.14 ± 7.38% and 13.06 ± 5.24%, respectively) and without membrane (21.13 ± 0.55%; 12.45 ± 6.34% and 6.56 ± 1.20%, respectively). Group 2 showed the lowest percentage of non-mineralized tissue area, followed by Group 1 and Control Group (P < 0.05) for both situations, with membrane (50.59 ± 6.64%; 58.75 ± 7.14% and 73.41 ± 6.87%, respectively) and without membrane (57.97 ± 1.91%; 71.74 ± 6.63% and 80.37 ± 2.67%, respectively). The sides in which the defects were covered with the barrier membrane showed

  11. 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

  12. Paracrine Mechanisms of Intravenous Bone Marrow-Derived Mononuclear Stem Cells in Chronic Ischemic Stroke.

    PubMed

    Bhasin, Ashu; Srivastava, M V Padma; Mohanty, Sujata; Vivekanandhan, Sivasubramaniam; Sharma, Sakshi; Kumaran, Senthil; Bhatia, Rohit

    2016-01-01

    The emerging role of stem cell technology and transplantation has helped scientists to study their potential role in neural repair and regeneration. The fate of stem cells is determined by their niche, consisting of surrounding cells and the secreted trophic growth factors. This interim report evaluates the safety, feasibility and efficacy (if any) of bone marrow-derived mononuclear stem cells (BM-MNC) in chronic ischemic stroke by studying the release of serum vascular endothelial growth factor (VEGF) and brain-derived neurotrophic growth factor (BDNF). Twenty stroke patients and 20 age-matched healthy controls were recruited with the following inclusion criteria: 3 months to 1.5 years from the index event, Medical Research Council (MRC) grade of hand muscles of at least 2, Brunnstrom stage 2-5, conscious, and comprehendible. They were randomized to one group receiving autologous BM-MNC (mean 60-70 million) and to another group receiving saline infusion (placebo). All patients were administered a neuromotor rehabilitation regime for 8 weeks. Clinical assessments [Fugl Meyer scale (FM), modified Barthel index (mBI), MRC grade, Ashworth tone scale] were carried out and serum VEGF and BDNF levels were assessed at baseline and at 8 weeks. No serious adverse events were observed during the study. There was no statistically significant clinical improvement between the groups (FM: 95% CI 15.2-5.35, p = 0.25; mBI: 95% CI 14.3-4.5, p = 0.31). VEGF and BDNF expression was found to be greater in group 1 compared to group 2 (VEGF: 442.1 vs. 400.3 pg/ml, p = 0.67; BDNF: 21.3 vs. 19.5 ng/ml) without any statistically significant difference. Autologous mononuclear stem cell infusion is safe and tolerable by chronic ischemic stroke patients. The released growth factors (VEGF and BDNF) in the microenvironment could be due to the paracrine hypothesis of stem cell niche and neurorehabilitation regime. © 2016 The Author(s) Published by S. Karger AG, Basel.

  13. Paracrine Mechanisms of Intravenous Bone Marrow-Derived Mononuclear Stem Cells in Chronic Ischemic Stroke

    PubMed Central

    Bhasin, Ashu; Srivastava, M.V. Padma; Mohanty, Sujata; Vivekanandhan, Sivasubramaniam; Sharma, Sakshi; Kumaran, Senthil; Bhatia, Rohit

    2016-01-01

    Background The emerging role of stem cell technology and transplantation has helped scientists to study their potential role in neural repair and regeneration. The fate of stem cells is determined by their niche, consisting of surrounding cells and the secreted trophic growth factors. This interim report evaluates the safety, feasibility and efficacy (if any) of bone marrow-derived mononuclear stem cells (BM-MNC) in chronic ischemic stroke by studying the release of serum vascular endothelial growth factor (VEGF) and brain-derived neurotrophic growth factor (BDNF). Methods Twenty stroke patients and 20 age-matched healthy controls were recruited with the following inclusion criteria: 3 months to 1.5 years from the index event, Medical Research Council (MRC) grade of hand muscles of at least 2, Brunnstrom stage 2-5, conscious, and comprehendible. They were randomized to one group receiving autologous BM-MNC (mean 60-70 million) and to another group receiving saline infusion (placebo). All patients were administered a neuromotor rehabilitation regime for 8 weeks. Clinical assessments [Fugl Meyer scale (FM), modified Barthel index (mBI), MRC grade, Ashworth tone scale] were carried out and serum VEGF and BDNF levels were assessed at baseline and at 8 weeks. Results No serious adverse events were observed during the study. There was no statistically significant clinical improvement between the groups (FM: 95% CI 15.2-5.35, p = 0.25; mBI: 95% CI 14.3-4.5, p = 0.31). VEGF and BDNF expression was found to be greater in group 1 compared to group 2 (VEGF: 442.1 vs. 400.3 pg/ml, p = 0.67; BDNF: 21.3 vs. 19.5 ng/ml) without any statistically significant difference. Conclusion Autologous mononuclear stem cell infusion is safe and tolerable by chronic ischemic stroke patients. The released growth factors (VEGF and BDNF) in the microenvironment could be due to the paracrine hypothesis of stem cell niche and neurorehabilitation regime. PMID:27846623

  14. Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms.

    PubMed

    Otsuru, Satoru; Gordon, Patricia L; Shimono, Kengo; Jethva, Reena; Marino, Roberta; Phillips, Charlotte L; Hofmann, Ted J; Veronesi, Elena; Dominici, Massimo; Iwamoto, Masahiro; Horwitz, Edwin M

    2012-08-30

    Transplantation of whole bone marrow (BMT) as well as ex vivo-expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non-(plastic)-adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell-depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018.

  15. Bone marrow mononuclear cell therapy in ischaemic stroke: a systematic review.

    PubMed

    Kumar, A; Prasad, M; Jali, V P; Pandit, A K; Misra, S; Kumar, P; Chakravarty, K; Kathuria, P; Gulati, A

    2017-05-01

    Bone marrow mononuclear cell (BM-MNC) therapy has emerged as a potential therapy for the treatment of stroke. We performed a systematic review of published studies using BM-MNC therapy in patients with ischaemic stroke (IS). Literature was searched using MEDLINE, PubMed, EMBASE, Trip Database, Cochrane library and clinicaltrial.gov to identify studies on BM-MNC therapy in IS till June, 2016. Data were extracted independently by two reviewers. STATA version 13 was used for carrying out meta-analysis. We included non-randomized open-label, single-arm and non-randomized comparative studies or randomized controlled trials (RCTs) if BM-MNCs were used to treat patients with IS in any phase after the index stroke. One randomized trial, two non-randomized comparative trials and four single-arm open-label trials (total seven studies) involving 227 subjects (137 patients and 90 controls) were included in the systematic review and meta-analysis. The pooled proportion for favourable clinical outcome (modified Rankin Scale score ≤2) in six studies involving 122 subjects was 29% (95% CI 0.16-0.43) who were exposed to BM-MNCs and pooled proportion for favourable clinical outcome of 69 subjects (taken from two trials) who did not receive BM-MNCs was 20% (95% CI 0.12-0.32). The pooled difference in the safety outcomes was not significant between both the groups. Our systematic review suggests that BM-MNC therapy is safe up to 1 year post-intervention and is feasible; however, its efficacy in the case of IS patients is debatable. Well-designed randomized controlled trials are required to provide more information on the efficacy of BM-MNC transplantation in patients with IS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Bone marrow mononuclear cells and mannose receptor expression in focal cortical ischemia.

    PubMed

    Giraldi-Guimarães, Arthur; de Freitas, Helder Teixeira; Coelho, Bárbara de Paula; Macedo-Ramos, Hugo; Mendez-Otero, Rosalia; Cavalcante, Leny A; Baetas-da-Cruz, Wagner

    2012-05-03

    The use of bone marrow mononuclear cells (BMMCs) has been shown as a putative efficient therapy for stroke. However, the mechanisms of therapeutic action are not yet completely known. Mannose receptor (MR) is a subgroup of the C-type lectin receptor superfamily involved in innate immune response in several tissues. Although known primarily for its immune function, MR also has important roles in cell migration, cell debris clearance and tissue remodeling during inflammation and wound healing. Here we analyzed MR expression in brains of rats one week after induction of unilateral focal cortical ischemia by thermocoagulation in blood vessels of sensorimotor cortex. Additionally, we evaluated possible changes in such expression in cortices of rats subjected to ischemia plus treatment with BMMCs. Our results showed high expression of MR in an unknown GFAP(+) cell type and in phagocytic macrophages/microglia within the lesion boundary zone whereas in the non-injured (contralateral) cortical parenchyma, low levels of MR expression were observed. Moreover, therapy with BMMCs induced overexpression of MR in ipsilateral (injured) cortex. Previous studies from our group have shown functional recovery and decreased neurodegeneration in BMMC-treated rats in the same model of focal cortical ischemia. Thus, we suggest that ischemic injury induces large increase in MR expression as part of a mechanism for clearance of damage-associated molecular patterns (DAMPs). In addition, induction of MR overexpression by BMMCs might increase the efficiency of clearance, being one of the protective mechanisms of these cells. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Bone Marrow Mononuclear Cell Transplantation Restores Inflammatory Balance of Cytokines after ST Segment Elevation Myocardial Infarction

    PubMed Central

    Alestalo, Kirsi; Miettinen, Johanna A.; Vuolteenaho, Olli; Huikuri, Heikki; Lehenkari, Petri

    2015-01-01

    Background Acute myocardial infarction (AMI) launches an inflammatory response and a repair process to compensate cardiac function. During this process, the balance between proinflammatory and anti-inflammatory cytokines is important for optimal cardiac repair. Stem cell transplantation after AMI improves tissue repair and increases the ventricular ejection fraction. Here, we studied in detail the acute effect of bone marrow mononuclear cell (BMMNC) transplantation on proinflammatory and anti-inflammatory cytokines in patients with ST segment elevation myocardial infarction (STEMI). Methods Patients with STEMI treated with thrombolysis followed by percutaneous coronary intervention (PCI) were randomly assigned to receive either BMMNC or saline as an intracoronary injection. Cardiac function was evaluated by left ventricle angiogram during the PCI and again after 6 months. The concentrations of 27 cytokines were measured from plasma samples up to 4 days after the PCI and the intracoronary injection. Results Twenty-six patients (control group, n = 12; BMMNC group, n = 14) from the previously reported FINCELL study (n = 80) were included to this study. At day 2, the change in the proinflammatory cytokines correlated with the change in the anti-inflammatory cytokines in both groups (Kendall’s tau, control 0.6; BMMNC 0.7). At day 4, the correlation had completely disappeared in the control group but was preserved in the BMMNC group (Kendall’s tau, control 0.3; BMMNC 0.7). Conclusions BMMNC transplantation is associated with preserved balance between pro- and anti-inflammatory cytokines after STEMI in PCI-treated patients. This may partly explain the favorable effect of stem cell transplantation after AMI. PMID:26690350

  18. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial.

    PubMed

    Prasad, Kameshwar; Sharma, Alka; Garg, Ajay; Mohanty, Sujata; Bhatnagar, Shinjini; Johri, Sharat; Singh, Kunwar Karni; Nair, Velu; Sarkar, Ravi Shankar; Gorthi, Sankar Prasad; Hassan, Kaukab Maqbool; Prabhakar, Sudesh; Marwaha, Neelam; Khandelwal, Niranjan; Misra, Usha Kant; Kalita, Jayantee; Nityanand, Soniya

    2014-12-01

    Pilot studies have suggested benefit from intravenous administration of bone marrow mononuclear stem cells (BMSCs) in stroke. We explored the efficacy and safety of autologous BMSCs in subacute ischemic stroke. This was a phase II, multicenter, parallel group, randomized trial with blinded outcome assessment that included 120 patients. Patients with subacute ischemic stroke were randomly assigned to the arm that received intravenous infusion of autologous BMSCs or to control arm. Coprimary clinical efficacy outcomes were Barthel Index score and modified Rankin scale at day 180. Secondary outcomes were change in infarct volume, National Institute of Health Stroke Scale (NIHSS) at day 90 and 180. Main safety outcomes were adverse events, any new area of (18)fluorodeoxyglucose positron emission tomography uptake in any body part over 365 days. Fifty-eight patients received a mean of 280.75 million BMSCs at median of 18.5 days after stroke onset. There was no significant difference between BMSCs arm and control arm in the Barthel Index score (63.1 versus 63.6; P=0.92), modified Rankin scale shift analysis (P=0.53) or score >3 (47.5% versus 49.2%; P=0.85), NIHSS score (6.3 versus 7.0; P=0.53), change in infarct volume (-11.1 versus -7.36; P=0.63) at day 180. Adverse events were also similar in the 2 arms, and no patient showed any new area of (18)fluorodeoxyglucose uptake. With the methods used, results of this hitherto first randomized controlled trial indicate that intravenous infusion of BMSCs is safe, but there is no beneficial effect of treatment on stroke outcome. URLs: http://ctri.nic.in/Clinicaltrials and http://www.clinicaltrials.gov. Unique identifiers: CTRI-ROVCTRI/2008/091/0004 and NCT0150177. © 2014 American Heart Association, Inc.

  19. Mesenchymal stromal cells derived from CD271(+) bone marrow mononuclear cells exert potent allosuppressive properties.

    PubMed

    Kuçi, Zyrafete; Kuçi, Selim; Zircher, Susanne; Koller, Stefanie; Schubert, Ralf; Bönig, Halvard; Henschler, Reinhard; Lieberz, Ralf; Klingebiel, Thomas; Bader, Peter

    2011-11-01

    BACKGROUND AIMS. Because data on the immunosuppressive effect of different subsets of mesenchymal stromal cells (MSC) are sparse, we investigated the molecular and cellular mechanisms underlying the allosuppressive effect of MSC generated from bone marrow CD271(+) cells (CD271-MSC) and asked whether this potential is comparable with that of MSC generated through plastic adherence (PA-MSC). METHODS. The immunosuppressive effect of CD271-MSC on the allogeneic reaction was investigated by mixed lymphocyte reaction (MLR). RESULTS. CD271-MSC significantly suppressed the alloantigen-induced proliferation of mononuclear cells (MNC) of two HLA-disparate donors at all MSC:MNC ratios, 1:1, 1:2 and 1:10. They also demonstrated a significantly higher allosuppression than PA-MSC at an MSC:MNC ratio of 1:1. This inhibitory effect was associated with significantly elevated levels of prostaglandin E2 (PGE2) at ratios of 1:1 and 1:2 (about 4-fold), but not at a ratio of 1:10. Indomethacin, and inhibitor of cyclooxygenase-1 and 2 necessary for the biosynthesis of PGE2, mitigated suppressive effects of CD271-MSC only at a ratio of 1:1, indicating that PGE2 is not involved in MSC-mediated inhibition when allogeneic MNC are in excess. The increase of PGE2 was associated with a significant decrease of pro-inflammatory cytokine levels (interferon-gamma and tumor necrosis-alpha), while no changes in levels of interleukin-10, soluble HLA-G and nitric oxide were observed. In addition, CD271-MSC induced an expansion of highly suppressive naive CD4(+)CD25(high)CD45RA(+)CD62L(+) T-regulatory cells, which may extend their allosuppressive effect. CONCLUSIONS. Our data suggest that CD271-MSC exert potent allosuppressive properties and therefore can be used as a reasonable alternative to PA-MSC for the treatment of patients with graft-versus-host disease.

  20. [Tissue-engineered graft constructed by bone marrow mononuclear cells and heterogeneous acellularized tissue matrix: an animal experiment].

    PubMed

    Huang, Hui-min; Ma, Liang-long; Ren, Hong; Wu, Shao-feng; Jiang, Zu-ming

    2007-12-25

    To construct a tissue-engineered graft by using bone marrow cells as seeding cells and heterogeneous acellularized matrix as scaffold. Mononuclear cells were isolated from the bone marrow from piglets and cultured in different mediums including either vessel endothelial growth factor (VEGF) or platelet derived growth factor BB (PDGF-BB) to observe the differentiation of cells. Immunoassay was used to detect the expression of specific markers of endothelial cells or specific markers of smooth muscle cells. Adult dogs were killed and their thoracic or abdominal aortas were taken out and processed by multi-step decellularizing technique to remove the original cells while the elastic and collagen fibers were preserved. The undifferentiated bone marrow mononuclear cells were seeded onto the acellularized matrix and incubated in vitro. The cell-seeded grafts were then transplanted to the bone marrow donating piglets to substitute part of the native pulmonary artery. Three weeks later right ventriculography was performed. 100 days later the piglets were sacrificed. The transplanted vessels and the nearby tissues of native pulmonary vessels were excised for inspection. The mononuclear cells cultured in the medium including VEGF showed the morphological features of endothelial cells and were positive of the specific markers of endothelial cells: platelet-endothelial cell adhesion molecule-l, vascular endothelial growth factor receptor Flk-1, VE-cadherin, and plasma factor VIII. The cells cultured in the medium including PDGF-BB showed morphological feature of smooth muscle cells and were positive of he specific marks of smooth muscle cells: alpha-SMA and calponin. One hundred days after transplantation, the inner surfaces of the grafts were smooth without thrombosis, calcification, and aneurysm. The maximal load was 2.76 N and the maximal elongation was 20.31 mm. Under the microscopy a great number of growing endothelial cells and smooth muscle cells could be seen and

  1. Autologous Bone Marrow Mononuclear Cells Reduce Therapeutic Intensity for Severe Traumatic Brain Injury in Children

    PubMed Central

    Liao, George P.; Harting, Matthew T.; Hetz, Robert A.; Walker, Peter A.; DO, Shinil K. Shah; Corkins, Christopher J.; Hughes, Travis G.; Jimenez, Fernando; Kosmach, Steven C.; Day, Mary-Clare; Tsao, KuoJen; Lee, Dean A.; Worth, Laura L.; Baumgartner, James E.; Cox, Charles S.

    2014-01-01

    Objective The devastating effect of traumatic brain injury (TBI) is exacerbated by an acute secondary neuroinflammatory response, clinically manifest as elevated intracranial pressure (ICP) due to cerebral edema. The treatment effect of cell based therapies in the acute post-TBI period has not been clinically studied although preclinical data demonstrate that bone marrow derived mononuclear cell (BMMNC) infusion downregulates the inflammatory response. Our study evaluates whether pediatric TBI patients receiving intravenous, autologous BMMNCs within 48 hours of injury experienced a reduction in therapeutic intensity directed towards managing elevated ICP relative to matched controls. Design The study was a retrospective cohort design comparing pediatric patients in a Phase I clinical trial treated with intravenous autologous BMMNCs (n=10) to a control group of age and severity matched children (n=19). Setting The study setting was at Children's Memorial Hermann Hospital, an American College of Surgeons Level 1 Pediatric Trauma Center and teaching hospital for the University of Texas Health Science Center at Houston from 2000-2008. Patients Study patients were 5-14 years with post resuscitation Glasgow Coma Scale scores of 5-8. Interventions The treatment group received 6 million autologous BMMNC/kg body weight intravenously within 48 hours of injury. The control group was treated in an identical fashion, per standard of care, guided by our TBI management protocol, derived from American Association of Neurological Surgeons guidelines. Measurements The primary measure was the Pediatric Intensity Level of Therapy (PILOT) scale, used to quantify treatment of elevated ICP. Secondary measures included the Pediatric Logistic Organ Dysfunction (PELOD) score and days of ICP monitoring as a surrogate for length of neurointensive care. Main Results A repeated measure mixed model with marginal linear predictions identified a significant reduction in the PILOT score beginning

  2. Concise review: bone marrow mononuclear cells for the treatment of ischemic syndromes: medicinal product or cell transplantation?

    PubMed

    Cuende, Natividad; Rico, Laura; Herrera, Concha

    2012-05-01

    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.

  3. 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

  4. Long term outcome after mononuclear bone marrow or peripheral blood cells infusion after myocardial infarction.

    PubMed

    Delewi, Ronak; van der Laan, Anja M; Robbers, Lourens F H J; Hirsch, Alexander; Nijveldt, Robin; van der Vleuten, Pieter A; Tijssen, Jan G P; Tio, René A; Waltenberger, Johannes; Ten Berg, Jurrien M; Doevendans, Pieter A; Gehlmann, Helmut R; van Rossum, Albert C; Piek, Jan J; Zijlstra, Felix

    2015-03-01

    This study reports the long-term follow-up of the randomised controlled HEBE trial. The HEBE study is a multicentre trial that randomised 200 patients with large first acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention to either intracoronary infusion of bone marrow mononuclear cells (BMMCs) (n=69), peripheral blood mononuclear cells (PBMCs) (n=66) or standard therapy (n=65). In addition to 3-5 days, and 4 months after AMI, all patients underwent cardiac MRI after 2 years. A follow-up for 5 years after AMI was performed to assess clinical adverse events, including death, myocardial reinfarction and hospitalisation for heart failure. Of the 200 patients enrolled, 9 patients died and 12 patients were lost to follow-up at 5 years after AMI. BMMC group showed less increase in LV end-diastolic volume (LVEDV) (3.5±16.9 mL/m(2)) compared with (11.2±19.8 mL/m(2), p=0.03) in the control group, with no difference between the PBMC group (9.2±20.9 mL/m(2)) and controls (p=0.69). Moreover, the BMMC group showed a trend for decrease in LV end systolic volume (-1.8±15.0 mL/m(2)) as compared with controls (3.0±16.3 mL/m(2), p=0.07), with again no difference between PBMC (3.3±18.8 mL/m(2)) and controls (p=0.66). The combined endpoint of death and hospitalisation for heart failure was non-significantly less frequent in the BMMC group compared with the control group (n=4 vs n=1, p=0.20), with no difference between PBMC and controls (n=6 vs n=4, p=0.74). The composite endpoint of death or recurrent myocardial infarction was significantly higher in the PBMC group compared with controls (14 patients vs 3 patients, p=0.008), with no difference between the BMMC group and controls (2 vs 3 patients, p=0.67). Long-term follow-up of the HEBE trial showed that increase in LVEDV was lower in the BMMC group. This study supports the long-term safety of intracoronary BMMC therapy. However, major clinical cardiovascular adverse

  5. Chitosan nerve conduits seeded with autologous bone marrow mononuclear cells for 30 mm goat peroneal nerve defect

    PubMed Central

    Muheremu, Aikeremujiang; Chen, Lin; Wang, Xiyuan; Wei, Yujun; Gong, Kai; Ao, Qiang

    2017-01-01

    In the current research, to find if the combination of chitosan nerve conduits seeded with autologous bone marrow mononuclear cells (BM-MNCs) can be used to bridge 30 mm long peroneal nerve defects in goats, 15 animals were separated into BM-MNC group (n = 5), vehicle group (n = 5), and autologous nerve graft group (n = 5). 12 months after the surgery, animals were evaluated by behavioral observation, magnetic resonance imaging tests, histomorphological and electrophysiological analysis. Results revealed that animals in BM-MNC group and autologous nerve graft group achieved fine functional recovery; magnetic resonance imaging tests and histomorphometry analysis showed that the nerve defect was bridged by myelinated nerve axons in those animals. No significant difference was found between the two groups concerning myelinated axon density, axon diameter, myelin sheath thickness and peroneal nerve action potential. Animals in vehicle group failed to achieve significant functional recovery. The results indicated that chitosan nerve conduits seeded with autologous bone marrow mononuclear cells have strong potential in bridging long peripheral nerve defects and could be applied in future clinical trials. PMID:28287100

  6. Chitosan nerve conduits seeded with autologous bone marrow mononuclear cells for 30 mm goat peroneal nerve defect.

    PubMed

    Muheremu, Aikeremujiang; Chen, Lin; Wang, Xiyuan; Wei, Yujun; Gong, Kai; Ao, Qiang

    2017-03-13

    In the current research, to find if the combination of chitosan nerve conduits seeded with autologous bone marrow mononuclear cells (BM-MNCs) can be used to bridge 30 mm long peroneal nerve defects in goats, 15 animals were separated into BM-MNC group (n = 5), vehicle group (n = 5), and autologous nerve graft group (n = 5). 12 months after the surgery, animals were evaluated by behavioral observation, magnetic resonance imaging tests, histomorphological and electrophysiological analysis. Results revealed that animals in BM-MNC group and autologous nerve graft group achieved fine functional recovery; magnetic resonance imaging tests and histomorphometry analysis showed that the nerve defect was bridged by myelinated nerve axons in those animals. No significant difference was found between the two groups concerning myelinated axon density, axon diameter, myelin sheath thickness and peroneal nerve action potential. Animals in vehicle group failed to achieve significant functional recovery. The results indicated that chitosan nerve conduits seeded with autologous bone marrow mononuclear cells have strong potential in bridging long peripheral nerve defects and could be applied in future clinical trials.

  7. Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients.

    PubMed

    Taguchi, Akihiko; Sakai, Chiaki; Soma, Toshihiro; Kasahara, Yukiko; Stern, David M; Kajimoto, Katsufumi; Ihara, Masafumi; Daimon, Takashi; Yamahara, Kenichi; Doi, Kaori; Kohara, Nobuo; Nishimura, Hiroyuki; Matsuyama, Tomohiro; Naritomi, Hiroaki; Sakai, Nobuyuki; Nagatsuka, Kazuyuki

    2015-10-01

    The goal of this clinical trial was to assess the feasibility and safety of transplanting autologous bone marrow mononuclear cells into patients suffering severe embolic stroke. Major inclusion criteria included patients with cerebral embolism, age 20-75 years, National Institute of Health Stroke Scale (NIHSS) score displaying improvement of ≤ 5 points during the first 7 days after stroke, and NIHSS score of ≥ 10 on day 7 after stroke. Bone marrow aspiration (25 or 50 mL; N = 6 patients in each case) was performed 7-10 days poststroke, and bone marrow mononuclear cells were administrated intravenously. Mean total transplanted cell numbers were 2.5 × 10(8) and 3.4 × 10(8) cells in the lower and higher dose groups, respectively. No apparent adverse effects of administering bone marrow cells were observed. Compared with the lower dose, patients receiving the higher dose of bone marrow cells displayed a trend toward improved neurologic outcomes. Compared with 1 month after treatment, patients receiving cell therapy displayed a trend toward improved cerebral blood flow and metabolic rate of oxygen consumption 6 months after treatment. In comparison with historical controls, patients receiving cell therapy had significantly better neurologic outcomes. Our results indicated that intravenous transplantation of autologous bone marrow mononuclear cells is safe and feasible. Positive results and trends favoring neurologic recovery and improvement in cerebral blood flow and metabolism by cell therapy underscore the relevance of larger scale randomized controlled trials using this approach.

  8. Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy.

    PubMed

    Liu, Xuebin; Fu, Xiaojun; Dai, Guanghui; Wang, Xiaodong; Zhang, Zan; Cheng, Hongbin; Zheng, Pei; An, Yihua

    2017-02-24

    Bone marrow mesenchymal stem cells (BMMSCs) and bone marrow mononuclear cells (BMMNCs) are both used to treat spastic cerebral palsy. However, the differences in therapeutic effect remain unknown. A total of 105 patients with spastic cerebral palsy were enrolled and randomly assigned to three groups: the BMMSC group, the BMMNC group and the control group. Patients in both transplantation groups received four intrathecal cell injections. Patients in the control group received Bobath therapy. The gross motor function measure (GMFM) and the fine motor function measure (FMFM) were used to evaluate the therapeutic efficacy before transplantation and 3, 6, and 12 months after transplantation. Three months after cell transplantation, scores in the A dimension of GMFM and the A and C dimensions of FMFM scores in the BMMSC group are all higher than those of the BMMNC and the control groups (P < 0.05). Six months after cell transplantation, scores in the A, B dimensions of GMFM and the A, B, C, D, and E dimensions of FMFM scores in the BMMSC group are higher than those of the BMMNC and the control groups (P < 0.05). Twelve months after cell transplantation, scores in the A, B, and C dimensions of GMFM and the A, B, C, D, and E dimensions of FMFM scores in the BMMSC group are all higher than those of the BMMNC and the control groups (P < 0.05). No obvious adverse effects were investigated during follow-up. BMMSC transplantation for the treatment of cerebral palsy is safe and feasible, and can improve gross motor and fine motor function significantly. In addition, compared with BMMNC, the motor function of children improved significantly in terms of gross motor and fine motor functions.

  9. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats

    PubMed Central

    Brenneman, Miranda; Sharma, Sushil; Harting, Matthew; Strong, Roger; Cox, Charles S; Aronowski, Jarek; Grotta, James C; Savitz, Sean I

    2010-01-01

    We investigated intra-arterially administered autologous bone marrow mononuclear cells (MNCs) in rats with acute ischemic stroke. Long Evans rats (2 to 3 months or 12 months old) underwent tandem reversible common carotid artery (CCA)/middle cerebral artery (MCA) occlusion (CCAo/MCAo) for 3 h and then 24 h later underwent tibial bone marrow harvest. Ten million or 4 million cells were re-injected by an intra-carotid infusion. Control animals underwent marrow needle insertion and then saline injection into the carotid artery. Animals were assessed on a battery of neurological tests. MNCs in the ischemic brain were tracked using Q-dot nanocrystal labeling. Infarct volume and cytokines in the ischemia-affected brain were analyzed. Cell-treated animals in the younger and older groups showed improvement from 7 to 30 days after stroke compared with vehicle-treated animals. MNCs significantly reduced infarct volume compared with saline. There was a significant reduction in tumor necrosis factor-α, interleukin-1α (IL-1α), IL-β, IL-6, and a significant increase in IL-10 in injured brains harvested from the cell-treated groups compared with saline controls. Labeled MNCs were found in the peri-infarcted area at 1 h and exponentially decreased over the ensuing week after injection. Autologous bone marrow MNCs can be safely harvested from rodents after stroke, migrate to the peri-infarct area, enhance recovery, and modulate the post-ischemic inflammatory response. PMID:19773802

  10. Long-term three-dimensional perfusion culture of human adult bone marrow mononuclear cells in bioreactors.

    PubMed

    Schmelzer, Eva; Finoli, Anthony; Nettleship, Ian; Gerlach, Jörg C

    2015-04-01

    The construction and long-term maintenance of three-dimensional in vitro bone marrow models is of great interest but still quite challenging. Here we describe the use of a multi-compartment hollow-fiber membrane based three-dimensional perfusion bioreactor for long-term culture of whole human bone marrow mononuclear cells. We also investigated bioreactors with incorporated open-porous foamed hydroxyapatite scaffolds, mimicking the in vivo bone matrix. Cells in bioreactors with and without scaffolds were cultured to 6 weeks and compared to Petri dish controls. Cells were analyzed for gene expression, surface markers by flow cytometry, metabolic activity, hematopoietic potential, viability, and attachment by immunocytochemistry. Cells in bioreactors were metabolic active during long-term culture. The percentages of hematopoietic stem cell and mature endothelial cell fractions were maintained in bioreactors. The expression of most of the analyzed genes stabilized and increased after long-term culture of 6 weeks. Compared to Petri dish culture controls, bioreactor perfusion culture improved in both the short and long-term, the colony formation unit capacity of hematopoietic progenitors. Cells attached to the ample surface area provided by hydroxyapatite scaffolds. The implementation of a hydroxyapatite scaffold did not influence colony formation capacity, percentages of cell type specific fractions, gene expression, cell viability or metabolic turnover when compared to control cells cultured in bioreactors without scaffolds. In conclusion, three-dimensional perfusion bioreactor culture enables long-term maintenance of primary human bone marrow cells, with hydroxyapatite scaffolds providing an in vivo-like scaffold for three-dimensional culture. © 2015 Wiley Periodicals, Inc.

  11. Effect of age and gender on recovery after stroke in rats treated with bone marrow mononuclear cells.

    PubMed

    Coelho, Bárbara Paula; Giraldi-Guimarães, Arthur

    2014-11-01

    Stroke is a disease of the elderly. However, most of the preclinical studies about the treatment of stroke with bone marrow-derived cells have used young animals. Here, it was assessed whether the sensorimotor recovery promoted by the treatment of the brain ischemia with the bone marrow mononuclear cells (BMMCs) is influenced by age and/or gender. Unilateral cortical ischemia by thermocoagulation was made in the primary motor and sensorimotor cortices in young and middle-aged rats of both genders. Twenty four hours after ischemia, animals received intravenous injection of BMMCs or vehicle. Each combination of age and gender received BMMCs from donor with the same combination. Survival rate and ischemic lesion size were quantified. Sensorimotor recovery was evaluated by the cylinder and adhesive tests. The results showed that the treatment with BMMCs resulted in sensorimotor recovery of both young and middle-aged ischemic rats. No important effect of gender was found, but age was a significant factor. Middle-aged animals had increased mortality and lesion sizes. In the adhesive test, middle-aged animals had lower BMMCs-induced sensorimotor recovery. The results suggest that the treatment of stroke with the BMMCs should be beneficial for males and females in the elderly. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  12. Intramyocardial delivery of bone marrow mononuclear cells and mechanical assist device implantation in patients with end-stage cardiomyopathy.

    PubMed

    Nasseri, Boris A; Kukucka, Marian; Dandel, Michael; Knosalla, Christoph; Potapov, Evgenij; Lehmkuhl, Hans B; Meyer, Rudolph; Ebell, Wolfram; Stamm, Christof; Hetzer, Roland

    2007-01-01

    In end-stage heart failure, mechanical ventricular assist devices (VAD) are being used as bridge-to-transplantation, as a bridge-to-recovery, or as the definitive therapy. We tested the hypothesis that myocardial implantation of autologous bone marrow mononuclear cells (BMNC) increases the likelihood of successful weaning from left VAD (LVAD) support. Ten patients (aged 14-60 years) with deteriorating heart function underwent LVAD implantation and concomitant implantation of autologous BMNC. Bone marrow was harvested prior to VAD implantation and BMNC were prepared by density centrifugation. Two patients received a pulsatile, extracorporeal LVAD and eight a nonpulsatile implantable device. Between 52 and 164 x 10(7) BMNC containing between 1 and 12 x 10(6) CD34+ cells were injected into the LV myocardium. There was one early and one late death. The median time on LVAD support was 243 days (range 24-498 days). Repeated echocardiographic examinations under increased hemodynamic load revealed a significant improvement of LV function in one patient. Three patients underwent heart transplantation, and four patients remain on LVAD support >1 year without evidence of recovery. Only one patient was successfully weaned from LVAD support after 4 months, and LV function has remained stable ever since. In patients with endstage cardiomyopathy, intramyocardial injection of BMNC at the time of LVAD implantation does not seem to increase the likelihood of successful weaning from VAD support. Other cell-based strategies should be pursued to harness the potential of cell therapy in LVAD patients.

  13. 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; ...

  14. Direct intramyocardial transthoracic transplantation of bone marrow mononuclear cells for non-ischemic dilated cardiomyopathy: INTRACELL, a prospective randomized controlled trial

    PubMed Central

    Sant'Anna, Roberto T.; Fracasso, James; Valle, Felipe H.; Castro, Iran; Nardi, Nance B.; Sant'Anna, João Ricardo M.; Nesralla, Ivo Abrahão; Kalil, Renato A. K.

    2014-01-01

    Objective We tested the hypothesis that direct intramyocardial injection of bone marrow mononuclear cells in patients with non-ischemic dilated cardiomyopathy can improve left ventricular function and physical capacity. Methods Thirty non-ischemic dilated cardiomyopathy patients with left ventricular ejection fraction <35% were randomized at a 1:2 ratio into two groups, control and treated. The bone marrow mononuclear cells group received 1.06±108 bone marrow mononuclear cells through mini-thoracotomy. There was no intervention in the control group. Assessment was carried out through clinical evaluations as well as a 6-min walk test, nuclear magnectic resonance imaging and echocardiogram. Results The bone marrow mononuclear cells group showed a trend toward left ventricular ejection fraction improvement, with magnectic resonance imaging - at 3 months, showing an increase from 27.80±6.86% to 30.13±9.06% (P=0.08) and returning to baseline at 9 months (28.78%, P=0.77). Magnectic resonance imaging showed no changes in left ventricular ejection fraction during follow-up of the control group (28.00±4.32%, 27.42±7.41%, and 29.57±4.50%). Echocardiogram showed left ventricular ejection fraction improved in the bone marrow mononuclear cells group at 3 months, 25.09±3.98 to 30.94±9.16 (P=0.01), and one year, 30.07±7.25% (P=0.001). The control group showed no change (26.1±4.4 vs 26.5±4.7 and 30.2±7.39%, P=0.25 and 0.10, respectively). Bone marrow mononuclear cells group showed improvement in New York Heart Association functional class, from 3.40±0.50 to 2.41±0.79 (P=0.002); patients in the control group showed no change (3.37±0.51 to 2.71±0.95; P=0.17). Six-minute walk test improved in the bone marrow mononuclear cells group (348.00±93.51m at baseline to 370.41±91.56m at 12 months, P=0.66) and there was a non-significant decline in the control group (361.25±90.78m to 330.00±123.42m after 12 months, P=0.66). Group comparisons were non-significant. Conclusion

  15. Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients

    PubMed Central

    Sakai, Chiaki; Soma, Toshihiro; Kasahara, Yukiko; Stern, David M.; Kajimoto, Katsufumi; Ihara, Masafumi; Daimon, Takashi; Yamahara, Kenichi; Doi, Kaori; Kohara, Nobuo; Nishimura, Hiroyuki; Matsuyama, Tomohiro; Naritomi, Hiroaki; Sakai, Nobuyuki; Nagatsuka, Kazuyuki

    2015-01-01

    The goal of this clinical trial was to assess the feasibility and safety of transplanting autologous bone marrow mononuclear cells into patients suffering severe embolic stroke. Major inclusion criteria included patients with cerebral embolism, age 20–75 years, National Institute of Health Stroke Scale (NIHSS) score displaying improvement of ≤5 points during the first 7 days after stroke, and NIHSS score of ≥10 on day 7 after stroke. Bone marrow aspiration (25 or 50 mL; N = 6 patients in each case) was performed 7–10 days poststroke, and bone marrow mononuclear cells were administrated intravenously. Mean total transplanted cell numbers were 2.5 × 108 and 3.4 × 108 cells in the lower and higher dose groups, respectively. No apparent adverse effects of administering bone marrow cells were observed. Compared with the lower dose, patients receiving the higher dose of bone marrow cells displayed a trend toward improved neurologic outcomes. Compared with 1 month after treatment, patients receiving cell therapy displayed a trend toward improved cerebral blood flow and metabolic rate of oxygen consumption 6 months after treatment. In comparison with historical controls, patients receiving cell therapy had significantly better neurologic outcomes. Our results indicated that intravenous transplantation of autologous bone marrow mononuclear cells is safe and feasible. Positive results and trends favoring neurologic recovery and improvement in cerebral blood flow and metabolism by cell therapy underscore the relevance of larger scale randomized controlled trials using this approach. PMID:26176265

  16. Combined autologous bone marrow mononuclear cell and gene therapy as the last resort for patients with critical limb ischemia

    PubMed Central

    Skóra, Jan; Pupka, Artur; Janczak, Dariusz; Barć, Piotr; Dawiskiba, Tomasz; Korta, Krzysztof; Baczyńska, Dagmara; Garcarek, Jerzy

    2014-01-01

    Introduction Our study was designed to investigate the safety and efficacy of combined autologous bone marrow mononuclear cell (MNC) and gene therapy in comparison to conventional drug therapy in patients with critical limb ischemia (CLI). Material and methods Thirty-two patients with CLI persisting for 12–48 months (average time 27.5 months) were randomized into 2 groups, each group consisting of 16 patients. In the first group, administration of autologous bone marrow MNC and vascular endothelial growth factor (VEGF) plasmid was performed. The patients from the second group were treated pharmacologically with pentoxifylline. Ankle-brachial index (ABI) was measured and angiography was performed before and finally 3 months after treatment. The pain was evaluated using the Visual Analog Scale (VAS) before and after 3 months. Results Ankle-brachial index improved significantly from 0.29 ±0.21 to 0.52 ±0.23 (p < 0.001) in 12 patients (75.0%) 3 months after the experimental therapy in group 1. In this group angiography showed the development of collateral vessels. Ischemic ulcers healed completely in 11 patients (68.75%). In group 2 the ABI did not improve in any patient; moreover the complete healing of skin ulcers was not found in any of the patients of this group. Amputation was performed in 4 (25.0%) patients in group 1, and in 8 patients (50%) from group 2. Conclusions These data after 3-month follow-up indicate that intramuscular injection of MNC combined with gene therapy in patients with chronic CLI is safe, and a more feasible and effective method of treatment than the conventional therapy. However, both therapies are limited by the degree of microcirculation damage. PMID:25995748

  17. Fifteen years of bone marrow mononuclear cell therapy in acute myocardial infarction

    PubMed Central

    Micheu, Miruna Mihaela; Dorobantu, Maria

    2017-01-01

    In spite of modern treatment, acute myocardial infarction (AMI) still carries significant morbidity and mortality worldwide. Even though standard of care therapy improves symptoms and also long-term prognosis of patients with AMI, it does not solve the critical issue, specifically the permanent damage of cardiomyocytes. As a result, a complex process occurs, namely cardiac remodeling, which leads to alterations in cardiac size, shape and function. This is what has driven the quest for unconventional therapeutic strategies aiming to regenerate the injured cardiac and vascular tissue. One of the latest breakthroughs in this regard is stem cell (SC) therapy. Based on favorable data obtained in experimental studies, therapeutic effectiveness of this innovative therapy has been investigated in clinical settings. Of various cell types used in the clinic, autologous bone marrow derived SCs were the first used to treat an AMI patient, 15 years ago. Since then, we have witnessed an increasing body of data as regards this cutting-edge therapy. Although feasibility and safety of SC transplant have been clearly proved, it’s efficacy is still under dispute. Conducted studies and meta-analysis reported conflicting results, but there is hope for conclusive answer to be provided by the largest ongoing trial designed to demonstrate whether this treatment saves lives. In the meantime, strategies to enhance the SCs regenerative potential have been applied and/or suggested, position papers and recommendations have been published. But what have we learned so far and how can we properly use the knowledge gained? This review will analytically discuss each of the above topics, summarizing the current state of knowledge in the field. PMID:28491241

  18. Bone marrow culture

    MedlinePlus

    ... are very rare. Alternative Names Culture - bone marrow Images Bone marrow aspiration References Chernecky CC, Berger BJ. Bone marrow aspiration analysis-specimen (biopsy, bone marrow iron stain, iron stain, ...

  19. Infection of chicken bone marrow mononuclear cells with subgroup J avian leukosis virus inhibits dendritic cell differentiation and alters cytokine expression.

    PubMed

    Liu, Di; Qiu, Qianqian; Zhang, Xu; Dai, Manman; Qin, Jianru; Hao, Jianjong; Liao, Ming; Cao, Weisheng

    2016-10-01

    Subgroup J avian leukosis virus (ALV-J) is an oncogenic retrovirus known to induce tumor formation and immunosuppression in infected chickens. One of the organs susceptible to ALV-J is the bone marrow, from which specialized antigen-presenting cells named dendritic cells (BM-DCs) are derived. Notably, these cells possess the unique ability to induce primary immune responses. In the present study, a method of cultivating and purifying DCs from chicken bone marrow in vitro was established to investigate the effects of ALV-J infection on BM-DC differentiation or generation. The results indicated that ALV-J not only infects the chicken bone marrow mononuclear cells but also appears to inhibit the differentiation and maturation of BM-DCs and to trigger apoptosis. Moreover, substantial reductions in the mRNA expression of TLR1, TLR2, TLR3, MHCI, and MHCII and in cytokine production were detected in the surviving BM-DCs following ALV-J infection. These findings indicate that ALV-J infection disrupts the process of bone marrow mononuclear cell differentiation into BM-DCs likely via altered antigen presentation, resulting in a downstream immune response in affected chickens.

  20. Intravenous transplantation of bone marrow-derived mononuclear cells prevents memory impairment in transgenic mouse models of Alzheimer's disease.

    PubMed

    Kanamaru, Takuya; Kamimura, Naomi; Yokota, Takashi; Nishimaki, Kiyomi; Iuchi, Katsuya; Lee, Hyunjin; Takami, Shinya; Akashiba, Hiroki; Shitaka, Yoshitsugu; Ueda, Masayuki; Katsura, Ken-Ichiro; Kimura, Kazumi; Ohta, Shigeo

    2015-04-24

    Stem cell transplantation therapy is currently in clinical trials for the treatment of ischemic stroke, and several beneficial aspects have been reported. Similarly, in Alzheimer's disease (AD), stem cell therapy is expected to provide an efficient therapeutic approach. Indeed, the intracerebral transplantation of stem cells reduced amyloid-β (Aβ) deposition and rescued memory deficits in AD model mice. Here, we show that intravenous transplantation of bone marrow-derived mononuclear cells (BMMCs) improves cognitive function in two different AD mouse models, DAL and APP mice, and prevents neurodegeneration. GFP-positive BMMCs were isolated from tibiae and femurs of 4-week-old mice and then transplanted intravenously into DAL and APP mice. Transplantation of BMMCs suppressed neuronal loss and restored memory impairment of DAL mice to almost the same level as in wild-type mice. Transplantation of BMMCs to APP mice reduced Aβ deposition in the brain. APP mice treated with BMMCs performed significantly better on behavioral tests than vehicle-injected mice. Moreover, the effects were observed even with transplantation after the onset of cognitive impairment in DAL mice. Together, our results indicate that intravenous transplantation of BMMCs has preventive effects against the cognitive decline in AD model mice and suggest a potential therapeutic effect of BMMC transplantation therapy.

  1. Infusion of Bone Marrow Mononuclear Cells Reduces Lung Fibrosis but Not Inflammation in the Late Stages of Murine Silicosis

    PubMed Central

    Lopes-Pacheco, Miquéias; Ventura, Túlio G.; de Oliveira, Helena D'Anunciação; Monção-Ribeiro, Leonardo C.; Gutfilen, Bianca; de Souza, Sergio A. L.; Rocco, Patrícia R. M.; Borojevic, Radovan; Morales, Marcelo M.; Takiya, Christina M.

    2014-01-01

    We hypothesized that infusion of bone marrow mononuclear cells (BMMCs) in the late stages of silica-induced damage would reduce the remodelling process in a murine model of silicosis. C57BL/6 mice were assigned to 2 groups. In the SIL group, mice were instilled with a silica particle suspension intratracheally. Control (C) mice received saline under the same protocol. On the 40th day, some of the animals from both groups were killed. The others were treated with either saline or BMMCs (1×106cells) intravenously (C+BMMC and SIL+BMMC), and the mice were killed 70 days after the start of the protocol. In the mice in the SIL+BMMC group, collagen deposition, the presence of silica particles inside nodules, the presence of macrophages and cells reactive for inducible nitric oxide synthase were reduced. Lung parameters also improved. Beyond that, the total and differential cellularity of bronchoalveolar lavage fluid, immunoexpression of transforming growth factor-β, the number of T regulatory cells and apoptosis were increased. However, the presence of male donor cells in lung tissue was not observed using GFP+ cells (40d) or Y chromosome DNA (70d). Therefore, BMMC therapy in the late stages of experimental silicosis improved lung function by diminishing fibrosis but inflammatory cells persisted, which could be related to expansion of T regulatory cells, responsible for the beneficial effects of cell therapy. PMID:25299237

  2. Intratracheal therapy with autologous bone marrow-derived mononuclear cells reduces airway inflammation in horses with recurrent airway obstruction.

    PubMed

    Barussi, Fernanda C M; Bastos, Fernanda Z; Leite, Lidiane M B; Fragoso, Felipe Y I; Senegaglia, Alexandra C; Brofman, Paulo R S; Nishiyama, Anita; Pimpão, Cláudia T; Michelotto, Pedro V

    2016-10-01

    This research evaluated the effects of bone marrow-derived mononuclear cells (BMMCs) on the inflammatory process in the equine recurrent airway obstruction (RAO). Eight horses in RAO clinical score were divided into cell therapy group (Gcel) treated with a single intratracheal dose of BMMCs, and dexamethasone group (Gdex) treated with 21days of oral dexamethasone. The horses were clinically revaluated on days 7 and 21, together with cytological evaluation of the BALF, and detection of inflammatory markers (interleukins [IL]-10, -4, and -17, and interferon γ and α). There were decreases in respiratory effort and clinical score on days 7 and 21(p<0.05) for both groups. The percentage of neutrophils decreased and macrophages increased on days 7 and 21 (p<0.005) in both groups. IL-10 levels increased in the Gcel group on day 21 compared to days 0 and 7 (p<0.05), but this was not observed in the Gdex group. The quantification of IL-4, IL-17, IFN-γ, and IFN-α did not change between evaluations in both groups. These preliminary results suggest that BMMCs may ameliorate the inflammatory response of RAO. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Transplantation of Bone Marrow-Derived Mononuclear Cells Improves Mechanical Hyperalgesia, Cold Allodynia and Nerve Function in Diabetic Neuropathy

    PubMed Central

    Funakubo, Megumi; Hata, Masaki; Nakamura, Nobuhisa; Kobayashi, Yasuko; Kamiya, Hideki; Shibata, Taiga; Kondo, Masaki; Himeno, Tatsuhito; Matsubara, Tatsuaki; Oiso, Yutaka; Nakamura, Jiro

    2011-01-01

    Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy. PMID:22125614

  4. Transplantation of bone marrow-derived mononuclear cells improves mechanical hyperalgesia, cold allodynia and nerve function in diabetic neuropathy.

    PubMed

    Naruse, Keiko; Sato, Jun; Funakubo, Megumi; Hata, Masaki; Nakamura, Nobuhisa; Kobayashi, Yasuko; Kamiya, Hideki; Shibata, Taiga; Kondo, Masaki; Himeno, Tatsuhito; Matsubara, Tatsuaki; Oiso, Yutaka; Nakamura, Jiro

    2011-01-01

    Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy.

  5. Systemic Transplantation of Bone Marrow Mononuclear Cells Promotes Axonal Regeneration and Analgesia in a Model of Wallerian Degeneration.

    PubMed

    Usach, Vanina; Malet, Mariana; López, Margarita; Lavalle, Lucía; Piñero, Gonzalo; Saccoliti, María; Cueto, Alicia; Brumovsky, Pablo; Brusco, Alicia; Setton-Avruj, Patricia

    2017-07-01

    Reinnervation timing after nerve injury is critical for favorable axonal regeneration, remyelination, and clinical improvement. Considering bone marrow mononuclear cells (BMMC) are easily obtained and readily available for transplant, this work analyzed the effect of BMMC systemic administration on nerve repair and pain behavior. Adult rats with sciatic nerve crush were immediately and systemically injected BMMC through the caudal artery. Nontreated, sham and naïve rats were also included. Histological, immunohistochemical, biochemical, functional, and behavioral analyses were performed in nerves harvested from each group at different survival times. Axons in BMMC-treated rats exhibited a more conserved morphological appearance than those in nontreated rats, as observed at different survival times both in semithin sections and ultrastructural analysis. BMMC-treated rats also showed a reduction in major myelin protein immunoreactive clusters 7 and 14 days postinjury, as compared with nontreated rats. Electrophysiological analysis showed BMMC treatment to slightly improve the amplitude of compound muscle action potential starting at 14 days postinjury. Finally, mechanical withdrawal threshold revealed a full preventive action against transient mechanical hypersensitivity in BMMC-treated rats. These data demonstrate the efficiency of BMMC, systemically and noninvasively transplanted, in correcting morphological, functional and behavioral alterations resulting from peripheral nerve injury.

  6. Concise Review: Prospects of Bone Marrow Mononuclear Cells and Mesenchymal Stem Cells for Treating Status Epilepticus and Chronic Epilepsy.

    PubMed

    Agadi, Satish; Shetty, Ashok K

    2015-07-01

    Mononuclear cells (MNCs) and mesenchymal stem cells (MSCs) derived from the bone marrow and other sources have received significant attention as donor cells for treating various neurological disorders due to their robust neuroprotective and anti-inflammatory effects. Moreover, it is relatively easy to procure these cells from both autogenic and allogenic sources. Currently, there is considerable interest in examining the usefulness of these cells for conditions such as status epilepticus (SE) and chronic epilepsy. A prolonged seizure activity in SE triggers neurodegeneration in the limbic brain areas, which elicits epileptogenesis and evolves into a chronic epileptic state. Because of their potential for providing neuroprotection, diminishing inflammation and curbing epileptogenesis, early intervention with MNCs or MSCs appears attractive for treating SE as such effects may restrain the development of chronic epilepsy typified by spontaneous seizures and learning and memory impairments. Delayed administration of these cells after SE may also be useful for easing spontaneous seizures and cognitive dysfunction in chronic epilepsy. This concise review evaluates the current knowledge and outlook pertaining to MNC and MSC therapies for SE and chronic epilepsy. In the first section, the behavior of these cells in animal models of SE and their efficacy to restrain neurodegeneration, inflammation, and epileptogenesis are discussed. The competence of these cells for suppressing seizures and improving cognitive function in chronic epilepsy are conferred in the next section. The final segment ponders issues that need to be addressed to pave the way for clinical application of these cells for SE and chronic epilepsy.

  7. Bone-marrow mononuclear cells reduce neurodegeneration in hippocampal CA1 layer after transient global ischemia in rats.

    PubMed

    Ramos, Alane Bernardo; Vasconcelos-Dos-Santos, Andréia; Lopes de Souza, Sergio Augusto; Rosado-de-Castro, Paulo Henrique; Barbosa da Fonseca, Lea Mirian; Gutfilen, Bianca; Cintra, Wagner Monteiro; Mendez-Otero, Rosalia

    2013-07-19

    Global cerebral ischemia (GCI) results in death of the pyramidal neurons in the CA1 layer of the hippocampus. In this study we used the four-vessel occlusion (4VO) model of GCI to investigate a potential neuroprotective role of bone-marrow mononuclear cells (BMMCs) transplantation. BMMCs (3×10(7)) were injected through the carotid artery, 1 or 3 days after ischemia (DAI), and the number of cells undergoing degeneration was investigated in brains at 7 DAI. A significant decrease in the number of dying cells was observed in the treated group, compared to animals treated with saline. Biodistribution of the injected cells (1 or 3 DAI) was investigated by (99m)Technetium labeling of the BMMCs and subsequent image analysis 2h after transplantation. In addition, the presence of CellTrace(™)-labeled BMMCs was investigated in tissue sections of the hippocampal area of these transplanted animals. BMMCs treatment significantly reduced the number of FJ-C positive cells in the hippocampal CA1 layer at 7 DAI. We also observed a decrease in the number of activated microglia/macrophage (ED1-positive cells) in the BMMCs-treated group compared with the untreated group. Our data show that BMMCs are able to modulate the microglial response and reduce neurodegeneration in the CA1 layer. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Combined delivery of bone marrow-derived mononuclear cells in chronic ischemic heart disease: rationale and study design.

    PubMed

    Sürder, Daniel; Radrizzani, Marina; Turchetto, Lucia; Cicero, Viviana Lo; Soncin, Sabrina; Muzzarelli, Stefano; Auricchio, Angelo; Moccetti, Tiziano

    2013-08-01

    Treatment with bone marrow-derived mononuclear cells (BM-MNC) may improve left ventricular (LV) function in patients with chronic ischemic heart disease (IHD). Delivery method of the cell product may be crucial for efficacy. We aimed to demonstrate that the combination of intramyocardial and intracoronary injection of BM-MNC is safe and improves LV function in patients with chronic IHD. After a safety/feasibility phase of 10 patients, 54 patients will be randomly assigned in a 1:1:1 pattern to 1 control and 2 BM-MNC treatment groups. The control group will be treated with state-of-the-art medical management. The treatment groups will receive either exclusively intramyocardial injection or a combination of intramyocardial and intracoronary injection of autologous BM-MNC. Left ventricular function as well as scar size, transmural extension, and regional wall-motion score will be assessed by cardiac magnetic resonance imaging studies at baseline and after 6 months. The primary endpoint is the change in global LV ejection fraction by cardiac magnetic resonance from 6 months to baseline. The results, it is hoped, will have important clinical impact and provide essential information to improve the design of future regenerative-medicine protocols in cardiology. As cell delivery may play an important role in chronic IHD, we aim to demonstrate feasibility and efficacy of a combined cell-delivery approach in patients with decreased LV function. © 2013 Wiley Periodicals, Inc.

  9. Dissociation between dopaminergic response and motor behavior following intrastriatal, but not intravenous, transplant of bone marrow mononuclear stem cells in a mouse model of Parkinson's disease.

    PubMed

    Calice da Silva, Caroline; Azevedo, Bárbara Nunes; Machado, Denise Cantarelli; Zimmer, Eduardo R; Martins, Leo Anderson Meira; da Costa, Jaderson Costa

    2017-05-01

    Parkinson's disease is characterized by the progressive loss of dopaminergic neurons from the substantia nigra, a process that leads to a dopamine deficiency in the striatum. This deficiency is responsible for the development of motor symptoms, including resting tremor, bradykinesia, rigidity and postural instability. Based on the observation of substantial neuronal death, alternatives to Parkinson's disease treatment have been studied, including cell-based therapies. The present study aimed to assess the therapeutic potential of intravenous and intrastriatal transplant of bone marrow mononuclear cells in a mouse model of Parkinson's disease. Animals underwent stereotaxic surgery and received an injection of 6-hydroxydopamine into their medial forebrain bundle. Three weeks later, mice were injected with bone marrow mononuclear cells or saline through the caudal vein or directly into their right striatum. Motor function was assessed using the rotarod and apomorphine-induced rotation tests. Our results showed that intrastriatal bone marrow mononuclear cells, but not intravenous, have a short-term therapeutic effect on dopaminergic response in this mice model of parkinsonism assessed by the apomorphine-induced rotation test. This phenomenon was not identified on the rotarod test, showing dissociation between dopaminergic response and motor behavior. Further experiments are needed to elucidate the precise mechanisms involved in these effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Bone marrow aspiration (image)

    MedlinePlus

    ... amount of bone marrow is removed during a bone marrow aspiration. The procedure is uncomfortable, but can be tolerated by both children and adults. The marrow can be studied to determine ... metabolic products are stored in certain bone marrow cells.

  11. Catheter–Based Transendocardial Delivery of Autologous Bone-Marrow-Derived Mononuclear Cells in Patients Listed for Heart Transplantation

    PubMed Central

    Silva, Guilherme V.; Perin, Emerson C.; Dohmann, Hans F.R.; Borojevic, Radovan; Silva, Suzana A.; Sousa, Andre L.S.; Assad, Joao A.R.; Vaughn, William K.; Mesquita, Claudio T.; Belém, Luciano; Carvalho, Antonio C.; Dohmann, Hans J.F.; do Amaral, Ellen Barroso; Coutinho, Joaquim; Branco, Rodrigo; Oliveira, Edie; Willerson, James T.

    2004-01-01

    Growing evidence suggests that transplantation of autologous bone-marrow mononuclear cells (ABMMNCs) can improve the perfusion and contractile function of ischemic myocardium. This procedure could potentially benefit transplant candidates awaiting a donor heart. To study the safety and feasibility of ABMMNC injection, we performed a prospective, nonrandomized, open-label study in 5 heart transplant candidates with severe ischemic heart failure. Each patient underwent baseline single-photon emission computed tomography, a ramp treadmill protocol, 2-dimensional echocardiography, 24-hour Holter monitoring, and signal-averaged electrocardiography, which were repeated at 2 and 6 months. Transendocardial delivery of ABMMNCs was done with the aid of electromechanical mapping to identify viable myocardium. Each patient received 15 ABMMNC injections of 0.2 cc each. There were no deaths, significant arrhythmias, or other major complications. The ABMMNC injection reduced the amount of ischemic myocardium (not statistically significant). More important, exercise test results improved significantly. Myocardial volume oxygen consumption increased from 10.6 ± 3 mL/kg/min (baseline) to 16.3 ± 7 mL/kg/min (2 months) and 23 ± 7 mL/kg/min (6 months) (P = 0.0091). In 4 of the 5 cases, this was such an improvement that the patients were no longer eligible for cardiac transplantation. In addition, metabolic equivalents improved from 3.03 ± 0.66 (baseline) to 4.65 ± 1.99 (2 months) and 6.5 ± 2.0 (6 months) (P = 0.0092). In conclusion, ABMMNC injections were performed safely and resulted in improved exercise capacity. This technique may hold promise as an alternative to medical management in patients with severe ischemic heart failure who are ineligible for conventional revascularization. PMID:15562839

  12. Functional improvement in patients with dilated cardiomyopathy after the intracoronary infusion of autologous bone marrow mononuclear cells.

    PubMed

    Suárez de Lezo, José; Herrera, Concepción; Romero, Miguel; Pan, Manuel; Suárez de Lezo, Javier; Carmona, María Dolores; Jiménez, Rosario; Segura, José; Nogueras, Sonia; Mesa, Dolores; Pavlovic, Djordje; Ojeda, Soledad; Mazuelos, Francisco; Delgado, Mónica; Ruiz, Martin; Castilla, María Luisa; Torres, Antonio

    2013-06-01

    Different studies have shown improvement in patients with idiopathic nonischemic dilated cardiomyopathy treated with cell-therapy. However, factors influencing responsiveness are not well known. This trial investigates functional changes and factors influencing the 6-month gain in ejection fraction in 27 patients with dilated cardiomiopathy treated with intracoronary cell-therapy. Patients received intracoronary infusion of autologous bone-marrow mononuclear cells (mean infused, 10.2 [2.9]×10(8)). Flow cytometry and functional analyses of the cells were also performed. The 6-month angiographic gain in ejection fraction ranged from -9% to 34% (mean, 9%). These changes were distinguished into 2 groups: 21 patients (78%) with a significant improvement at the 6-month evaluation (mean gain, 14 [7]%), and 6 patients who had no response (mean gain, -5 [3]%). The responders were younger as compared to the nonresponders (50 [12] years vs 62 [9] years; P<.04). There was an inverse correlation (r=-0.41; P<.003) between the gain in ejection fraction and the high density lipoprotein level, suggesting higher functional gain with low high density lipoprotein levels. The 24 h migratory capability of the infused cells was significantly reduced in the responders' group (5.4 [1.7]×10(8) vs 8.1 [2.3]×10(8); P<.009 for vascular endothelial growth factor and 5.8 [1.7]×10(8) vs 8.4 [2.9]×10(8); P<.002 for stromal cell-derived factor-1). Younger patients with dilated cardiomiopathy and lower plasma high density lipoprotein levels gain greater benefit from intracoronary cell-therapy. Functional improvement also seems to be enhanced by a lower migratory capacity of the infused cells. Copyright © 2012 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  13. Sustained effect of bone marrow mononuclear cell therapy in axonal regeneration in a model of optic nerve crush.

    PubMed

    Zaverucha-do-Valle, Camila; Mesentier-Louro, Louise; Gubert, Fernanda; Mortari, Nicoli; Padilha, Ana Beatriz; Paredes, Bruno D; Mencalha, Andre; Abdelhay, Eliana; Teixeira, Camila; Ferreira, Fernanda G M; Tovar-Moll, Fernanda; de Souza, Sergio Augusto L; Gutfilen, Bianca; Mendez-Otero, Rosalia; Santiago, Marcelo F

    2014-10-31

    In adult mammals, the regeneration of the optic nerve is very limited and at the moment there are several groups trying different approaches to increase retinal ganglion cell (RGC) survival and axonal outgrowth. One promising approach is cell therapy. In previous work, we performed intravitreal transplantation of bone-marrow mononuclear cells (BMMCs) after optic nerve crush in adult rats and we demonstrated an increase in RGC survival and axon outgrowth 14 days after injury. In the present work, we investigated if these results could be sustained for a longer period of time. Optic nerve crush was performed in Lister-hooded adult rats and BMMC or saline injections were performed shortly after injury. Neuronal survival and regeneration were evaluated in rats׳ retina and optic nerve after 28 days. We demonstrated an increase of 5.2 fold in the axon outgrowth 28 days after lesion, but the BMMCs had no effect on RGC survival. In an attempt to prolong RGC survival, we established a new protocol with two BMMC injections, the second one 7 days after the injury. Untreated animals received two injections of saline. We observed that although the axonal outgrowth was still increased after the second BMMC injection, the RGC survival was not significantly different from untreated animals. These results demonstrate that BMMCs transplantation promotes neuroregeneration at least until 28 days after injury. However, the effects on RGC survival previously observed by us at 14 days were not sustained at 28 days and could not be prolonged with a second dose of BMMC. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Systematic Review and Meta-Analysis of Bone Marrow-Derived Mononuclear Cells in Animal Models of Ischemic Stroke.

    PubMed

    Vahidy, Farhaan S; Rahbar, Mohammad H; Zhu, Hongjian; Rowan, Paul J; Bambhroliya, Arvind B; Savitz, Sean I

    2016-06-01

    Bone marrow-derived mononuclear cells (BMMNCs) offer the promise of augmenting poststroke recovery. There is mounting evidence of safety and efficacy of BMMNCs from preclinical studies of ischemic stroke; however, their pooled effects have not been described. Using Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, we conducted a systematic review of preclinical literature for intravenous use of BMMNCs followed by meta-analyses of histological and behavioral outcomes. Studies were selected based on predefined criteria. Data were abstracted by 2 independent investigators. After quality assessment, the pooled effects were generated using mixed-effect models. Impact of possible biases on estimated effect size was evaluated. Standardized mean difference and 95% confidence interval for reduction in lesion volume was significantly beneficial for BMMNC treatment (standardized mean difference: -3.3; 95% confidence interval, -4.3 to -2.3). n=113 each for BMMNC and controls. BMMNC-treated animals (n=161) also had improved function measured by cylinder test (standardized mean difference: -2.4; 95% confidence interval, -3.1 to -1.6), as compared with controls (n=205). A trend for benefit was observed for adhesive removal test and neurological deficit score. Study quality score (median: 6; Q1-Q3: 5-7) was correlated with year of publication. There was funnel plot asymmetry; however, the pooled effects were robust to the correction of this bias and remained significant in favor of BMMNC treatment. BMMNCs demonstrate beneficial effects across histological and behavioral outcomes in animal ischemic stroke models. Although study quality has improved over time, considerable degree of heterogeneity calls for standardization in the conduct and reporting of experimentation. © 2016 American Heart Association, Inc.

  15. 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 - ...

  16. [A FOLLOW-UP STUDY ON AUTOLOGOUS BONE MARROW MONONUCLEAR CELLS TRANSPLANTATION FOR CRITICAL LOWER ARTERIOSCLEROSIS OBLITERANS IN DIABETIC PATIENTS].

    PubMed

    Dou, Yanhua; Zhao, Jin; Zhang, Li; Wang, Xueying; Yuan, Hong; Yuan, Chunhui

    2015-07-01

    To assess the long-term effectiveness and safety of autologous bone marrow mononuclear cells (BM-MNC) transplantation in the treatment of critical diabetic lower arteriosclerosis obliterans (ASO). Between January 2007 and January 2010, 61 patients with critical diabetic lower ASO were treated with standard medical therapies in 29 cases (control group) or with standard medical therapies and autologous BM-MNC transplantation in 32 cases (treatment group). There was no significant difference in gender, age, disease duration, Fontatine stage, glucose (GLU), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein-cholesterol (LDL-C), hemoglobin Alc (HbA1c), systolic blood pressure (SBP), and diastolic blood pressure (DBP) between 2 groups (P > 0.05). The endpoints were overall survival (OS) and amputation-free survival (AFS). The risk indexes for ASO were observed and compared between 2 groups before and after treatments. The patients were followed up 2-36 months, and no malignant tumor occurred. The OS rate, OS time, AFS rate, and AFS time were 82.76% (24/29), (32.31 ± 9.08) months, 37.50% (9/24), and (21.28 ± 13.35) months in the control group and were 78.13% (25/32), (32.47 ± 6.96) months, 68.00% (17/25), and (28.38 ± 9.48) months in the treatment group; all indexes showed no significant differences (P > 0.05). OS rate, OS time, AFS rate, and AFS time showed no significant differences between 2 groups at the other time (P > 0.05) except AFS time at 1 year, which was significantly short in the control group than the treatment group (t = 2.806, P = 0.007). At the endpoint of follow-up, the indexes of GLU, TG, CHOL, LDL-C, HbAlc, SBP, and DBP showed no significant differences between before and after treatments and between 2 groups (P > 0.05) in 49 survival patients (24 in control group and 25 in treatment group). Autologous BM-MNC transplantation is safe and effective in the treatment of critical diabetic lower ASO, which can significantly improve AFS

  17. Rationale and Design for the Intramyocardial Injection of Autologous Bone Marrow Mononuclear Cells for Patients with Chronic Ischemic Heart Disease and Left Ventricular Dysfunction Trial (FOCUS)

    PubMed Central

    Willerson, James T.; Perin, Emerson C.; Ellis, Stephen G.; Pepine, Carl J.; Henry, Timothy D.; Zhao, David X.M.; Lai, Dejian; Penn, Marc S.; Byrne, Barry J.; Silva, G; Gee, Adrian; Traverse, Jay H.; Hatzopoulos, Antonis K.; Forder, John R.; Martin, Daniel; Kronenberg, Marvin; Taylor, Doris A.; Cogle, Christopher R.; Baraniuk, Sarah; Westbrook, Lynette; Sayre, Shelly L.; Vojvodic, Rachel W.; Gordon, David J.; Skarlatos, Sonia I.; Moyé, Lemuel A.; Simari, Robert D.

    2010-01-01

    Background The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide. Trial Design The Cardiovascular Cell Therapy Research Network (CCTRN) was established by the National Institutes of Health to investigate the role of cell therapy in the treatment of chronic cardiovascular disease. FOCUS is a CCTRN-designed randomized Phase II, placebo-controlled clinical trial that will assess the effect of autologous bone marrow mononuclear cells delivered transendocardially to patients with left ventricular (LV) dysfunction and symptomatic heart failure or angina. All patients need to have limiting ischemia by reversible ischemia on SPECT assessment. Results After thoughtful consideration of both statistical and clinical principles, we will recruit 87 patients (58 cell treated and 29 placebo) to receive either bone marrow–derived stem cells or placebo. Myocardial perfusion, LV contractile performance, and maximal oxygen consumption are the primary outcome measures. Conclusions The designed clinical trial will provide a sound assessment of the effect of autologous bone marrow mononuclear cells in improving blood flow and contractile function of the heart. The target population is patients with CAD and LV dysfunction with limiting angina or symptomatic heat failure. Patient safety is a central concern of the CCTRN, and patients will be followed for at least 5 years. PMID:20691824

  18. Bone Marrow Transplantation

    MedlinePlus

    Bone marrow is the spongy tissue inside some of your bones, such as your hip and thigh bones. ... platelets, which help the blood to clot. A bone marrow transplant is a procedure that replaces a person's ...

  19. Comparative study between bone marrow mononuclear fraction and mesenchymal stem cells treatment in sensorimotor recovery after focal cortical ablation in rats.

    PubMed

    de Freitas, Helder Teixeira; da Silva, Viviane Gomes; Giraldi-Guimarães, Arthur

    2012-12-13

    Different models of cortical lesion lead to different effects on plasticity of connections and loss of function. In opposition to ischemia, cortical lesion made by ablation does not induce significant adaptive plasticity of corticocortical and corticostriatal projections and leads to functional alterations other than those observed after ischemia. We have demonstrated sensorimotor recovery after treatment with bone marrow-derived mesenchymal stem cells (MSCs) or bone marrow mononuclear cells (BMMCs) in a model of focal cortical ischemia. Here, we extended this analysis evaluating the effect of these cells on sensorimotor recovery after focal cortical ablation, reproducing the same size and location of previous ischemic lesion. Focal cerebral aspiration of the six cortical layers in left frontoparietal cortex was performed in male Wistar rats. One day later, MSCs or BMMCs were administrated (i.v.) in the ablated animals. Vehicle was administrated in the control group. Sensorimotor tests were performed before and after injury followed by i.v. injection. The monitoring of functional recovery was performed weekly during three post-ablation months. The results showed significant sensorimotor recovery with both treatments, whereas control groups had no recovery. Moreover, both cell types induced the same level of recovery. Bone marrow cells showed therapeutic efficacy in a model of brain injury known to promote low structural plasticity. Thus, the results support the idea of BMMCs as better candidates to treat acute CNS injuries than MSCs, since they have the same therapeutic potential, but its obtainment for autologous transplantation has been shown to be faster and easier.

  20. No evidence of myocardial restoration following transplantation of mononuclear bone marrow cells in coronary bypass grafting surgery patients based upon cardiac SPECT and 18F-PET

    PubMed Central

    Tossios, Paschalis; Müller-Ehmsen, Jochen; Schmidt, Matthias; Scheid, Christof; Ünal, Nermin; Moka, Detlef; Schwinger, Robert HG; Mehlhorn, Uwe

    2006-01-01

    Background We tested the hypothesis, that intramyocardial injection of mononuclear bone marrow cells combined with coronary artery bypass grafting (CABG) surgery improves tissue viability or function in infarct regions with non-viable myocardium as assessed by nuclear imaging techniques. Methods Thus far, 7 patients (60 ± 10 [SD] years) undergoing elective CABG surgery after a myocardial infarction were included in this study. Prior to sternotomy, bone marrow was harvested by sternal puncture. Mononuclear bone marrow cells were isolated by gradient centrifugation and resuspended in 2 ml volume of Hank's buffered salt solution. At the end of CABG surgery 10 injections of 0.2 ml each were applied to the core area and borderzones of the infarct. Global and regional perfusion and viability were evaluated by ECG-gated 99mTc-tetrofosmin myocardial single-photon emission computed tomograph (SPECT) imaging and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in all study patients < 6 days before and 3 months after the intervention. Results Non-viable segments indicating transmural defects were identified in 5 patients. Two patients were found to have non-transmural defects before surgery. Concomitant surgical revascularisation and bone marrow cell injection was performed in all patients without major complications. The median total injected mononuclear cell number was 7.0 × 107 (range: 0.8–20.4). At 3 months 99mTc-tetrofosmin SPECT and 18F-FDG-PET scanning showed in 5 patients (transmural defect n = 4; non-transmural defect n = 1) no change in myocardial viability and in two patients (transmural defect n = 1, non-transmural defect n = 1) enhanced myocardial viability by 75%. Overall, global and regional LV ejection fraction was not significantly increased after surgery compared with the preoperative value. Conclusion In CABG surgery patients with non-viable segments the concurrent use of intramyocardial cell transfer did not show any clear improvement in

  1. Autologous Bone Marrow Mononuclear Cell Therapy is Safe and Promotes Amputation Free Survival in Patients with Critical Limb Ischemia

    PubMed Central

    Murphy, Michael P.; Lawson, Jeffrey H.; Rapp, Brian M.; Dalsing, Michael C.; Klein, Janet; Wilson, Michael G.; Hutchins, Gary D.; March, Keith L.

    2011-01-01

    Objective The purpose of this phase I open label non-randomized trial was to assess the safety and efficacy of autologous bone marrow mononuclear cell (ABMNC) therapy in promoting amputation free survival (AFS) in patients with critical limb ischemia (CLI). Methods Between September 2005 and March 2009 twenty-nine patients (30 limbs), with a median age of 66 (range 23–84) (14 male,15 female) with CLI were enrolled . Twentyone limbs presented with rest pain (RP), six with RP and ulceration, and three with ulcer only. All patients were not candidates for surgical bypass due to absence of a patent artery below the knee and/or endovascular approaches to improving perfusion was not possible as determined by an independent vascular surgeon. Patients were treated with an average dose of 1.7 ± 0.7 × 109 ABMNC injected intramuscularly in the index limb distal to the anterior tibial tuberosity. The primary safety endpoint was accumulation of serious adverse events and the primary efficacy endpoint was AFS at one year. Secondary endpoints at 12 weeks post-treatment were changes in first toe pressure (FTP), toe-brachial index (TBI), ankle-brachial index (ABI), and transcutaneous oxygen measurements (TcPO2). Perfusion of the index limb was measured with PET-CT with intra-arterial infusion of H2O15. Rest pain (RP), using a 10-cm visual analog scale, quality of life using the VascuQuol questionnaire, and ulcer healing were assessed at each follow-up interval. Subpopulations of endothelial progenitor cells were quantified prior to ABMNC administration using immunocytochemistry and fluorescent activated cell sorting. Results There were two serious adverse events however there no procedure related deaths. Amputation-free survival at one-year was 86.3%. There was a significant increase in FTP (10.2+ 6.2 mmHg, P=.02) and TBI (0.10± 0.05, P=.02) and a trend in improvement in ABI (0.08±0.04, P=.73). Perfusion Index by PET-CT H2O15 increased by 19.3 ± 3.1 and RP decreased

  2. Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia.

    PubMed

    Murphy, Michael P; Lawson, Jeffrey H; Rapp, Brian M; Dalsing, Michael C; Klein, Janet; Wilson, Michael G; Hutchins, Gary D; March, Keith L

    2011-06-01

    The purpose of this Phase I open label nonrandomized trial was to assess the safety and efficacy of autologous bone marrow mononuclear cell (ABMNC) therapy in promoting amputation-free survival (AFS) in patients with critical limb ischemia (CLI). Between September 2005 and March 2009, 29 patients (30 limbs), with a median age of 66 years (range, 23-84 years; 14 male, 15 female) with CLI were enrolled. Twenty-one limbs presented with rest pain (RP), six with RP and ulceration, and three with ulcer only. All patients were not candidates for surgical bypass due to absence of a patent artery below the knee and/or endovascular approaches to improving perfusion was not possible as determined by an independent vascular surgeon. Patients were treated with an average dose of 1.7 ± 0.7 × 10(9) ABMNC injected intramuscularly in the index limb distal to the anterior tibial tuberosity. The primary safety end point was accumulation of serious adverse events, and the primary efficacy end point was AFS at 1 year. Secondary end points at 12 weeks posttreatment were changes in first toe pressure (FTP), toe-brachial index (TBI), ankle-brachial index (ABI), and transcutaneous oxygen measurements (TcPO(2)). Perfusion of the index limb was measured with positron emission tomography-computed tomography (PET-CT) with intra-arterial infusion of H(2)O(15). RP, using a 10-cm visual analogue scale, quality of life using the VascuQuol questionnaire, and ulcer healing were assessed at each follow-up interval. Subpopulations of endothelial progenitor cells were quantified prior to ABMNC administration using immunocytochemistry and fluorescent-activated cell sorting. There were two serious adverse events; however, there were no procedure-related deaths. Amputation-free survival at 1 year was 86.3%. There was a significant increase in FTP (10.2 ± 6.2 mm Hg; P = .02) and TBI (0.10 ± 0.05;P = .02) and a trend in improvement in ABI (0.08 ± 0.04; P = .73). Perfusion index by PET-CT H(2)O(15

  3. Comparison of neointimal hyperplasia with drug-eluting stents versus bare metal stents in patients undergoing intracoronary bone-marrow mononuclear cell transplantation following acute myocardial infarction.

    PubMed

    Villa, Adolfo; Arnold, Roman; Sánchez, Pedro L; Gimeno, Federico; Ramos, Benigno; Cantero, Teresa; Fernández, Maria Eugenia; Sanz, Ricardo; Gutiérrez, Oliver; Mota, Pedro; García-Frade, Javier; San Román, José Alberto; Fernández-Avilés, Francisco

    2009-06-15

    The aims of this study were to assess the safety of drug-eluting stent (DES) use and to compare the incidence of in-stent restenosis (ISR) and neointimal hyperplasia formation according to the type of stent implanted (DES vs bare-metal stents [BMS]) in patients who underwent intracoronary bone marrow mononuclear cell transplantation after acute ST elevation myocardial infarction. Fifty-nine patients with successfully revascularized ST elevation myocardial infarction (37 using BMS and 22 using DES) underwent paired angiographic examinations at baseline and 6 to 9 months after the intracoronary injection of 91 million +/- 56 million autologous bone marrow mononuclear cells. A subgroup of 30 patients also underwent serial intravascular ultrasound examinations. Off-line angiographic assessment showed 4 cases of binary ISR, primarily in BMS (3 cases), and no major adverse cardiac events were associated with stent type (mean follow-up period 41 +/- 10 months). At follow-up, angiographic late luminal loss was significantly lower in patients with DES than in those patients with BMS (0.35 +/- 0.66 vs 0.71 +/- 0.38 mm, p = 0.011). Multivariate analysis identified the use of DES (beta = -0.32, 95% confidence interval [CI] -0.57 to -0.26, p = 0.03) and a smaller baseline reference vessel diameter (beta = 0.29, 95% CI 0.04 to 0.54, p = 0.02) as independent predictors of lower late loss. Moreover, intravascular ultrasound showed a significant reduction of in-stent neointimal hyperplasia formation related to DES use compared with BMS use (Delta neointimal hyperplasia volume 5.4 mm(3) [95% CI 2.7 to 28.1] vs 35.9 mm(3) [95% CI 22.0 to 43.6], p = 0.035). In conclusion, these findings suggest that the use of DES is safe and may prevent ISR and neointimal hyperplasia formation in patients who undergo intracoronary bone marrow mononuclear cell transplantation after a successfully revascularized ST elevation myocardial infarction.

  4. Long-term outcomes after transplantation of HLA-identical related G-CSF-mobilized peripheral blood mononuclear cells versus bone marrow.

    PubMed

    Mielcarek, Marco; Storer, Barry; Martin, Paul J; Forman, Stephen J; Negrin, Robert S; Flowers, Mary E; Inamoto, Yoshihiro; Chauncey, Thomas R; Storb, Rainer; Appelbaum, Frederick R; Bensinger, William I

    2012-03-15

    Between 1996 and 1999, 172 patients (median age, 42 years) with hematologic malignancies were randomly assigned to receive either HLA-identical related bone marrow or G-CSF-mobilized peripheral blood mononuclear cells (G-PBMCs) after myeloablative conditioning. Early results showed that transplantation of G-PBMCs, compared with marrow, was associated with significantly superior 2-year disease-free survival (DFS) and overall survival. Ten-year follow-up showed a sustained DFS benefit associated with G-PBMCs (mortality or relapse hazard ratio, 0.64; 95% confidence interval, 0.4-1.0; P = .03), although the likelihood of overall survival was not significantly different between the 2 groups (mortality hazard ratio, 0.75; 95% confidence interval, 0.5-1.2; P = .20). The 10-year cumulative incidence of chronic GVHD and the duration of systemic immunosuppression were similar in the 2 groups. In summary, transplantation of HLA-identical related G-PBMCs, compared with marrow, was associated with superior short-term and long-term DFS, and there was no evidence that this benefit was outweighed by GVHD-related late mortality.

  5. NS-018, a selective JAK2 inhibitor, preferentially inhibits CFU-GM colony formation by bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients.

    PubMed

    Kuroda, Junya; Kodama, Ayumi; Chinen, Yoshiaki; Shimura, Yuji; Mizutani, Shinsuke; Nagoshi, Hisao; Kobayashi, Tsutomu; Matsumoto, Yosuke; Nakaya, Yohei; Tamura, Ayako; Kobayashi, Yutaka; Naito, Haruna; Taniwaki, Masafumi

    2014-05-01

    JAK2/STAT signaling promotes survival and expansion of myelodysplastic syndrome (MDS) clones, but little is known about the potential of JAK2/STAT as a therapeutic target in MDS. We investigated the effect of NS-018, a novel antagonist for JAK2, on the colony-forming ability of bone marrow mononuclear cells (BMMNCs) from high-risk MDS patients. NS-018 decreased colony-forming unit-granulocyte/macrophage (CFU-GM) colony numbers from MDS-derived BMMNCs in a dose-dependent manner, and this effect was significantly more potent than against normal BMMNCs. In addition, NS-018 suppressed the phosphorylation of STAT3 in colony-forming cells from MDS patients. Collectively, NS-018 could be a new therapeutic option for high-risk MDS.

  6. Bone Marrow Diseases

    MedlinePlus

    ... that help with blood clotting. With bone marrow disease, there are problems with the stem cells or ... marrow makes too many white blood cells Other diseases, such as lymphoma, can spread into the bone ...

  7. Comparative study between bone marrow mononuclear fraction and mesenchymal stem cells treatment in sensorimotor recovery after focal cortical ablation in rats

    PubMed Central

    2012-01-01

    Background Different models of cortical lesion lead to different effects on plasticity of connections and loss of function. In opposition to ischemia, cortical lesion made by ablation does not induce significant adaptive plasticity of corticocortical and corticostriatal projections and leads to functional alterations other than those observed after ischemia. We have demonstrated sensorimotor recovery after treatment with bone marrow-derived mesenchymal stem cells (MSCs) or bone marrow mononuclear cells (BMMCs) in a model of focal cortical ischemia. Here, we extended this analysis evaluating the effect of these cells on sensorimotor recovery after focal cortical ablation, reproducing the same size and location of previous ischemic lesion. Findings Focal cerebral aspiration of the six cortical layers in left frontoparietal cortex was performed in male Wistar rats. One day later, MSCs or BMMCs were administrated (i.v.) in the ablated animals. Vehicle was administrated in the control group. Sensorimotor tests were performed before and after injury followed by i.v. injection. The monitoring of functional recovery was performed weekly during three post-ablation months. The results showed significant sensorimotor recovery with both treatments, whereas control groups had no recovery. Moreover, both cell types induced the same level of recovery. Conclusions Bone marrow cells showed therapeutic efficacy in a model of brain injury known to promote low structural plasticity. Thus, the results support the idea of BMMCs as better candidates to treat acute CNS injuries than MSCs, since they have the same therapeutic potential, but its obtainment for autologous transplantation has been shown to be faster and easier. PMID:23237581

  8. A Randomized Comparative Study on the Efficacy of Intracoronary Infusion of Autologous Bone Marrow Mononuclear Cells and Mesenchymal Stem Cells in Patients With Dilated Cardiomyopathy.

    PubMed

    Xiao, Wentao; Guo, Suping; Gao, Chuanyu; Dai, Guoyou; Gao, Yongjv; Li, Muwei; Wang, Xianpei; Hu, Dayi

    2017-02-13

    Stem cell therapy has shown therapeutic benefit in dilated cardiomyopathy (DCM), but doubt remains about the most appropriate stem cell subpopulation. The current study compared the efficacy of intracoronary administration of bone marrow mononuclear cells (BMMC) or mesenchymal stem cells (BMSC) in patients with DCM.Fifty-three patients with DCM and reduced (< 40%) left ventricular ejection fraction (LVEF), were randomized to intracoronary infusion of BMMC (BMMC group, n = 16) or BMSC (BMSC group, n = 17) or equal volume normal saline (CTRL group, n = 20). LVEF, New York Heart Association (NYHA) class, left ventricular end-diastolic diameter (LVEDd), and myocardial perfusion were assessed at baseline and at 3-month and 12-month follow-ups. Major adverse cardiovascular events (MACE) were also recorded.At the 3-month follow-up, LVEF, NYHA class, and myocardial perfusion had improved significantly in the BMSC group (P = 0.004, 0.020 and 0.019, respectively) along with significant changes in LVEF and NYHA class in the BMMC group compared with CTRL (P = 0.042 and 0.047, respectively), however, LVEDd remained unchanged. In comparison with CTRL, LVEF, NYHA class, and myocardial perfusion improved significantly in the BMSC group at the 12-month follow-up (P = 0.005, 0.050 and 0.038 respectively), but not in the BMMC group (P > 0.05). There were no significant differences between the transplantation groups during follow-up (P > 0.05). There were no differences in MACE among the 3 groups (P = 0.817).Intracoronary bone marrow stem cell transplantation in DCM is safe and effective, while BMSC and BMMC infusion possess comparable effectiveness.

  9. Percutaneous Intramyocardial Delivery of Mesenchymal Stem Cells Induces Superior Improvement in Regional Left Ventricular Function Compared with Bone Marrow Mononuclear Cells in Porcine Myocardial Infarcted Heart

    PubMed Central

    Tao, Bo; Cui, Mingliang; Wang, Chen; Ma, Sai; Wu, Feng; Yi, Fu; Qin, Xing; Liu, Junting; Wang, Haichang; Wang, Zhe; Ma, Xiaowei; Tian, Jie; Chen, Yundai; Wang, Jing; Cao, Feng

    2015-01-01

    Aim: To investigate the efficacy and feasibility of percutaneous intramyocardial injection of bone marrow mesenchymal stem cells (MSC) and autologous bone marrow-derived mononuclear cells (BMMNC) on cardiac functional improvement in porcine myocardial infarcted hearts. Methods and Results: Acute myocardial infarction (AMI) was induced in 22 minipigs by temporary balloon occlusion of the left anterior descending coronary artery for 60min.Two weeks post AMI, BMMNC (n = 7, 245 ± 98×106), MSC (n = 8, 56 ± 17×106), or phosphate buffered saline (PBS; n = 7) were injected intramyocardially. Cardiac function and myocardial perfusion were analyzed by echocardiography and gated single-photon emission computed tomography/computed tomography (SPECT/CT) at 1 week before AMI and 2 and 10 weeks after AMI. Cell engraftment, proliferation, vascular density, and cardiac fibrosis were evaluated by histology analysis. In all groups, the echocardiography revealed no significant change in the left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), or left ventricular end-diastolic volume (LVEDV) at 10 weeks after AMI compared with those at 2 weeks after AMI. However, the wall motion score index (WMSI) and left ventricular systolic wall thickening (WT%) were significantly improved at 10 weeks compared with those at 2 weeks after AMI in the MSC group (WMSI 1.55 ± 0.06 vs. 1.87 ± 0.10, WT 33.4 ± 2.3% vs.24.8 ± 2.7%,p < 0.05) but not in the BMMNC group. In addition, myocardial perfusion quantified by SPECT/CT was improved in both the MSC and BMMNC groups, whereas the MSC group showed a superior improvement in vascular density and collagen volume fraction (p < 0.05). Conclusion: This preclinically relevant study suggests that when delivered by percutaneous (transcatheter) intramyocardial injection, MSC might be more effective than BMMNC to improve ischemia and reperfusion after AMI. PMID:25553108

  10. Percutaneous intramyocardial delivery of mesenchymal stem cells induces superior improvement in regional left ventricular function compared with bone marrow mononuclear cells in porcine myocardial infarcted heart.

    PubMed

    Tao, Bo; Cui, Mingliang; Wang, Chen; Ma, Sai; Wu, Feng; Yi, Fu; Qin, Xing; Liu, Junting; Wang, Haichang; Wang, Zhe; Ma, Xiaowei; Tian, Jie; Chen, Yundai; Wang, Jing; Cao, Feng

    2015-01-01

    To investigate the efficacy and feasibility of percutaneous intramyocardial injection of bone marrow mesenchymal stem cells (MSC) and autologous bone marrow-derived mononuclear cells (BMMNC) on cardiac functional improvement in porcine myocardial infarcted hearts. Acute myocardial infarction (AMI) was induced in 22 minipigs by temporary balloon occlusion of the left anterior descending coronary artery for 60 min.Two weeks post AMI, BMMNC (n = 7, 245 ± 98 × 10(6)), MSC (n = 8, 56 ± 17 × 10(6)), or phosphate buffered saline (PBS; n = 7) were injected intramyocardially. Cardiac function and myocardial perfusion were analyzed by echocardiography and gated single-photon emission computed tomography/computed tomography (SPECT/CT) at 1 week before AMI and 2 and 10 weeks after AMI. Cell engraftment, proliferation, vascular density, and cardiac fibrosis were evaluated by histology analysis. In all groups, the echocardiography revealed no significant change in the left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), or left ventricular end-diastolic volume (LVEDV) at 10 weeks after AMI compared with those at 2 weeks after AMI. However, the wall motion score index (WMSI) and left ventricular systolic wall thickening (WT%) were significantly improved at 10 weeks compared with those at 2 weeks after AMI in the MSC group (WMSI 1.55 ± 0.06 vs. 1.87 ± 0.10, WT 33.4 ± 2.3% vs.24.8 ± 2.7%,p < 0.05) but not in the BMMNC group. In addition, myocardial perfusion quantified by SPECT/CT was improved in both the MSC and BMMNC groups, whereas the MSC group showed a superior improvement in vascular density and collagen volume fraction (p < 0.05). This preclinically relevant study suggests that when delivered by percutaneous (transcatheter) intramyocardial injection, MSC might be more effective than BMMNC to improve ischemia and reperfusion after AMI.

  11. Safety and feasibility of cell-based therapy of autologous bone marrow-derived mononuclear cells in plate-stabilized proximal humeral fractures in humans.

    PubMed

    Seebach, Caroline; Henrich, Dirk; Meier, Simon; Nau, Christoph; Bonig, Halvard; Marzi, Ingo

    2016-11-15

    Local implantation of ex vivo concentrated, washed and filtrated human bone marrow-derived mononuclear cells (BMC) seeded onto β-tricalciumphosphate (TCP) significantly enhanced bone healing in a preclinical segmental defect model. Based on these results, we evaluated in a first clinical phase-I trial safety and feasibility of augmentation with preoperatively isolated autologous BMC seeded onto β-TCP in combination with angle stable plate fixation for the therapy of proximal humeral fractures as a potential alternative to autologous bone graft from the iliac crest. 10 patients were enrolled to assess whether cell therapy with 1.3 × 10(6) autologous BMC/ml/ml β-TCP, collected on the day preceding the definitive surgery, is safe and feasible when seeded onto β-TCP in patients with a proximal humeral fracture. 5 follow-up visits for clinical and radiological controls up to 12 weeks were performed. β-tricalciumphosphate fortification with BMC was feasible and safe; specifically, neither morbidity at the harvest site nor at the surgical wound site were observed. Neither local nor systemic inflammation was noted. All fractures healed within the observation time without secondary dislocation. Three adverse events were reported: one case each of abdominal wall shingles, tendon loosening and initial screw perforation, none of which presumed related to the IND. Cell therapy with autologous BMC for bone regeneration appeared to be safe and feasible with no drug-related adverse reactions being described to date. The impression of efficacy was given, although the study was not powered nor controlled to detect such. A clinical trial phase-II will be forthcoming in order to formally test the clinical benefit of BMC-laden β-TCP for PHF patients. Trial registration The study was registered in the European Clinical Trial Register as EudraCT No. 2012-004037-17. Date of registration 30th of August 2012. Informed consent was signed from all patients enrolled.

  12. Intravitreal use of bone marrow mononuclear fraction containing CD34+ stem cells in patients with atrophic age-related macular degeneration

    PubMed Central

    Cotrim, Carina Costa; Toscano, Luiza; Messias, André; Jorge, Rodrigo; Siqueira, Rubens Camargo

    2017-01-01

    Purpose To evaluate the therapeutic potential and safety of intravitreal injections of bone marrow mononuclear fraction (BMMF) containing CD34+ cells in patients with atrophic age-related macular degeneration (AMD). Methods Ten patients with atrophic AMD and best-corrected visual acuity (BCVA) in the worse-seeing eye of ≤20/100 were enrolled in this study. The bone marrow from all patients was aspirated and processed for mononuclear cell separation. A 0.1 mL suspension of BMMF CD34+ cells was injected into the vitreous cavity of the worse-seeing eye. Patients were evaluated at Baseline and 1,3,6,9 and 12 months after injection. Ophthalmic evaluation included BCVA measurement, microperimetry, infrared imaging, fundus autofluorescence and SD-optical coherence tomography at all study visits. Fluorescein angiography was performed at Baseline and at 6 and 12 months after intravitreal therapy. Results All patients completed the 6-month follow-up, and six completed the 12-month follow-up. Prior to the injection, mean BCVA was 1.18 logMAR (20/320−1), ranging from 20/125 to 20/640−2, and improved significantly at every follow-up visit, including the 12-month one, when BCVA was 1.0 logMAR (20/200) (P<0.05). Mean sensitivity threshold also improved significantly at 6, 9 and 12 months after treatment (P<0.05). Considering the area of atrophy identified by fundus autofluorescence, significant mean BCVA and mean sensitivity threshold improvement were observed in patients with the smallest areas of atrophy. Fluorescein angiography did not identify choroidal new vessels or tumor growth. Conclusion The use of intravitreal BMMF injections in patients with AMD is safe and is associated with significant improvement in BCVA and macular sensitivity threshold. Patients with small areas of atrophy have a better response. The paracrine effect of CD34+ cells may explain the functional improvement observed; however, larger series of patients are necessary to confirm these preliminary

  13. Effects of Lycium barbarum Polysaccharides on Apoptosis, Cellular Adhesion, and Oxidative Damage in Bone Marrow Mononuclear Cells of Mice Exposed to Ionizing Radiation Injury

    PubMed Central

    Zhou, Jing; Pang, Hua; Li, Wenbo; Liu, Qiong; Xu, Lu; Liu, Qian; Liu, Ying

    2016-01-01

    Lycium barbarum has been used for more than 2500 years as a traditional herb and food in China. We investigated the effects of Lycium barbarum polysaccharides (LBP) on apoptosis, oxidative damage, and expression of adhesion molecules in bone marrow mononuclear cells (BMNC) of mice injured by ionizing radiation. Kunming mice were exposed to X-rays; then mice in the LBP groups were continuously injected with various concentrations of LBP intraperitoneally for 14 days. Mice in the control group were continuously injected with normal saline (NS) by the same route for 14 days. A normal group was set up. After 1, 7, and 14 days of treatment, mice were killed and BMNC were extracted. Cell cycle, apoptosis, and the expression of adhesion molecules CD44 and CD49d were detected by flow cytometry. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were identified by colorimetric analyses. LBP significantly decreased the percentage of G0/G1 phase, apoptosis, MDA level, and expression of CD44 and CD49d and distinctly increased the activity of SOD. LBP showed a protective effect on BMNC against ionizing radiation-induced apoptosis and oxidative damage and altered the expression of adhesion molecule. PMID:27314019

  14. Bone marrow mononuclear cells migrate to the demyelinated sciatic nerve and transdifferentiate into Schwann cells after nerve injury: attempt at a peripheral nervous system intrinsic repair mechanism.

    PubMed

    Usach, Vanina; Goitia, Belén; Lavalle, Lucía; Martinez Vivot, Rocío; Setton-Avruj, Patricia

    2011-08-01

    In the present work, we analyzed whether endogenous and/or transplanted bone marrow mononuclear cells (BMMC) migrate spontaneously to the crushed sciatic nerve and whether they transdifferentiate into Schwann cells (SC) in order to help repair the damaged tissue. We also studied both the immunohistochemical evolution of myelin proteins MBP and P(0) and the myelin composition of both the proximal and distal stumps of the crushed sciatic nerve to determine the demyelination-remyelination period. Immunohistochemical analysis of crushed animals showed that the degeneration process consists of loss of nerve fiber integrity accompanied by degradation of myelin basic proteins MBP and P(0) , which is anticipated by protein cluster formation. The remyelination process appears as a recovery in nerve fiber structure as well as in MBP and P(0) immunoreactivity; results obtained studying isolated myelin from the crushed sciatic nerve show a strong correlation between them. As opposed to demyelination, axonal damage is observed for a short period of time and takes place mostly in the crush area and the segments adjacent to the lesion. Evidence of spontaneous migration of endogenous or intravascularly transplanted BMMC (CD34(+) and vimentin(+) ) is found during the demyelination period exclusively to the injured sciatic nerve. Once migration takes place, transdifferentiation to SC is observed. Such migration and transdifferentiation processes might be inferred to constitute a spontaneous repair mechanism after nerve injury. Copyright © 2011 Wiley-Liss, Inc.

  15. Trophic activity derived from bone marrow mononuclear cells increases peripheral nerve regeneration by acting on both neuronal and glial cell populations.

    PubMed

    Ribeiro-Resende, V T; Pimentel-Coelho, P M; Mesentier-Louro, L A; Mendez, R M B; Mello-Silva, J P C; Cabral-da-Silva, M C; de Mello, F G; de Melo Reis, R A; Mendez-Otero, R

    2009-03-17

    A rat model of complete sciatic nerve transection was used to evaluate the effect of bone marrow mononuclear cells (BMMC) transplanted to the injury site immediately after lesion. Rats treated with BMMC had both sensory and motor axons reaching the distal stump earlier compared to untreated animals. In addition, BMMC transplantation reduced cell death in dorsal root ganglia (DRG) compared to control animals. Transplanted BMMC remained in the lesion site for several days but there is no evidence of BMMC differentiation into Schwann cells. However, an increase in the number of Schwann cells, satellite cells and astrocytes was observed in the treated group. Moreover, neutralizing antibodies for nerve growth factor (NGF) (but not for brain-derived neurotrophic factor and ciliary-derived neurotrophic factor) added to the BMMC-conditioned medium reduced neurite growth of sensory and sympathetic neurons in vitro, suggesting that BMMC release NGF, improve regeneration of the sciatic nerve in the adult rat and stimulate Schwann and satellite cell proliferation or a combination of both.

  16. Multicenter double blind trial of autologous bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction – MiHeart/AMI study

    PubMed Central

    Dohmann, Hans FR; Silva, Suzana A; Sousa, André LS; Braga, Alcione MS; Branco, Rodrigo VC; Haddad, Andréa F; Oliveira, Mônica A; Moreira, Rodrigo C; Tuche, Fabio AA; Peixoto, Cíntia M; Tura, Bernardo R; Borojevic, Radovan; Ribeiro, Jorge P; Nicolau, José C; Nóbrega, Antonio C; Carvalho, Antonio CC

    2008-01-01

    Background Myocardial infarction remains as a major cause of mortality worldwide and a high rate of survivors develop heart failure as a sequel, resulting in a high morbidity and elevated expenditures for health system resources. We have designed a multicenter trial to test for the efficacy of autologous bone marrow (ABM) mononuclear cell (MC) transplantation in this subgroup of patients. The main hypothesis to be tested is that treated patients will have a significantly higher ejection fraction (EF) improvement after 6 months than controls. Methods A sample of 300 patients admitted with ST elevation acute myocardial infarction (STEMI) and left ventricle (LV) systolic dysfunction, and submitted to successful mechanical or chemical recanalization of the infarct-related coronary artery will be selected for inclusion and randomized to either treated or control group in a double blind manner. The former group will receive 100 × 106 MC suspended in saline with 5% autologous serum in the culprit vessel, while the latter will receive placebo (saline with 5% autologous serum). Implications Many phase I/II clinical trials using cell therapy for STEMI have been reported, demonstrating that cell transplantation is safe and may lead to better preserved LV function. Patients with high risk to develop systolic dysfunction have the potential to benefit more. Larger randomized, double blind and controlled trials to test for the efficacy of cell therapies in patients with high risk for developing heart failure are required. Trial Register This trial is registered at the NIH registry under the number NCT00350766. PMID:18598362

  17. Transplantation of bone marrow mononuclear cells prolongs survival, delays disease onset and progression and mitigates neuronal loss in pre-symptomatic, but not symptomatic ALS mice.

    PubMed

    Venturin, Gianina Teribele; Greggio, Samuel; Zanirati, Gabriele; Marinowic, Daniel Rodrigo; de Oliveira, Iuri Marques; Pêgas Henriques, João Antonio; DaCosta, Jaderson Costa

    2016-10-28

    Cell-based therapy provides a novel strategy to restore lost neurons or modulate the degenerating microenvironment in amyotrophic lateral sclerosis (ALS). This study verified the therapeutic potential of bone marrow mononuclear cells (BMMCs) in SOD1(G93A) mice. BMMCs were obtained from enhanced green fluorescent protein (EGFP) transgenic C57BL/6 mice ((EGFP)BMMCs) or from SOD1(G93A) transgenic mice ((mSOD1)BMMCs) and given to mice at the pre-symptomatic or late symptomatic stage. Survival, body weight and motor performance data were recorded. DNA integrity was evaluated using the alkaline comet assay. The spinal cords were collected to assess motoneuron preservation and cell migration. (EGFP)BMMCs and (mSOD1)BMMCs transplantation to pre-symptomatic SOD1(G93A) mice prolonged survival and delayed disease progression. The effects were more significant for the (EGFP)BMMC-transplanted mice. In late symptomatic mice, (EGFP)BMMCs promoted a discrete increase in survival, without other clinical improvements. DNA from (EGFP)BMMCs and (mSOD1)BMMCs was found in the spinal cords of transplanted animals. DNA damage was not modified by BMMCs in any of the studied groups. Despite positive behavioral effects observed in our study, the limited results we observed for late transplanted mice call for caution before clinical application of BMMCs in ALS.

  18. The effect of autologous bone marrow mononuclear cell transplantation on the survival duration in Amyotrophic Lateral Sclerosis - a retrospective controlled study.

    PubMed

    Sharma, Alok K; Sane, Hemangi M; Paranjape, Amruta A; Gokulchandran, Nandini; Nagrajan, Anjana; D'sa, Myola; Badhe, Prerna B

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with fatal prognosis. Cellular therapy has been studied for ALS in various animal models and these advances have highlighted its potential to be a treatment modality. This is a retrospective controlled cohort study of total 57 patients. Out of these, 37 patients underwent autologous bone marrow mononuclear cell transplantation in addition to standard rehabilitation and Riluzole. Control group consisted of 20 patients who did not receive cell transplantation. The survival duration since the onset of the disease for both the groups was computed using a Kaplan-Meier Survival analysis and compared using log-rank test. Effect of age at onset, type of onset and lithium on survival duration in the intervention group was analyzed. Mean survival duration of patients in intervention group was 87.76 months which was higher than the control group mean survival duration of 57.38 months. Survival duration was significantly (p = 0.039) higher in people with the onset of the disease below 50 years of age. Limb onset and lithium also showed positive influence on the survival duration. Mean survival duration of the intervention group was also higher than the survival duration of ALS patients in previous epidemiological studies. In addition to the standard treatment with Riluzole, early intervention with combination of BMMNCs transplantation and Lithium may have a positive effect on the survival duration in ALS. Prospective randomized controlled studies with a larger sample size and rigorous methodology are required for conclusive findings.

  19. Co-culture of spleen stromal cells with bone marrow mononuclear cells leads to the generation of a novel macrophage subset.

    PubMed

    Wang, X; Li, Y; Xiao, H; Zhang, X; Cao, J; Zhang, D; Zhang, J; Li, X; Shen, B; Wang, Q; Shi, Y

    2014-01-01

    Macrophages adopt diverse activation states depending on the microenvironment. Recently, stromal cells have been demonstrated to be organizers of the microenvironment. Here, using splenic stromal cells to mimic the splenic microenvironment in vivo, we show that spleen stromal cells can programme bone marrow-derived mononuclear cells to differentiate and polarize into a novel macrophage subset. These differentiated macrophages (Diff-Mφ) exhibited pronounced production of IL-10, IL-6 and TNF-α, but diminished the production of IL-12 in response to LPS. The generation of Diff-Mφ depended on cell-cell contact as well as on soluble factors. Diff-Mφ directly suppressed the antigen-non-specific (CD3/CD28) CD4(+) T cell proliferative response and induced cell death of activated CD4(+) T cells. As for cytokine production in CD4(+) T cells, Diff-Mφ promoted IL-10 and IL-17 production, whereas inhibited IL-4 production and did not alter IFN-γ production. Besides, Diff-Mφ also expressed iNOS, CD16/CD32, CD54, CD43, CCR7, CD44, PD-L1 and FasL, which might be involved in the function of Diff-Mφ. These results suggest that splenic microenvironment may physiologically induce a novel type of macrophages differentiation. © 2013 John Wiley & Sons Ltd.

  20. Cell Size Critically Determines Initial Retention of Bone Marrow Mononuclear Cells in the Heart after Intracoronary Injection: Evidence from a Rat Model.

    PubMed

    Campbell, Niall G; Kaneko, Masahiro; Shintani, Yasunori; Narita, Takuya; Sawhney, Vinit; Coppen, Steven R; Yashiro, Kenta; Mathur, Anthony; Suzuki, Ken

    2016-01-01

    Intracoronary injection of bone marrow mononuclear cells (BMMNC) is an emerging treatment for heart failure. Initial donor cell retention in the heart is the key to the success of this approach, but this process remains insufficiently characterized. Although it is assumed that cell size of injected cells may influence their initial retention, no scientific evidence has been reported. We developed a unique model utilizing an ex-vivo rat heart perfusion system, enabling quantitative assessment of retention of donor cells after intracoronary injection. The initial (5 minutes after intracoronary injection) retention rate of BMMNC was as low as approximately 20% irrespective of donor cell doses injected (1×106, 8×106, 4×107). Quantitative cell-size assessment revealed a positive relationship between the size of BMMNC and retention ratio; larger subpopulations of BMMNC were more preferentially retained compared to smaller ones. Furthermore, a larger cell type-bone marrow-derived mesenchymal stromal cells (median size = 11.5μm versus 7.0μm for BMMNC)-had a markedly increased retention rate (77.5±1.8%). A positive relationship between the cell size and retention ratio was also seen in mesenchymal stromal cells. Flow-cytometric studies showed expression of cell-surface proteins, including integrins and selectin-ligands, was unchanged between pre-injection BMMNC and those exited from the heart, suggesting that biochemical interaction between donor cells and host coronary endothelium is not critical for BMMNC retention. Histological analyses showed that retained BMMNC and mesenchymal stromal cells were entrapped in the coronary vasculature and did not extravasate by 60 minutes after transplantation. Whilst BMMNC did not change coronary flow after intracoronary injection, mesenchymal stromal cells reduced it, suggesting coronary embolism, which was supported by the histological finding of intravascular cell-clump formation. These data indicate that cell-size dependent

  1. Comparison of the biological equivalence of two methods for isolating bone marrow mononuclear cells for fabricating tissue-engineered vascular grafts.

    PubMed

    Kurobe, Hirotsugu; Tara, Shuhei; Maxfield, Mark W; Rocco, Kevin A; Bagi, Paul S; Yi, Tai; Udelsman, Brooks V; Dean, Ethan W; Khosravi, Ramak; Powell, Heather M; Shinoka, Toshiharu; Breuer, Christopher K

    2015-06-01

    Our approach for fabricating tissue-engineered vascular grafts (TEVG), applied in the surgical management of congenital heart disease, is accomplished by seeding isolated bone marrow-derived mononuclear cells (BM-MNCs) onto biodegradable scaffolds. The current method used for isolation of BM-MNCs is density centrifugation in Ficoll. This is a time-consuming, labor-intensive, and operator-dependent method. We previously demonstrated that a simpler, faster, and operator-independent method for isolating BM-MNCs using a filter elution technique was feasible. In this study, we compare the use of each technique to determine if the BM-MNCs isolated by the filtration elution method are biologically equivalent to BM-MNCs isolated using density centrifugation. Scaffolds were constructed from a nonwoven poly(glycolic acid) fiber mesh coated with 50:50 poly(l-lactide-co-ɛ-caprolactone) sealant. BM-MNCs were isolated from the bone marrow of syngeneic C57BL/6 mice by either density centrifugation with Ficoll or filtration (Ficoll vs. Filter), then statically seeded onto scaffolds, and incubated overnight. The TEVG were implanted in 10-week-old C57BL/6 mice (n=23 for each group) as inferior vena cava interposition grafts and explanted at 14 days for analysis. At 14 days after implantation, there were no significant differences in graft patency between groups (Ficoll: 87% vs. Filter: 78%, p=0.45). Morphometric analysis by hematoxylin and eosin staining showed no difference of graft luminal diameter or neointimal thickness between groups (luminal diameter, Ficoll: 620.3±82.9 μm vs. Filter: 633.3±131.0 μm, p=0.72; neointimal thickness, Ficoll: 37.9±7.8 μm vs. Filter: 37.9±11.2 μm, p=0.99). Histologic examination demonstrated similar degrees of cellular infiltration and extracellular matrix deposition, and endothelial cell coverage on the luminal surface, in either group. Macrophage infiltration showed no difference in the number of F4/80-positive cells or macrophage

  2. Aspiration and Biopsy: Bone Marrow

    MedlinePlus

    ... Your 1- to 2-Year-Old Aspiration and Biopsy: Bone Marrow KidsHealth > For Parents > Aspiration and Biopsy: Bone Marrow A A A What's in this ... ósea What It Is Bone marrow aspirations and biopsies are performed to examine bone marrow, the spongy ...

  3. Aspiration and Biopsy: Bone Marrow

    MedlinePlus

    ... A Week of Healthy Breakfasts Shyness Aspiration and Biopsy: Bone Marrow KidsHealth > For Teens > Aspiration and Biopsy: Bone Marrow A A A What's in this ... Questions What It Is Bone marrow aspirations and biopsies are performed to examine bone marrow, the spongy ...

  4. c-kit+AT2R+ Bone Marrow Mononuclear Cell Subset Is a Superior Subset for Cardiac Protection after Myocardial Infarction

    PubMed Central

    Du, Mingjun; Zhang, Wentian; Wang, Chenxi; Lian, Feng; Xue, Song

    2016-01-01

    Although the bone marrow mononuclear cell (BMMNC) is known as an ideal cell type for cell-based therapy for MI treatment, the effective subpopulation still remains unknown. Our study aimed at identifying the optimal subset of BMMNCs suited for cardiac regeneration. In this study, we observed that MI led to (i) a significant increase of the c-kit+AT2R+ BMMNC subpopulation in mice and (ii) a modest increase of AT2R+ BMMNCs in humans. c-kit+AT2R+ and c-kit+AT2R− BMMNC subpopulations were obtained from mice after MI. Then, we cocultured cardiac H9C2 cells with c-kit+AT2R+, c-kit+AT2R−, and unfractionated BMMNCs; finally, we found that the c-kit+AT2R+ subset is superior to the c-kit+AT2R− subset in improving cardiomyocyte protection in vitro. Of note, c-kit+AT2R+ BMMNCs showed a more robust migration capacity than c-kit+AT2R− and unfractionated BMMNCs in vitro and in vivo. Additionally, compared to c-kit+AT2R− and unfractionated BMMNCs, intravenous transplantation of c-kit+AT2R+ BMMNC resulted in smaller infarct size and lower levels of inflammatory reactions in heart tissue, leading to a higher global heart function improvement. In conclusion, our results indicate that the c-kit+AT2R+ BMMNC subpopulation exerts a protective effect against MI and shows promising therapeutic possibilities with regard to the treatment of ischemic heart disease. PMID:27429622

  5. Intracoronary autologous bone marrow-derived mononuclear cell transplantation improves coronary collateral vessel formation and recruitment capacity in patients with ischemic cardiomyopathy: a combined hemodynamic and scintigraphic approach.

    PubMed

    Tayyareci, Yelda; Sezer, Murat; Umman, Berrin; Besisik, Sevgi; Mudun, Ayse; Sanli, Yasemin; Oncul, Aytac; Gurses, Nuray; Sargin, Deniz; Meric, Mehmet; Nisanci, Yilmaz

    2008-01-01

    This study investigated the effects of intracoronary autologous bone marrow-derived mononuclear cell (BMC) transplantation on coronary microcirculation. Fifteen patients with ischemic cardiomyopathy were treated by intracoronary infusion of BMCs via the patent infarct-related artery. The thermodilution-derived coronary flow reserve, index of microvascular resistance, pressure-derived collateral flow index, and coronary wedge pressure were measured at baseline and at 6 months. Successive balloon inflations during BMC transplantation were performed to observe the recruitment in pressure-derived collateral flow index and coronary wedge pressure, and the percentage changes between baseline and 6 months were calculated. The mean (SD) coronary flow reserve increased from 1.3 (0.4) to 2.1 (0.5), and the mean (SD) index of microvascular resistance decreased from 44.9 (24.4) to 21.2 (14.1) (P = .001 for both). The mean (SD) improvement in pressure-derived collateral flow index (from 0.14 [0.05] to 0.22 [0.08]) was also statistically significant (P = .001). Similarly, the percentage improvements in pressure-derived collateral flow index and coronary wedge pressure were statistically significant (P = .01 for both). The percentage improvement in perfusion assessed by single-photon emission computed tomography strongly correlated with the percentage changes in pressure-derived collateral flow index (r = 0.88, P = .001) and coronary wedge pressure (r = 0.69, P = .01). These results demonstrate for the first time (to our knowledge) that intracoronary autologous BMC transplantation improves coronary collateral vessel formation and recruitment capacity in human subjects.

  6. Effect of Bone Marrow-Derived Mononuclear Cell Treatment, Early or Late After Acute Myocardial Infarction: Twelve Months CMR and Long-Term Clinical Results.

    PubMed

    Sürder, Daniel; Manka, Robert; Moccetti, Tiziano; Lo Cicero, Viviana; Emmert, Maximilian Y; Klersy, Catherine; Soncin, Sabrina; Turchetto, Lucia; Radrizzani, Marina; Zuber, Michel; Windecker, Stephan; Moschovitis, Aris; Bühler, Ines; Kozerke, Sebastian; Erne, Paul; Lüscher, Thomas F; Corti, Roberto

    2016-07-22

    Intracoronary delivery of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction (AMI). To demonstrate long-term efficacy of BM-MNC treatment after AMI. In a multicenter study, we randomized 200 patients with large AMI in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were either administered 5 to 7 days (early) or 3 to 4 weeks (late) after AMI. Cardiac magnetic resonance imaging was performed at baseline and after 12 months. The current analysis investigates the change from baseline to 12 months in global LV ejection fraction, LV volumes, scar size, and N-terminal pro-brain natriuretic peptide values comparing the 2 treatment groups with control in a linear regression model. Besides the complete case analysis, multiple imputation analysis was performed to address for missing data. Furthermore, the long-term clinical event rate was computed. The absolute change in LV ejection fraction from baseline to 12 months was -1.9±9.8% for control (mean±SD), -0.9±10.5% for the early treatment group, and -0.7±10.1% for the late treatment group. The difference between the groups was not significant, both for complete case analysis and multiple imputation analysis. A combined clinical end point occurred equally in all the groups. Overall, 1-year mortality was low (2.25%). Among patients with AMI and LV dysfunction, treatment with BM-MNC either 5 to 7 days or 3 to 4 weeks after AMI did not improve LV function at 12 months, compared with control. The results are limited by an important drop out rate. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186. © 2016 American Heart Association, Inc.

  7. Assessment of selective homing and contribution to vessel formation of cryopreserved peripherally injected bone marrow mononuclear cells following experimental myocardial damage.

    PubMed

    Ciulla, M M; Ferrero, S; Montelatici, E; Gianelli, U; Braidotti, P; Calderoni, S; Paliotti, R; Annoni, G; De Camilli, E; Busca, G; Magrini, F; Bosari, S; Lazzari, L; Rebulla, P

    2006-09-01

    In view of a potential clinical use we aimed this study to assess the selective homing to the injured myocardium and the definitive fate of peripherally injected labeled and previously cryopreserved Bone Marrow Mononuclear cells (BMMNCs). The myocardial damage (cryoinjury) was produced in 59 rats (45 treated, 14 controls). From 51 donor rats 4.4 x 10(9) BMMNCs were isolated and cryopreserved (slow-cooling protocols); the number of CD34+ and the viability of pooled cells was assessed by flow-cytometry analysis before and after cryopreservation and simulated delivery through a 23G needle. Seven days after injury, BMMNCs were thawed, labeled with PKH26 dye and peripherally injected (20 x 10(6) cells in 500 microl) in recipient rats. Two weeks after experimental injury, the heart, lungs, liver, kidneys, spleen and thymus were harvested to track transplanted cells. Except a small amount in the spleen, PKH26+ cells were found only in the infarcted myocardium of the treated animals. Typical vascular structures CD34+ were found in the infarcted areas of all animals; treated rats showed a significantly higher number of these structures if compared with untreated. Morphological ultra-structural examination of infarcted areas confirmed in treated rats the presence of early-stage PKH26+ vascular structures derived from injected BMMNCs. The estimated mean CD34+ cells loss due to the cryopreservation procedure and to the system of delivery was 0.24% and 0.1%, respectively, confirming the feasibility of the procedure. This study supports the possible therapeutic use of cryopreserved peripherally injecetd BMMNCs as a source of CD34+ independent vascular structures following myocardial damage.

  8. Clonal analysis of multipotent stromal cells derived from CD271+ bone marrow mononuclear cells: functional heterogeneity and different mechanisms of allosuppression

    PubMed Central

    Kuçi, Zyrafete; Seiberth, Julia; Latifi-Pupovci, Hatixhe; Wehner, Sibylle; Stein, Stefan; Grez, Manuel; Bönig, Halvard; Köhl, Ulrike; Klingebiel, Thomas; Bader, Peter; Kuçi, Selim

    2013-01-01

    Previous reports demonstrated a relationship between proliferation potential and trilineage differentiation in mesenchymal stromal cell-derived clones generated using plastic adherence (PA-MSCs). However, there are no reports presenting a clonal analysis of the proliferative potential, differentiation potential and allosuppressive effects of human mesenchymal stromal cell subsets. In this study, we performed a clonal analysis of mesenchymal stromal cells generated from human CD271+ bone marrow mononuclear cells (CD271-MSCs). After transfection with the gene encoding green fluorescent protein, the cells were single-cell sorted and cultured for 2–4 weeks. A population doubling analysis demonstrated that 25% of CD271-MSC clones are fast-proliferating clones compared to only 10% of PA-MSC clones. Evaluation of the allosuppressive potential demonstrated that 81.8% of CD271-MSC clones were highly allosuppressive compared to only 58% of PA-MSC clones. However, no consistent correlation was observed between allosuppression and proliferative potential. Prostaglandin E2 levels were positively correlated with the allosuppressive activity of individual clones, suggesting that this molecule may be a useful predictive biomarker for the allosuppressive potential of mesenchymal stromal cells. In contrast, inhibitory studies of indoleamine 2,3 dioxygenase indicated that none of the clones used this enzyme to mediate their allosuppressive effect. Differentiation studies revealed the presence of tripotent, bipotent and unipotent CD271-MSC and PA-MSC clones which suppressed the allogeneic reaction to differing extents in vitro. In conclusion, our findings demonstrate differences between CD271-MSCs and PA-MSCs and indicate that neither proliferation potential nor differentiation potential represents a consistent predictive parameter for the immunomodulatory effects of either type of mesenchymal stromal cells. PMID:23975178

  9. Intra-Spinal Bone Marrow Mononuclear Cells Transplantation Inhibits the Expression of Nuclear Factor-κB in Acute Transection Spinal Cord Injury in Rats.

    PubMed

    Shrestha, Rajiv Prasad; Qiao, Jian Min; Shen, Fu Guo; Bista, Krishna Bahadur; Zhao, Zhong Nan; Yang, Jianhua

    2014-11-01

    To assess the effect of bone marrow mononuclear cells (BMMNCs) transplantation in the expression of nuclear factor-κB (NF-κB) in spinal cord injury (SCI) in rats. BMMNCs were isolated from tibia and femur by a density gradient centrifugation. After establishment of acute transection SCI, rats were divided into experiment (BMMNCs), experiment control (0.1 M PBS infused) and sham surgery groups (laminectomy without any SCI). Locomotor function was assessed weekly for 5 weeks post-injury using BBB locomotor score and urinary bladder function daily for 4 weeks post-injury. Activity of NF-κB in spinal cord was assessed by immunohistochemistry and reverse transcriptase polymerase chain reaction. At each time point post-injury, sham surgery group had significantly higher Basso, Beattie, Bresnahan locomotor and urinary bladder function scores than experiment and experiment control group (p<0.05). At subsequent time interval there were gradual improvement in both experiment and experiment control group, but experiment group had higher score in comparison to experiment control group (p<0.05). Comparisons were also made for expression of activated NF-κB positive cells and level of NF-κB messenger RNA in spinal cord at various time points between the groups. Activated NF-κB immunoreactivity and level of NF-κB mRNA expression were significantly higher in control group in comparison to experiment and sham surgery group (p<0.05). BMMNCs transplantation attenuates the expression of NF-κB in injured spinal cord tissue and thus helps in recovery of neurological function in rat models with SCI.

  10. Neuroprotection by intravenous transplantation of bone marrow mononuclear cells from 5-fluorouracil pre-treated rats in a model of ischemic stroke.

    PubMed

    Li, Yi; Chen, Chun-Hua; Yin, Yu; Mao, Wen-Wei; Hua, Xu-Ming; Cheng, Juan

    2016-10-01

    Our previous studies showed that bone marrow mononuclear cells (BMMNCs) from 5-fluorouracil (5-FU) pre-treated rats (named BMRMNCs) had a better therapeutic efficacy in ischemia/reperfusion rats as compared to BMMNCs from untreated rats. This study was undertaken to further explore the potential mechanisms underlying the neuroprotective effects of BMRMNCs in the same model. Rats were intravenously pre-treated with 5-FU, and BMRMNCs were collected 7 days later and subjected to flow cytometry for detection of CD34, CD45 and CD90. Middle cerebral artery occlusion (MCAO) was induced in rats, and BMMNCs and BMRMNCs were independently transplanted via the tail vein at 24 h after MCAO. NISSL staining was performed 14 days after cell transplantation and the viable cells in the hippocampus were counted. Stromal cell-derived factor 1 (SDF-1) mRNA expression was detected in the penumbra at 7 and 14 days after treatment. The contents of pro-inflammatory cytokines and growth factors as well as microvessel density (MVD) were determined at 14 days. Results showed more BMRMNCs were positive for CD34, CD45 and CD90. After transplantation, more viable cells were observed in the hippocampus of BMRMNCs treated rats. In addition, BMRMNCs transplantation significantly increased MVD, reduced pro-inflammatory cytokines and raised growth factors in the penumbra. However, the SDF-1 mRNA expression was comparable between BMRMNCs group and BMMNCs group. Our results indicate that BMRMNCs are likely to more effectively improve the local microenvironment to increase viable cells and elevate angiogenesis, exerting neuroprotective effects on cerebral ischemia in rats.

  11. Bone marrow biopsy

    MedlinePlus

    ... myelodysplastic syndrome; MDS) A nerve tissue tumor called neuroblastoma Bone marrow disease that leads to an abnormal ... Hairy cell leukemia Hodgkin lymphoma Multiple myeloma Myelofibrosis Neuroblastoma Non-Hodgkin lymphoma Platelet count Polycythemia vera Primary ...

  12. Effects of Aging and Hypercholesterolemia on Oxidative Stress and DNA Damage in Bone Marrow Mononuclear Cells in Apolipoprotein E-deficient Mice

    PubMed Central

    Tonini, Clarissa L.; Campagnaro, Bianca P.; Louro, Lis P. S.; Pereira, Thiago M. C.; Vasquez, Elisardo C.; Meyrelles, Silvana S.

    2013-01-01

    Recent evidence from apolipoprotein E-deficient (apoE−/−) mice shows that aging and atherosclerosis are closely associated with increased oxidative stress and DNA damage in some cells and tissues. However, bone marrow cells, which are physiologically involved in tissue repair have not yet been investigated. In the present study, we evaluated the influence of aging and hypercholesterolemia on oxidative stress, DNA damage and apoptosis in bone marrow cells from young and aged apoE−/− mice compared with age-matched wild-type C57BL/6 (C57) mice, using the comet assay and flow cytometry. The production of both superoxide and hydrogen peroxide in bone marrow cells was higher in young apoE−/− mice than in age-matched C57 mice, and reactive oxygen species were increased in aged C57 and apoE−/− mice. Similar results were observed when we analyzed the DNA damage and apoptosis. Our data showed that both aging and hypercholesterolemia induce the increased production of oxidative stress and consequently DNA damage and apoptosis in bone marrow cells. This study is the first to demonstrate a functionality decrease of the bone marrow, which is a fundamental extra-arterial source of the cells involved in vascular injury repair. PMID:23385237

  13. Bone and bone marrow: the same organ.

    PubMed

    Del Fattore, Andrea; Capannolo, Marta; Rucci, Nadia

    2010-11-01

    Interplays between bone and bone marrow are not limited to merely anatomic and histological connections, but include a tight functional correlation. Bone marrow resides within the medullary cavity of the bones and the process of hematopoiesis is regulated, at least in part, by bone cells. Moreover, osteoclasts and osteoblasts derive from precursors of hematopoietic and mesenchymal origin, respectively, both residing within the bone marrow. Alterations in one of these components typically cause impairment in the other, so diseases of the bone marrow compartment often affect the bone and vice versa. All these findings could make us to speculate that bone and bone marrow are not two separate districts, but can be considered as the two elements of the same unique functional unit, the bone-bone marrow organ. Here we will describe histological and functional interplays between bone and bone marrow, and will illustrate some diseases in which this tight correlation is evident.

  14. Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Ischemic Heart Failure: The FOCUS-CCTRN Trial

    PubMed Central

    Perin, Emerson C.; Willerson, James T.; Pepine, Carl J.; Henry, Timothy D.; Ellis, Stephen G.; Zhao, David X.M.; Silva, Guilherme V.; Lai, Dejian; Thomas, James D.; Kronenberg, Marvin W.; Martin, A. Daniel; Anderson, R. David; Traverse, Jay H.; Penn, Marc S.; Anwaruddin, Saif; Hatzopoulos, Antonis K.; Gee, Adrian P.; Taylor, Doris A.; Cogle, Christopher R.; Smith, Deirdre; Westbrook, Lynette; Chen, James; Handberg, Eileen; Olson, Rachel E.; Geither, Carrie; Bowman, Sherry; Francescon, Judy; Baraniuk, Sarah; Piller, Linda B.; Simpson, Lara M.; Loghin, Catalin; Aguilar, David; Richman, Sara; Zierold, Claudia; Bettencourt, Judy; Sayre, Shelly L.; Vojvodic, Rachel W.; Skarlatos, Sonia I.; Gordon, David J.; Ebert, Ray F.; Kwak, Minjung; Moyé, Lemuel A.; Simari, Robert D.

    2013-01-01

    Context Previous studies utilizing autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. The FOCUS protocol was designed to assess efficacy of a larger cell dose in an adequately well-powered phase II study. Objective To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular (LV) end systolic volume, or enhances maximal oxygen consumption in patients with coronary artery disease (CAD), LV dysfunction, and limiting heart failure and/or angina. Design, Setting, and Patients This is a 100 million cell, first-in-man randomized, double-blind, placebo-controlled trial was performed by the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) in symptomatic patients (NYHA II-III and/or CCS II-IV) receiving maximal medical therapy, with a left ventricular ejection fraction (LVEF)≤45%, perfusion defect by single-photon emission tomography (SPECT), and CAD not amenable to revascularization. Intervention All patients underwent bone marrow aspiration, isolation of BMCs using a standardized automated system performed locally, and transendocardial injection of 100 million BMCs or placebo (2:1 BMC: placebo). Main Outcome Measures Three co-primary endpoints assessed at 6 months were changes in (a) LV end systolic volume (LVESV) by echocardiography, (b) maximal oxygen consumption (MVO2), and (c) reversibility on SPECT. Secondary measures included other SPECT measures, magnetic resonance imaging (MRI), echocardiography, clinical improvement, and major adverse cardiac events (MACE). Phenotypic and functional analyses of the cell product were performed by the CCTRN Biorepository lab. Results Of 153 consented patients, a total of 92 (82 men; average age, 63 years) were randomized (n= 61 BMC, 31 placebo) at 5 sites between April 29, 2009 and April 18, 2011. Changes in LVESV index

  15. Aspiration and Biopsy: Bone Marrow

    MedlinePlus

    ... 1- to 2-Year-Old Aspiration and Biopsy: Bone Marrow KidsHealth > For Parents > Aspiration and Biopsy: Bone Marrow Print A A A What's in this article? ... Aspiraciones y biopsias: médula ósea What It Is Bone marrow aspirations and biopsies are performed to examine bone ...

  16. Efficacy of Autologous Bone Marrow-Derived Mesenchymal Stem Cell and Mononuclear Cell Transplantation in Type 2 Diabetes Mellitus: A Randomized, Placebo-Controlled Comparative Study.

    PubMed

    Bhansali, Shobhit; Dutta, Pinaki; Kumar, Vinod; Yadav, Mukesh Kumar; Jain, Ashish; Mudaliar, Sunder; Bhansali, Shipra; Sharma, Ratti Ram; Jha, Vivekanand; Marwaha, Neelam; Khandelwal, Niranjan; Srinivasan, Anand; Sachdeva, Naresh; Hawkins, Meredith; Bhansali, Anil

    2017-04-01

    Drugs targeting β-cells have provided new options in the management of T2DM; however, their role in β-cell regeneration remains elusive. The recent emergence of cell-based therapies such as autologous bone marrow-derived mesenchymal stem cells (ABM-MSCs) and mononuclear cells (ABM-MNCs) seems to offer a pragmatic approach to augment β-cell function/mass. This study aims to examine the efficacy and safety of ABM-MSC and ABM-MNC transplantation in T2DM and explores alterations in glucose-insulin homeostasis by metabolic studies. Thirty patients of T2DM with duration of disease ≥5 years, receiving triple oral antidiabetic drugs along with insulin (≥0.4 IU/Kg/day) with HbA1c ≤7.5%(≤58.0 mmol/mol), were randomized to receive ABM-MSCs or ABM-MNCs through targeted approach and a sham procedure (n = 10 each). The primary endpoint was a reduction in insulin requirement by ≥50% from baseline, while maintaining HbA1c <7.0% (<53.0 mmol/mol) during 1-year follow-up. Six of 10 (60%) patients in both the ABM-MSC and ABM-MNC groups, but none in the control group, achieved the primary endpoint. At 12 months, there was a significant reduction in insulin requirement in ABM-MSC (P < 0.05) and ABM-MNC groups (P < 0.05), but not in controls (P = 0.447). There was a significant increase in second-phase C-peptide response during hyperglycemic clamp in the ABM-MNC (P < 0.05) group, whereas a significant improvement in insulin sensitivity index (P < 0.05) accompanied with an increase in insulin receptor substrate-1 gene expression was observed in the ABM-MSC group. In conclusion, both ABM-MSCs and ABM-MNCs result in sustained reduction in insulin doses in T2DM. Improvement in insulin sensitivity with MSCs and increase in C-peptide response with MNCs provide newer insights in cell-based therapies.

  17. Autologous bone marrow-derived mononuclear cells transplantation in type 2 diabetes mellitus: effect on β-cell function and insulin sensitivity.

    PubMed

    Bhansali, Shobhit; Dutta, Pinaki; Yadav, Mukesh Kumar; Jain, Ashish; Mudaliar, Sunder; Hawkins, Meredith; Kurpad, Anura V; Pahwa, Deepak; Yadav, Ashok Kumar; Sharma, Ratti Ram; Jha, Vivekanand; Marwaha, Neelam; Bhansali, Shipra; Bhansali, Anil

    2017-01-01

    Insulin resistance and insulin deficiency are the cardinal defects in the pathogenesis of type 2 diabetes mellitus (T2DM). Despite the plethora of anti-diabetic medications, drugs specifically targeting the β-cells are still desired. Stem cell therapy has emerged as a novel therapeutics strategy to target β-cells; however, their mechanism of action has not been well defined. This study aims to examine the efficacy and safety of autologous bone marrow-derived mononuclear cells (ABM-MNCs) transplantation in T2DM, and explores the mechanistic insights into stem cells action through metabolic studies. Seven T2DM patients with the duration of disease ≥5 years, receiving triple oral anti-diabetic drugs along with insulin (≥0.4 IU per kg per day) and HbA1c ≤ 7.5% (≤58.0 mmol/mol) were enrolled for ABM-MNCs administration through a targeted approach. The primary end-point was a reduction in insulin requirement by ≥50% from baseline, while maintaining HbA1c < 7.0% (<53.0 mmol/mol) with improvement in insulin secretion, and/or insulin sensitivity after ABM-MNCs transplantation. Six out of 7 (90%) patients achieved the primary end-point. At 6 months, there was a significant reduction in insulin requirement by 51% as compared to baseline (p < 0.003). This was accompanied by a significant increase in the 2nd phase C-peptide response during hyperglycemic clamp (p = 0.018), whereas there were no significant alterations in insulin sensitivity and glucose disposal rate during hyperinsulinemic-euglycemic clamp relative to the baseline. Other measures of β-cell indices like HOMA-β, and stimulated C-peptide response to glucagon and mixed meal tolerance test were non-contributory. ABM-MNCs transplantation results in significant reduction in insulin doses and improvement in C-peptide response in patients with T2DM. Metabolic studies may be more useful than conventional indices to predict β-cell function in patients with advanced duration of T2DM. Trial

  18. Extracellular high mobility group box 1 plays a role in the effect of bone marrow mononuclear cell transplantation for heart failure.

    PubMed

    Kaneko, Masahiro; Shintani, Yasunori; Narita, Takuya; Ikebe, Chiho; Tano, Nobuko; Yamahara, Kenichi; Fukushima, Satsuki; Coppen, Steven R; Suzuki, Ken

    2013-01-01

    Transplantation of unfractionated bone marrow mononuclear cells (BMCs) repairs and/or regenerates the damaged myocardium allegedly due to secretion from surviving BMCs (paracrine effect). However, donor cell survival after transplantation is known to be markedly poor. This discrepancy led us to hypothesize that dead donor BMCs might also contribute to the therapeutic benefits from BMC transplantation. High mobility group box 1 (HMGB1) is a nuclear protein that stabilizes nucleosomes, and also acts as a multi-functional cytokine when released from damaged cells. We thus studied the role of extracellular HMGB1 in the effect of BMC transplantation for heart failure. Four weeks after coronary artery ligation in female rats, syngeneic male BMCs (or PBS only as control) were intramyocardially injected with/without anti-HMGB1 antibody or control IgG. One hour after injection, ELISA showed that circulating extracellular HMGB1 levels were elevated after BMC transplantation compared to the PBS injection. Quantitative donor cell survival assessed by PCR for male-specific sry gene at days 3 and 28 was similarly poor. Echocardiography and catheterization showed enhanced cardiac function after BMC transplantation compared to PBS injection at day 28, while this effect was abolished by antibody-neutralization of HMGB1. BMC transplantation reduced post-infarction fibrosis, improved neovascularization, and increased proliferation, while all these effects in repairing the failing myocardium were eliminated by HMGB1-inhibition. Furthermore, BMC transplantation drove the macrophage polarization towards alternatively-activated, anti-inflammatory M2 macrophages in the heart at day 3, while this was abolished by HMGB1-inhibition. Quantitative RT-PCR showed that BMC transplantation upregulated expression of an anti-inflammatory cytokine IL-10 in the heart at day 3 compared to PBS injection. In contrast, neutralizing HMGB1 by antibody-treatment suppressed this anti-inflammatory expression

  19. Long-Term Outcome of Combined (Percutaneous Intramyocardial and Intracoronary) Application of Autologous Bone Marrow Mononuclear Cells Post Myocardial Infarction: The 5-Year MYSTAR Study

    PubMed Central

    Syeda, Bonni; Charwat, Silvia; Marzluf, Beatrice; Mascherbauer, Julia; Jakab, Andras; Zimba, Abelina; Sárközy, Márta; Pavo, Noemi; Sochor, Heinz; Graf, Senta; Lang, Irene; Maurer, Gerald; Bergler-Klein, Jutta

    2016-01-01

    Objective The long-term (5-year) outcome of early (3–6 weeks after acute myocardial infarction [AMI], BM-MNC Early group) and late (3–4 months after AMI, BM-MNC Late group) combined (percutaneous intramyocardial and intracoronary) delivery of autologous bone marrow mononuclear cells (BM-MNCs) was evaluated in patients with ejection fractions (EF) between 30–45% post-AMI. Methods Major adverse cardiac and cerebrovascular events (MACCE) and hospitalization were recorded. Left (LV) and right (RV) ventricular function were measured by transthoracic echocardiography. Cardiac magnetic resonance imaging (MRI) and myocardial single photon emission computed tomography was performed in a subgroup of patients. Pre-cell therapy myocardial voltage values of treated areas (assessed by NOGA mapping) were correlated with clinical outcome. Results Five-year MACCE incidences (7.4%. vs 24.1%) and the composite of all adverse events (11.1% vs 27.6%) were not different between the Early and Late treatment groups. The significant LV-EF increase at 1-year follow-up was preserved at the 5-year control (from baseline to 5-year: 5.3%, 95% CI:0.5–10.1, and 5.7%, 95% CI:1.7–9.6, p<0.05 in the Early and Late groups, respectively), with no significant changes between 1- and 5-year follow-ups. Similarly, RVEF increased significantly from baseline to the 5-year follow-up (Early group: 5.4%, 95% CI:1.0–9.6; and Late group: 8.4%, 95% CI:4.5–12.3). Lower baseline levels of myocardial viability of the treated cardiac area (6.3±2.4 vs 8.2±3.0 mV, p<0.05) were associated with incidence of MACCE. Conclusions Percutaneous combined delivery of autologous BM-MNCs is feasible and safe after 5 years, and may result in sustained improvement of cardiac function at 5 years in patients with low EF post-AMI (Clinicaltrials.gov NCT01395212). PMID:27764157

  20. Long-Term Outcome of Combined (Percutaneous Intramyocardial and Intracoronary) Application of Autologous Bone Marrow Mononuclear Cells Post Myocardial Infarction: The 5-Year MYSTAR Study.

    PubMed

    Gyöngyösi, Mariann; Giurgea, Georgiana-Aura; Syeda, Bonni; Charwat, Silvia; Marzluf, Beatrice; Mascherbauer, Julia; Jakab, Andras; Zimba, Abelina; Sárközy, Márta; Pavo, Noemi; Sochor, Heinz; Graf, Senta; Lang, Irene; Maurer, Gerald; Bergler-Klein, Jutta

    2016-01-01

    The long-term (5-year) outcome of early (3-6 weeks after acute myocardial infarction [AMI], BM-MNC Early group) and late (3-4 months after AMI, BM-MNC Late group) combined (percutaneous intramyocardial and intracoronary) delivery of autologous bone marrow mononuclear cells (BM-MNCs) was evaluated in patients with ejection fractions (EF) between 30-45% post-AMI. Major adverse cardiac and cerebrovascular events (MACCE) and hospitalization were recorded. Left (LV) and right (RV) ventricular function were measured by transthoracic echocardiography. Cardiac magnetic resonance imaging (MRI) and myocardial single photon emission computed tomography was performed in a subgroup of patients. Pre-cell therapy myocardial voltage values of treated areas (assessed by NOGA mapping) were correlated with clinical outcome. Five-year MACCE incidences (7.4%. vs 24.1%) and the composite of all adverse events (11.1% vs 27.6%) were not different between the Early and Late treatment groups. The significant LV-EF increase at 1-year follow-up was preserved at the 5-year control (from baseline to 5-year: 5.3%, 95% CI:0.5-10.1, and 5.7%, 95% CI:1.7-9.6, p<0.05 in the Early and Late groups, respectively), with no significant changes between 1- and 5-year follow-ups. Similarly, RVEF increased significantly from baseline to the 5-year follow-up (Early group: 5.4%, 95% CI:1.0-9.6; and Late group: 8.4%, 95% CI:4.5-12.3). Lower baseline levels of myocardial viability of the treated cardiac area (6.3±2.4 vs 8.2±3.0 mV, p<0.05) were associated with incidence of MACCE. Percutaneous combined delivery of autologous BM-MNCs is feasible and safe after 5 years, and may result in sustained improvement of cardiac function at 5 years in patients with low EF post-AMI (Clinicaltrials.gov NCT01395212).

  1. Effect of intramyocardial delivery of autologous bone marrow mononuclear stem cells on the regional myocardial perfusion. NOGA-guided subanalysis of the MYSTAR prospective randomised study.

    PubMed

    Charwat, Silvia; Lang, Irene; Dettke, Markus; Graf, Senta; Nyolczas, Noemi; Hemetsberger, Rayyan; Zamini, Sholeh; Khorsand, Aliasghar; Sochor, Heinz; Maurer, Gerald; Glogar, Dietmar; Gyöngyösi, Mariann

    2010-03-01

    The aim of the sub-study of the MYSTAR randomised trial was to analyse the changes in myocardial perfusion in NOGA-defined regions of interest (ROI) with intramyocardial injections of autologous bone marrow mononuclear cells (BM-MNC) using an elaborated transformation algorithm. Patients with recent first acute myocardial infarction (AMI) and left ventricular (LV) ejection fraction (EF) between 30-45% received BM-MNC by intramyocardial followed by intracoronary injection 68 +/- 34 days post-AMI (pooled data of MYSTAR). NOGA-guided endocardial mapping and 99m-Sestamibi-SPECT (single photon emission computer tomography) were performed at baseline and at three months follow-up (FUP). ROI was delineated as a best polygon by connecting of injection points of NOGA polar maps. ROIs were projected onto baseline and FUP polar maps of SPECT calculating the perfusion severity of ROI. Infarct size was decreased (from 27.2 +/- 10.7% to 24.1 +/- 11.5%, p<0.001), and global EF increased (from 38 +/- 6.1% to 41.5 +/- 8.4%, p<0.001) three months after BM-MNC delivery. Analysis of ROI resulted in a significant increase in unipolar voltage (index of myocardial viability) (from 7.9 +/- 3.0 mV to 9.9 +/- 2.7 mV at FUP, p<0.001) and local linear shortening (index of local wall motion disturbances) (from 11.0 +/- 3.9% to 12.7 +/- 3.4%, p=0.01). NOGA-guided analysis of the intramyocardially treated area revealed a significantly increased tracer uptake both at rest (from 56.7 +/- 16.1% to 62.9 +/- 14.2%, p=0.003) and at stress (from 59.3 +/- 14.2% to 62.3 +/- 14.9%, p=0.01). Patients exhibiting >or=5% improvement in perfusion defect severity received a significantly higher number of intramyocardial BM-MNC. In conclusion, combined cardiac BM-MNC delivery induces significant improvement in myocardial viability and perfusion in the intramyocardially injected area.

  2. Bone-marrow transplant - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100112.htm Bone-marrow transplant - series—Normal anatomy To use the sharing ... Go to slide 4 out of 4 Overview Bone-marrow is a soft, fatty tissue found inside of ...

  3. Marrow-tumor interactions: the role of the bone marrow in controlling chemically induced tumors

    SciTech Connect

    Rosse, C

    1980-01-01

    This report summarizes work done to evaluate the role of the bone marrow in tumor growth regulation. Work done with the MCA tumor showed that several subclasses of mononuclear bone marrow cells (e.g. natural regulatory cell, NRC) play a major role in the regulation of tumor growth. Experiments with the spontaneous CE mammary carcinoma system illustrate that a rapid growth of certain neoplasms may be due to the fact that through some as yet undefined mechanism the tumor eliminates mononuclear cells in the bone marrow of the host and stops their production. (KRM)

  4. CD11b+ and Sca-1+ Cells Exert the Main Beneficial Effects of Systemically Administered Bone Marrow-Derived Mononuclear Cells in a Murine Model of Mixed Th2/Th17 Allergic Airway Inflammation.

    PubMed

    Cruz, Fernanda F; Borg, Zachary D; Goodwin, Meagan; Coffey, Amy L; Wagner, Darcy E; Rocco, Patricia R M; Weiss, Daniel J

    2016-04-01

    Systemic administration of bone marrow-derived mononuclear cells (BMDMCs) or bone marrow-derived mesenchymal stromal cells (MSCs) reduces inflammation and airway hyperresponsiveness (AHR) in a murine model of Th2-mediated eosinophilic allergic airway inflammation. However, since BMDMCs are a heterogeneous population that includes MSCs, it is unclear whether the MSCs alone are responsible for the BMDMC effects. To determine which BMDMC population(s) is responsible for ameliorating AHR and lung inflammation in a model of mixed Th2-eosinophilic and Th17-neutrophilic allergic airway inflammation, reminiscent of severe clinical asthma, BMDMCs obtained from normal C57Bl/6 mice were serially depleted of CD45, CD34, CD11b, CD3, CD19, CD31, or Sca-1 positive cells. The different resulting cell populations were then assessed for ability to reduce lung inflammation and AHR in mixed Th2/Th17 allergic airway inflammation induced by mucosal sensitization to and challenge with Aspergillus hyphal extract (AHE) in syngeneic C56Bl/6 mice. BMDMCs depleted of either CD11b-positive (CD11b+) or Sca-1-positive (Sca-1+) cells were unable to ameliorate AHR or lung inflammation in this model. Depletion of the other cell types did not diminish the ameliorating effects of BMDMC administration. In conclusion, in the current model of allergic inflammation, CD11b+ cells (monocytes, macrophages, dendritic cells) and Sca-1+ cells (MSCs) are responsible for the beneficial effects of BMDMCs. This study shows that bone marrow-derived mononuclear cells (BMDMCs) are as effective as bone marrow-derived mesenchymal stromal cells (MSCs) in ameliorating experimental asthma. It also demonstrates that not only MSCs present in the pool of BMDMCs are responsible for BMDMCs' beneficial effects but also monocytes, which are the most important cell population to trigger these effects. All of this is in the setting of a clinically relevant model of severe allergic airways inflammation and thus provides further

  5. Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells.

    PubMed

    Hu, Kejin; Yu, Junying; Suknuntha, Kran; Tian, Shulan; Montgomery, Karen; Choi, Kyung-Dal; Stewart, Ron; Thomson, James A; Slukvin, Igor I

    2011-04-07

    Reprogramming blood cells to induced pluripotent stem cells (iPSCs) provides a novel tool for modeling blood diseases in vitro. However, the well-known limitations of current reprogramming technologies include low efficiency, slow kinetics, and transgene integration and residual expression. In the present study, we have demonstrated that iPSCs free of transgene and vector sequences could be generated from human BM and CB mononuclear cells using non-integrating episomal vectors. The reprogramming described here is up to 100 times more efficient, occurs 1-3 weeks faster compared with the reprogramming of fibroblasts, and does not require isolation of progenitors or multiple rounds of transfection. Blood-derived iPSC lines lacked rearrangements of IGH and TCR, indicating that their origin is non-B- or non-T-lymphoid cells. When cocultured on OP9, blood-derived iPSCs could be differentiated back to the blood cells, albeit with lower efficiency compared to fibroblast-derived iPSCs. We also generated transgene-free iPSCs from the BM of a patient with chronic myeloid leukemia (CML). CML iPSCs showed a unique complex chromosomal translocation identified in marrow sample while displaying typical embryonic stem cell phenotype and pluripotent differentiation potential. This approach provides an opportunity to explore banked normal and diseased CB and BM samples without the limitations associated with virus-based methods.

  6. Detection of the Epstein-Barr virus in blood and bone marrow mononuclear cells of patients with aggressive B-cell non-Hodgkin’s lymphoma is not associated with prognosis

    PubMed Central

    MARQUES, HERLANDER; CATARINO, RAQUEL; DOMINGUES, NELSON; BARROS, ELIANE; PORTELA, CATARINA; ALMEIDA, MARIA INÊS; COSTA, SANDRA; REIS, RUI MANUEL; MEDEIROS, RUI; LONGATTO-FILHO, ADHEMAR

    2012-01-01

    The Epstein-Barr virus (EBV) is associated with a large spectrum of lymphoproliferative diseases. Traditional methods of EBV detection include the immunohistochemical identification of viral proteins and DNA probes to the viral genome in tumoral tissue. The present study explored the detection of the EBV genome, using the BALF5 gene, in the bone marrow or blood mononuclear cells of patients with diffuse large B-cell lymphomas (DLBCL) and related its presence to the clinical variables and risk factors. The results show that EBV detection in 21.5% of patients is not associated with age, gender, staging, B symptoms, international prognostic index scores or any analytical parameters, including lactate dehydrogenase (LDH) or β-2 microglobulin (B2M). The majority of patients were treated with R-CHOP-like (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone or an equivalent combination) and some with CHOP-like chemotherapy. Response rates [complete response (CR) + partial response (PR)] were not significantly different between EBV-negative and -positive cases, with 93.2 and 88.9%, respectively. The survival rate was also similar in the two groups, with 5-year overall survival (OS) rates of 64.3 and 76.7%, respectively. However, when analyzing the treatment groups separately there was a trend in EBV-positive patients for a worse prognosis in patients treated with CHOP-like regimens that was not identified in patients treated with R-CHOP-like regimens. We conclude that EBV detection in the bone marrow and blood mononuclear cells of DLBC patients has the same frequency of EBV detection on tumoral lymphoma tissue but is not associated with the risk factors, response rate and survival in patients treated mainly with immunochemotherapy plus rituximab. These results also suggest that the addition of rituximab to chemotherapy improves the prognosis associated with EBV detection in DLBCL. PMID:23226803

  7. LateTIME: a phase-II, randomized, double-blinded, placebo-controlled, pilot trial evaluating the safety and effect of administration of bone marrow mononuclear cells 2 to 3 weeks after acute myocardial infarction.

    PubMed

    Traverse, Jay H; Henry, Timothy D; Vaughan, Douglas E; Ellis, Stephen G; Pepine, Carl J; Willerson, James T; Zhao, David X M; Simpson, Lara M; Penn, Marc S; Byrne, Barry J; Perin, Emerson C; Gee, Adrian P; Hatzopoulos, Antonis K; McKenna, David H; Forder, John R; Taylor, Doris A; Cogle, Christopher R; Baraniuk, Sarah; Olson, Rachel E; Jorgenson, Beth C; Sayre, Shelly L; Vojvodic, Rachel W; Gordon, David J; Skarlatos, Sonia I; Moyè, Lemuel A; Simari, Robert D

    2010-01-01

    A realistic goal for cardiac cell therapy may be to attenuate left ventricular remodeling following acute myocardial infarction to prevent the development of congestive heart failure. Initial clinical trials of cell therapy have delivered cells 1 to 7 days after acute myocardial infarction. However, many patients at risk of developing congestive heart failure may not be ready for cell delivery at that time-point because of clinical instability or hospitalization at facilities without access to cell therapy. Experience with cell delivery 2 to 3 weeks after acute myocardial infarction has not to date been explored in a clinical trial. The objective of the LateTIME study is to evaluate by cardiac magnetic resonance the effect on global and regional left ventricular function, between baseline and 6 months, of a single intracoronary infusion of 150 × 106 autologous bone marrow mononuclear cells (compared with placebo) when that infusion is administered 2 to 3 weeks after moderate-to-large acute myocardial infarction. The 5 clinical sites of the Cardiovascular Cell Therapy Research Network (CCTRN) will enroll a total of 87 eligible patients in a 2:1 bone marrow mononuclear cells-to-placebo patient ratio; these 87 will have undergone successful percutaneous coronary intervention of a major coronary artery and have left ventricular ejection fractions ≤0.45 by echocardiography. When the results become available, this study should provide insight into the clinical feasibility and appropriate timing of autologous cell therapy in high-risk patients after acute myocardial infarction and percutaneous coronary intervention.

  8. Bone and bone marrow involvement in sarcoidosis.

    PubMed

    Yachoui, Ralph; Parker, Brian J; Nguyen, Thanhcuong T

    2015-11-01

    Bone and bone marrow involvement in sarcoidosis have been infrequently reported. We aimed to describe the clinical features, radiological descriptions, pathological examinations, and outcomes of three patients with osseous sarcoidosis and one patient with bone marrow sarcoidosis seen at our institution. Our case series included fluorodeoxyglucose positron emission tomography descriptions in assessing the whole-body extent of sarcoidosis. In the era of advanced imaging, large bone and axial skeleton sarcoidosis lesions are more common than previously reported.

  9. [Atrophy of the bone marrow].

    PubMed

    Dziecioł, J; Kemona, A; Sulik, M; Sulkowski, S; Brykalska, A; Sobaniec-Lotowska, M; Ostapiuk, H

    1990-01-01

    The authors made a quantitative analysis of the active hematopoietic tissue of the bone marrow with particular consideration of its atrophy in the course of various diseases. The material consisted of 407 non-selected autopsy cases. For a morphometric analysis the bone marrow was sampled from the sternum, ala ossis illi and spine. In the quantitative analysis of the active hematopoietic tissue we took into account age groups as quantitative changes appear with age. Atrophy of the bone marrow was in 19.4% of the studied cases. The presence of bone marrow atrophy was found in the course of various diseases, most frequently neoplastic, particularly in patients aged from 50 to 59 years.

  10. Aspiration and Biopsy: Bone Marrow

    MedlinePlus

    ... in determining treatment and prognosis) viral, bacterial, or fungal infections in the bone marrow that might be causing a lasting fever or other symptoms certain genetic diseases (such as lipid storage diseases) They also ...

  11. What Are Bone Marrow Tests?

    MedlinePlus

    ... for people with certain bleeding disorders such as hemophilia. Bone marrow tests can be done in a ... reading Anemia Aplastic Anemia Blood Tests Clinical Trials Hemophilia Thrombocythemia and Thrombocytosis Thrombocytopenia Rate This Content: Updated: ...

  12. Bone Marrow Diseases - Multiple Languages

    MedlinePlus

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Bone Marrow Diseases URL of this page: https://medlineplus.gov/languages/bonemarrowdiseases.html Other topics A-Z Expand Section ...

  13. Bone marrow transplantation reverses new-onset immunoinflammatory diabetes in a mouse model.

    PubMed

    Lv, Cheng-Lan; Wang, Jing; Xie, Ting; Ouyang, Jian

    2014-01-01

    Bone marrow transplantation might be an effective method to cure type 1 diabetes mellitus. This study aimed to investigate whether bone marrow transplantation could reverse hyperglycemia in diabetic mice and whether high-dose total body irradiation followed by high-dose bone marrow mononuclear cell infusion could improve the efficiency of bone marrow transplantation in treating diabetic mice. Diabetic mice after multiple low doses of streptozotocin injection were irradiated followed by infusion with approximately 1×10(7) bone marrow mononuclear cells intravenously. Before and after bone marrow transplantation, fasting blood glucose, intraperitoneal glucose tolerance test, serum insulin, pancreatic histology, and the examination of insulin and glucagon in islets were processed. All recipients returned to near euglycemic within 1 week after undergoing bone marrow transplantation. No mice became hyperglycemia again during investigation period. The change of serum insulin, glucose tolerance test, pancreatic histology and the expression of insulin and glucagon in recipient islets after bone marrow transplantation all revealed islets regeneration and significant amelioration when compared respectively with those of diabetic mice without bone marrow transplantation. Bone marrow transplantation contributed to reduce blood glucose, prevent further blood glucose hike in diabetic recipients, and promote islets regeneration. High-dose total body irradiation in combination with high-dose bone marrow monoclear cell infusion could improve the efficiency of bone marrow transplantation in treating streptozotocin-induced diabetes.

  14. Absence of accelerated atherosclerotic disease progression after intracoronary infusion of bone marrow derived mononuclear cells in patients with acute myocardial infarction--angiographic and intravascular ultrasound--results from the TErapia Celular Aplicada al Miocardio Pilot study.

    PubMed

    Arnold, Roman; Villa, Adolfo; Gutiérrez, Hipólito; Sánchez, Pedro L; Gimeno, Federico; Fernández, Maria E; Gutiérrez, Oliver; Mota, Pedro; Sánchez, Ana; García-Frade, Javier; Fernández-Avilés, Francisco; San Román, Jose A

    2010-06-01

    We tried to evaluate a putative negative effect on coronary atherosclerosis in patients receiving intracoronary infusion of unfractionated bone marrow mononuclear cells (BMMC) following an acute ST-elevation myocardial infarction. Peripheral blood mononuclear cells or enriched CD133(+) BMMC have been associated with accelerated atherosclerosis of the distal segment of the infarct related artery (IRA). Thirty-seven patients with ST-elevation myocardial infarction from the TECAM pilot study underwent intracoronary infusion of autologous BMMC 9 +/- 3.1 days after onset of symptoms. We compared angiographic changes from baseline to 9 months of follow-up in the distal non-stented segment of the IRA, as well as in the contralateral coronary artery, with a matched control group. A subgroup of 15 treated patients underwent additional IVUS within the distal segment of the IRA. No difference between stem cell and control group were found regarding changes in minimum lumen diameter (0.006 +/- 0.42 vs 0.06 +/- 0.41 mm, P = ns) and the percentage of stenosis (-2.68 +/- 12.33% vs -1.78 +/- 8.75%, P = ns) at follow-up. Likewise, no differences were seen regarding changes in the contralateral artery (minimum lumen diameter -0.004 +/- 0.54 mm vs -0.06 +/- 0.35 mm, P = ns). In the intravascular ultrasound substudy, no changes were demonstrated comparing baseline versus follow-up in maximum area stenosis and plaque volume. In this pilot study, analysis of a subgroup of patients found that intracoronary injection of unfractionated BMMC in patients with acute ST-elevation myocardial infarction was not associated with accelerated atherosclerosis progression at mid term. Prospective, randomised studies in large cohorts with long-term angiographic and intravascular ultrasound follow-up are necessary to determine the safety of this therapy. Copyright 2010 Mosby, Inc. All rights reserved.

  15. [Normal bone marrow and common reactive alterations].

    PubMed

    Tzankov, A; Dirnhofer, S; Beham-Schmid, C

    2012-11-01

    Histological examination of bone marrow biopsies is an important and powerful diagnostic tool to assess various hematological and non-hematological disorders. Morphological examination of such biopsies requires knowledge of the composition of normal bone marrow and its variations, such as age-related changes. Diagnostic problems may arise due to poor specimen quality, insufficient sections or stainings and insufficient experience with reactive bone marrow changes which occasionally resemble neoplastic disorders. Reactive bone marrow processes can affect one or more hematopoietic cell lines, lead to disruption of the normal architecture and specifically affect the bone marrow stroma. Optimal bone marrow diagnosis requires adequately stained slides and, when needed, immunophenotyping and molecular examinations. Furthermore, rather than biopsy interpretation of other organs, pathologists routinely need clinical history information for correct interpretation and diagnosis of bone marrow changes. In this article, the normal features of bone marrow as well as the most frequent reactive bone marrow alterations are described.

  16. Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches.

    PubMed

    Kaur, Simranpreet; Raggatt, Liza Jane; Batoon, Lena; Hume, David Arthur; Levesque, Jean-Pierre; Pettit, Allison Robyn

    2017-01-01

    Macrophages, named for their phagocytic ability, participate in homeostasis, tissue regeneration and inflammatory responses. Bone and adjacent marrow contain multiple functionally unique resident tissue macrophage subsets which maintain and regulate anatomically distinct niche environments within these interconnected tissues. Three subsets of bone-bone marrow resident tissue macrophages have been characterised; erythroblastic island macrophages, haematopoietic stem cell niche macrophages and osteal macrophages. The role of these macrophages in controlling homeostasis and repair in bone and bone marrow niches is reviewed in detail.

  17. Methotrexate and bone marrow metaphases.

    PubMed

    Cunningham, J J; Potter, A M; Watmore, A E; Winfield, D A

    1988-07-15

    The efficacy of a methotrexate (MTX) block/thymidine release synchronization technique has been assessed in bone marrow cultures from patients with acute nonlymphocytic leukemia and myelodysplasia. In contrast to cultures of stimulated lymphocytes from normal individuals, no improvement in mitotic index (MI) or metaphase quality could be detected using this technique. Demonstration of an unchanged level of division in bone marrow cultures in the presence of MTX suggests that the technique is unsuitable for synchronization purposes in this tissue. The influence of preincubation prior to MTX exposure and duration of exposure to colcemid on MI and metaphase quality have also been examined.

  18. Blood and Bone MarrowTransplant?

    MedlinePlus

    ... page from the NHLBI on Twitter. Blood and Bone Marrow Transplant Also known as hematopoietic stem cell ... autologous transplant, or allogeneic transplant. A blood or bone marrow transplant replaces abnormal blood-forming stem cells ...

  19. Progenitor Cell Therapy to Treat Acute Myocardial Infarction: The Promise of High-Dose Autologous CD34+ Bone Marrow Mononuclear Cells

    PubMed Central

    Poole, Joseph C.; Quyyumi, Arshed A.

    2013-01-01

    ST elevation myocardial infarction (STEMI) is associated with an increased risk for congestive heart failure and long-term mortality despite the widespread use of thrombolysis and catheter-based revascularization. The need for improved post-STEMI therapies has led to a surge of novel therapeutics, especially regenerative approaches using autologous mononuclear cells. Indeed, the past decade has been marked by a number of human trials studying the safety and efficacy of progenitor cell delivery in the post-STEMI setting. While a variety of cell types and delivery techniques have been utilized, directed therapy to the infarct-related artery has been the most widely used approach. From over 1300 subjects randomized in these studies, there is sufficient evidence to conclude that cell therapy after STEMI is uniformly safe, while the efficacy of this intervention for improving outcomes is less clear. Recent meta-analyses have highlighted the importance of both timing of cell delivery, as well as the type, quantity, and mobility of delivered cells as determinants of response. Here, we show the case in which higher doses of CD34+ cells, which are more potent in terms of their migratory capacity, offer the best hope for preserving cardiac function following STEMI. PMID:23737803

  20. Bone scan appearances following bone and bone marrow biopsy

    SciTech Connect

    McKillop, J.H.; Maharaj, D.; Boyce, B.F.; Fogelman, I.

    1984-01-01

    Bone marrow and bone biopsies are performed not infrequently in patients referred for bone scans and represent a potential cause of a ''false positive'' focal abnormality on the bone scan. The authors have therefore examined the scan appearances in a series of patients who had undergone either sternal marrow biopsy, (Salah needle, diameter 1.2 mm) trephine iliac crest marrow biopsy (Jamshidi 11 gauge needle, diameter 3.5 mm) or a transiliac bone biopsy (needle diameter 8 mm). Of 18 patients studied 1 to 45 days after sternal marrow 17 had normal scan appearances at the biopsy site and 1 had a possible abnormality. None of 9 patients studied 4 to 19 days after trephine iliac crest marrow biopsy had a hot spot at the biopsy site. A focal scan abnormality was present at the biopsy site in 9/11 patients studied 5 to 59 days after a trans iliac bone biopsy. No resultant scan abnormality was seen in 4 patients imaged within 3 days of the bone biopsy or in 3 patients imaged 79 to 138 days after the procedure. Bone marrow biopsy of the sternum or iliac crest does not usually cause bone scan abnormalities. A focal abnormality at the biopsy site is common in patients imaged 5 days to 2 months after bone biopsy. The gauge of the needle employed in the biopsy and thus the degree of bone trauma inflicted, is likely to be main factor determining the appearance of bone scan abnormalities at the biopsy site.

  1. Structural features of bone marrow

    PubMed Central

    Romaniuk, Anatolii; Lyndina, Yuliia; Sikora, Vladyslav; Lyndin, Mykola; Karpenko, Ludmyla; Gladchenko, Oksana; Masalitin, Igor

    2016-01-01

    Purpose This article is devoted to the investigation of the structural features of the bone marrow of mature rats. Materials and methods The investigation of the structural features of the bone marrow was performed on the femurs of the mature male rats. General structure of the organ was studied with hematoxylin–eosin and Van Gieson staining of samples. Certain features of the bone marrow structure were studied using immunohistochemical method (CD3, CD79α, S100, myeloperoxidase, and cyclin D1). Results We can state that stromal–parenchymal structure is typical for the bone marrow of rats as for any other organ. The stromal component is presented with bone tissue (48.8 ± 3.3% at epiphyses), the net of blood vessels (18.7 ± 2.1%), fat tissue (11 ± 2%), fibrous tissue (0.7 ± 0.2%), and the network of reticular fibers. Hematopoietic tissue covers 20.9 ± 3.7% at the femoral epiphyses and 69.6 ± 2.2% at diaphysis. Among these tissues, myelopoiesis occupies 74.2 ± 4.7%, erythropoiesis – 24.3 ± 4.7%, and lymphopoiesis – less than 5%. Megalokaryocytes take 0.1–0.3%. Conclusion Considering the lack of significant anatomical, morphological, and histological differences of red bone marrow of rats and humans, we can state that hematopoiesis in rats takes place on the basis of the same principles as in humans, although it has certain mechanisms. PMID:28203394

  2. Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey

    PubMed Central

    Kuçi, Zyrafete; Bönig, Halvard; Kreyenberg, Hermann; Bunos, Milica; Jauch, Anna; Janssen, Johannes W.G.; Škifić, Marijana; Michel, Kristina; Eising, Ben; Lucchini, Giovanna; Bakhtiar, Shahrzad; Greil, Johann; Lang, Peter; Basu, Oliver; von Luettichau, Irene; Schulz, Ansgar; Sykora, Karl-Walter; Jarisch, Andrea; Soerensen, Jan; Salzmann-Manrique, Emilia; Seifried, Erhard; Klingebiel, Thomas; Bader, Peter; Kuçi, Selim

    2016-01-01

    To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy “3rd-party” donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease. PMID:27175026

  3. Haemopoietic recovery in spleen and marrow after transplantation of bone marrow from either normal or hydroxyurea treated mice.

    PubMed

    Hasthorpe, S; Hodgson, G S

    1977-09-01

    Haemopoietic regeneration was studied following x-irradiation and transplantation of bone marrow from either normal or hydroxyurea-treated donor mice, to ascertain the contribution of proliferating progenitor cells to regeneration. With transplantation of equivalent numbers of CFU-S, total DNA and 3HTdR uptake into DNA in spleen and femoral bone marrow and the erythroid, granulocytic and mononuclear cell populations were not significantly different between normal (NBM) and hydroxyurea-treated (HUBM) marrow. The response of hypertransfused x-irradiated mice to erythropoietin (EPO) administration was also not significantly different in spleens of mice receiving normal or hydroxyurea-treated marrow.

  4. [Gelatinous transformation of the bone marrow].

    PubMed

    Kemona, A; Dziecioł, J; Sulik, M; Brykalska, A; Sobaniec-Lotowska, M; Baltaziak, M

    1990-01-01

    The incidence and histopathologic picture of gelatinous transformation of the bone marrow were analysed in non-selected autopsy material. It was found that gelatinous transformation of the bone marrow occurred in terminal stages of various diseases (malignant neoplasms, chronic inflammation). Histological studies showed that gelatinous transformation of the bone marrow led to atrophy of the hematopoietic and adipose tissues of the bone marrow and accumulation of acid mucopolysaccharides. The patients with gelatinous transformation of the bone marrow exhibit hematologic disorders, most frequently anemia and thrombocytopenia.

  5. Bone marrow and the control of immunity

    PubMed Central

    Zhao, Ende; Xu, Huanbin; Wang, Lin; Kryczek, Ilona; Wu, Ke; Hu, Yu; Wang, Guobin; Zou, Weiping

    2012-01-01

    Bone marrow is thought to be a primary hematopoietic organ. However, accumulated evidences demonstrate that active function and trafficking of immune cells, including regulatory T cells, conventional T cells, B cells, dendritic cells, natural killer T (NKT) cells, neutrophils, myeloid-derived suppressor cells and mesenchymal stem cells, are observed in the bone marrow. Furthermore, bone marrow is a predetermined metastatic location for multiple human tumors. In this review, we discuss the immune network in the bone marrow. We suggest that bone marrow is an immune regulatory organ capable of fine tuning immunity and may be a potential therapeutic target for immunotherapy and immune vaccination. PMID:22020068

  6. Bone scan appearances following biopsy of bone and bone marrow

    SciTech Connect

    McKillop, J.H.; Maharaj, D.; Boyce, B.F.; Fogelman, I.

    1984-10-01

    The influence of sternal marrow aspiration, iliac crest marrow aspiration, and iliac crest bone biopsy on bone scan appearances was examined. Eighteen patients were scanned a mean of 9.9 days after sternal marrow aspiration with a Salah needle. Bone scans obtained in 9 patients a mean of 10 days aftr iliac crest trephine marrow biopsy with a Jamshidi needle showed no abnormality at the biopsy site. In 18 patients with metabolic bone disease who had undergone iliac crest bone biopsy with an 8 mm needle, a scan abnormality due to the biopsy was usually present when the interval between the biopsy and the scan was 5 days to 2 months. Patients who were scanned within 3 days of iliac crest bone biopsy or more than 2 months after biopsy had normal scan appearance at the biopsy site.

  7. Bone Marrow Matters

    ERIC Educational Resources Information Center

    Dunne, Mark; Maklad, Rania; Heaney, Emma

    2014-01-01

    As a final-year student teacher specialising in primary science, Emma Heaney faced the challenge of having to plan, organise, and conduct a small-scale, classroom-based research project. She had to teach about bones in the final block practice session and thought it would be a good idea to bring in some biological specimens obtained from the local…

  8. Bone Marrow Matters

    ERIC Educational Resources Information Center

    Dunne, Mark; Maklad, Rania; Heaney, Emma

    2014-01-01

    As a final-year student teacher specialising in primary science, Emma Heaney faced the challenge of having to plan, organise, and conduct a small-scale, classroom-based research project. She had to teach about bones in the final block practice session and thought it would be a good idea to bring in some biological specimens obtained from the local…

  9. Primary bone marrow oedema syndromes.

    PubMed

    Patel, Sanjeev

    2014-05-01

    MRI scanning in patients with rheumatological conditions often shows bone marrow oedema, which can be secondary to inflammatory, degenerative, infective or malignant conditions but can also be primary. The latter condition is of uncertain aetiology and it is also uncertain whether it represents a stage in the progression to osteonecrosis in some patients. Patients with primary bone marrow oedema usually have lower limb pain, commonly the hip, knee, ankle or feet. The diagnosis is one of exclusion with the presence of typical MRI findings. Treatment is usually conservative and includes analgesics and staying off the affected limb. The natural history is that of gradual resolution of symptoms over a number of months. Evidence for medical treatment is limited, but open-label studies suggest bisphosphonates may help in the resolution of pain and improve radiological findings. Surgical decompression is usually used as a last resort.

  10. Bronchiectasis in bone marrow transplantation.

    PubMed

    Morehead, R S

    1997-04-01

    Two patients are described with clinical and radiographic bronchiectasis which occurred after allogeneic bone marrow transplantation for haematological malignancy. Both had evidence of chronic graft versus host disease in other organs. Increased immunosuppression with corticosteroids resulted in clinical response, although both patients persisted with chronic mucopurulent sputum production and one had progressive airflow obstruction. Bronchiectasis may be an under-recognised manifestation of chronic graft versus host disease of the lung.

  11. Advances in bone marrow stem cell therapy for retinal dysfunction.

    PubMed

    Park, Susanna S; Moisseiev, Elad; Bauer, Gerhard; Anderson, Johnathon D; Grant, Maria B; Zam, Azhar; Zawadzki, Robert J; Werner, John S; Nolta, Jan A

    2017-01-01

    The most common cause of untreatable vision loss is dysfunction of the retina. Conditions, such as age-related macular degeneration, diabetic retinopathy and glaucoma remain leading causes of untreatable blindness worldwide. Various stem cell approaches are being explored for treatment of retinal regeneration. The rationale for using bone marrow stem cells to treat retinal dysfunction is based on preclinical evidence showing that bone marrow stem cells can rescue degenerating and ischemic retina. These stem cells have primarily paracrine trophic effects although some cells can directly incorporate into damaged tissue. Since the paracrine trophic effects can have regenerative effects on multiple cells in the retina, the use of this cell therapy is not limited to a particular retinal condition. Autologous bone marrow-derived stem cells are being explored in early clinical trials as therapy for various retinal conditions. These bone marrow stem cells include mesenchymal stem cells, mononuclear cells and CD34(+) cells. Autologous therapy requires no systemic immunosuppression or donor matching. Intravitreal delivery of CD34(+) cells and mononuclear cells appears to be tolerated and is being explored since some of these cells can home into the damaged retina after intravitreal administration. The safety of intravitreal delivery of mesenchymal stem cells has not been well established. This review provides an update of the current evidence in support of the use of bone marrow stem cells as treatment for retinal dysfunction. The potential limitations and complications of using certain forms of bone marrow stem cells as therapy are discussed. Future directions of research include methods to optimize the therapeutic potential of these stem cells, non-cellular alternatives using extracellular vesicles, and in vivo high-resolution retinal imaging to detect cellular changes in the retina following cell therapy.

  12. Bone Marrow Therapies for Chronic Heart Disease.

    PubMed

    Behbahan, Iman Saramipoor; Keating, Armand; Gale, Robert Peter

    2015-11-01

    Chronic heart failure is a leading cause of death. The demand for new therapies and the potential regenerative capacity of bone marrow-derived cells has led to numerous clinical trials. We critically discuss current knowledge of the biology and clinical application of bone marrow cells. It appears unlikely that bone marrow cells can develop into functional cardiomyocyte after infusion but may have favorable paracrine effects. Most, but not all, clinical trials report a modest short- but not long-term benefit of infusing bone marrow-derived cells. Effect size appears to correlate with stringency of study-design: the most stringent trials report the smallest effect-sizes. We conclude there may be short- but not substantial long-term benefit of infusing bone marrow-derived cells into persons with chronic heart failure and any benefit observed is unlikely to result from trans-differentiation of bone marrow-derived cells into functioning cardiomyocytes. © 2015 AlphaMed Press.

  13. Effects of glucan on bone marrow

    PubMed Central

    Vannucci, Luca; Vetvicka, Vaclav

    2014-01-01

    Bone marrow damage represents a significant problem in cancer treatment. Therefore, it is clear that the pharmacologic protection against bone marrow damage is of considerable interest, since the development of novel and effective medical approaches to combat radiation or cytotoxic damage are of major importance not only to the medical field but also to several industries and the military. This review represents a summary of our knowledge of the effects of various glucans on bone marrow protection. PMID:25332994

  14. Intra-arterial Autologous Bone Marrow Cell Transplantation in a Patient with Upper-extremity Critical Limb Ischemia

    SciTech Connect

    Madaric, Juraj; Klepanec, Andrej; Mistrik, Martin; Altaner, Cestmir; Vulev, Ivan

    2013-04-15

    Induction of therapeutic angiogenesis by autologous bone marrow mononuclear cell transplantation has been identified as a potential new option in patients with advanced lower-limb ischemia. There is little evidence of the benefit of intra-arterial cell application in upper-limb critical ischemia. We describe a patient with upper-extremity critical limb ischemia with digital gangrene resulting from hypothenar hammer syndrome successfully treated by intra-arterial autologous bone marrow mononuclear cell transplantation.

  15. Analyzing the cellular contribution of bone marrow to fracture healing using bone marrow transplantation in mice

    SciTech Connect

    Colnot, C. . E-mail: colnotc@orthosurg.ucsf.edu; Huang, S.; Helms, J.

    2006-11-24

    The bone marrow is believed to play important roles during fracture healing such as providing progenitor cells for inflammation, matrix remodeling, and cartilage and bone formation. Given the complex nature of bone repair, it remains difficult to distinguish the contributions of various cell types. Here we describe a mouse model based on bone marrow transplantation and genetic labeling to track cells originating from bone marrow during fracture healing. Following lethal irradiation and engraftment of bone marrow expressing the LacZ transgene constitutively, wild type mice underwent tibial fracture. Donor bone marrow-derived cells, which originated from the hematopoietic compartment, did not participate in the chondrogenic and osteogenic lineages during fracture healing. Instead, the donor bone marrow contributed to inflammatory and bone resorbing cells. This model can be exploited in the future to investigate the role of inflammation and matrix remodeling during bone repair, independent from osteogenesis and chondrogenesis.

  16. Androgen, Estrogen and the Bone Marrow Microenvironment

    DTIC Science & Technology

    2009-12-01

    SUPPLEMENTARY NOTES 14. ABSTRACT We have accomplished the following: 1) Characterized androgen responsive genes in mouse bone marrow (BM) via...castration (androgen ablation) and estrogen stimulation. 2) Measurements of testosterone, dihydrotestosterone and of genes that regulate the local... gene expression in the bone marrow. In males, the main source of estrogen is through conversion of androgen by aromatase. We postulate that gene

  17. 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.

  18. HLA Typing for Bone Marrow Transplantation

    DTIC Science & Technology

    2007-01-31

    for Bone Marrow Transplantation Progress Report for the Period 7 Funding October 1, 2006 - December 31, 2006 Task 1: Product Validation Description...1-0310 HLA Typing for Bone Marrow Transplantation Progress Report for the Period 7 Funding October 1, 2006 - December 31, 2006 Task 2: Validation of

  19. Umbelliprenin is Potentially Toxic Against the HT29, CT26, MCF-7, 4T1, A172, and GL26 Cell Lines, Potentially Harmful Against Bone Marrow-Derived Stem Cells, and Non-Toxic Against Peripheral Blood Mononuclear Cells

    PubMed Central

    Rashidi, Mohsen; Ziai, Seyed Ali; Moini Zanjani, Taraneh; Khalilnezhad, Ahad; Jamshidi, Hamidreza; Amani, Davar

    2016-01-01

    Background Resistance to chemotherapy is a growing concern, thus natural anticancer agents are drawing the attention of many scientists and clinicians. One natural anticancer agent, umbelliprenin, is a coumarin produced by many species of Ferula. Objectives We aimed to examine the inhibitory effect of umbelliprenin on human and mouse bone marrow-derived stem cells (BMDSCs), peripheral blood mononuclear cells (PBMCs), and different cancer cell lines. Materials and Methods In this in vitro experimental study, the HT29, CT26, MCF-7, 4T1, A172, and GL26 cancer cells and human and mouse BMDSCs and PBMCs were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), incubated at 37°C for 24 hours in a 5% CO2 atmosphere, and then were treated with different concentrations of umbelliprenin dissolved in dimethyl sulfoxide (DMSO) (3, 6, 12, 25, 50, 100, and 200 µg/mL) for 24, 48, and 72 hours at 37°C. Each experiment was performed in triplicate. Finally, the cell survival rate was assessed by MTT assay. The IC50 values were calculated based on the log values using GraphPad Prism version 5 software for windows (La Jolla CA, USA) and were expressed as mean ± SEM. Results Umbelliprenin inhibited the cancer cells in a concentration-dependent (P < 0.05) but not time-dependent manner (P > 0.05). The most sensitive and resistant cell lines at the 24-hour incubation time were 4T1 (IC50, 30.9 ± 3.1 µg/mL) and A172 (IC50, 51.9 ± 6.7 µg/mL); at the 48-hour incubation time: 4T1 (IC50, 30.6 ± 2.6 µg/mL) and CT26 (IC50, 53.2 ± 3.6 µg/mL); and at the 72-hour incubation time: HT29 (IC50, 37.1 ± 1.4 µg/mL) and 4T1 (IC50, 62.2 ± 4.8 µg/mL). Both human and mouse BMDSCs showed the highest resistance at the 24-hour incubation time (IC50s, 254.7 ± 21 and 204.4 ± 4.5 µg/mL, respectively) and the highest sensitivity at the 72-hour incubation time (IC50s, 120.4 ± 5 and 159.0 ± 7.3 µg/mL, respectively). The PBMCs of both human and mouse origin revealed very

  20. Autoclaved bone autograph reconstituted with autologous bone marrow.

    PubMed

    Granados-García, Martín; Cabrera-Rojas, Jesús; Guzmán-Flores, Gerardo; Estrada-Lobato, Enrique; Cano-Valdés, Ana María; Santamaría-Linares, Erik

    2011-01-01

    Bone reconstruction is a common problem in the oncological setting. Mandibular reconstruction is done with microvascularized free flaps, but noticeable differences in shape and size exist in relation to the normal mandible; consequently, new reconstructive methods are desirable. We explored the feasibility of recovering osseous viability using a sterilized mandibular segment reconstituted with autologous bone marrow. A 6- to 7-cm mandibular segment was excised in three Creole dogs. The segment was autoclaved for 40 min. The bone was then drilled, producing 3-mm holes every 10-mm. Bone was reconstituted with autologous bone marrow from the iliac spine mixed with particulated bone. Bone autograph was installed underneath the latissimus dorsi muscle. On week four after surgery, dogs received colloidal rhenium and were placed in a gamma camera. The study showed uptake of the radiotracer in the bone graft, demonstrating viability of bone marrow. One hour later, the autograph was excised in two dogs and a histopathological study corroborated the viability of the bone marrow and the formation of new vessels and osteoid. On week twelve, the third dog was administered MDP-99Tc and placed in a gamma camera. Results proved production of new bone. Osseous reconstruction with microvascularized flaps may cause problems, but sterilized bone reconstituted with bone marrow becomes viable. This observation eventually would allow osseous reconstruction, including the mandibule, easily and reliably in patients with osseous tumors. Autoclaved bone reconstituted with bone marrow recovers its viability.

  1. Bone marrow examination in pancytopenia.

    PubMed

    Rangaswamy, M; Prabhu; Nandini, N M; Manjunath, G V

    2012-08-01

    Pancytopenia is defined by reduction of all the three formed elements of blood below the normal reference. It may be a manifestation of a wide variety of disorders, which primarily or secondarily affect the bone marrow. Haematological investigation forms the bedrock in the management of patients with pancytopenia and therefore needs detailed study. The total number of cases studied were 100 over a period of two years in the department of pathology, JSS Hospital, Mysore. Megaloblastic anaemia (33%) was the commonest cause of pancytopenia. Other causes were nutritional anaemia (16%), aplastic anaemia (14%), hypersplenism (10%), sepsis (9%) and leukaemia (5%). Less common causes were alcoholic liver disease, haemolytic anaemia, HIV, dengue, systemic lupus erythematosus, viral hepatitis, disseminated TB and multiple myeloma. Most of the patients were in the age group of 11-30 years with a male:female ratio of 1.6:1.Generalised weakness and fatigue (88%) were the commonest presenting complaints. Haemoglobin level varied from 1-10 g/dl with majorIty (70%) of them in the range of 5.1-10 g/dI. TLC was in the range of 500-4000 cells/cmm. Most (34%) of them had 3100-4000 cells/cmm. Platelet count was in the range of 4000-1,40,000 cells/cmm. Reticulocyte count varied from 0.1%-15% with majority (82%) of them ranging from 0.1%-2%. The bone marrow cellularity was hypocellular in 14%, hypercellular in 75%, and normocellular in 11% of the patients. Pancytopenia is a relatively common entity with inadequate attention in Indian subcontinent. A comprehensive clinical and haematological study of patients with pancytopenia will usually help in the identification of the underlying cause. However in view of wide array of aetiologies, pancytopenia continues to be a diagnostic challenge for haematologists.

  2. Question of bone marrow stromal fibroblast traffic

    SciTech Connect

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

    1985-01-01

    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, 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.

  3. Kinetics of erythrogenesis after bone marrow transplantation.

    PubMed

    Lazarus, H M; Chahine, A; Lacerna, K; Wamble, A; Iaffaldano, C; Straight, M; Rabinovitch, A; Schimenti, K J; Jacobberger, J

    1992-04-01

    To determine the kinetics of bone marrow erythrogenesis after bone marrow transplantation, the authors counted reticulocytes (by blood smear and flow cytometry) and compared those data with neutrophil and platelet recovery in 23 consecutive bone marrow transplant patients. The earliest indication of marrow recovery after allogeneic and autologous bone marrow transplantation was defined as the second increasing cell count after the lowest recorded count, provided that the trend continued upward. Recovery of marrow function was detected earlier in 10 of 23 patients using reticulocyte counts than by either neutrophil or platelet count alone. Specifically, in 8 of these 10 patients, recovery of erythropoiesis was determined earlier by flow cytometric examination than by the blood smear method. On the other hand, combining the data using the earliest value of platelet, neutrophil, and reticulocyte counts indicated that the mean day of recovery in our patient population was determined to be 12.1 +/- 4 days after marrow infusion. In patients undergoing autologous and allogeneic bone marrow transplantation, serial neutrophil and reticulocyte count determinations are complementary in early clinical detection of successful engraftment.

  4. Pituitary abscess after autologous bone marrow transplantation.

    PubMed

    Leff, R S; Martino, R L; Pollock, W J; Knight, W A

    1989-05-01

    The first case of pituitary abscess arising in a patient during recovery from autologous bone marrow transplantation is reported. A 31-year-old man with a 9 month history of T-cell lymphoma died suddenly more than 60 days after successful treatment with high-dose cyclophosphamide, total body irradiation, and autologous bone marrow infusion. Autopsy revealed a pituitary abscess associated with clinically silent sphenoid sinusitis. Unique aspects of this case are presented and clinical and pathologic features of pituitary abscess are reviewed. Although rare, pituitary abscess may complicate recovery from bone marrow transplantation.

  5. [Increased efficacy of allogenic bone marrow transplantation].

    PubMed

    Fedotenkov, A G; Danilova, L A; Ignasheva, L P

    1982-08-01

    Experiments made in vivo and vitro have demonstrated that conservation of allogeneic hemopoietic tissue with glycerin brings about a decrease in transplatation, homologous activity of T lymphocytes. Allogeneic bone marrow conserved with glycerin compares very favourably with freshly prepared allogeneic bone marrow since the transplant-versus-host reaction is attenuated under the effect of glycerin. Moreover, it shows a higher proliferative activity. The glycerin-induced reduction of the inactivating effect of lymphocytes against non-syngeneic colony-forming units enables the conserved bone marrow to be transplanted from several donors.

  6. Megakaryocytes, malignancy and bone marrow vascular niches.

    PubMed

    Psaila, B; Lyden, D; Roberts, I

    2012-02-01

    Dynamic interactions between hematopoietic cells and their specialized bone marrow microenvironments, namely the vascular and osteoblastic 'niches', regulate hematopoiesis. The vascular niche is conducive for thrombopoiesis and megakaryocytes may, in turn, regulate the vascular niche, especially in supporting vascular and hematopoietic regeneration following irradiation or chemotherapy. A role for platelets in tumor growth and metastasis is well established and, more recently, the vascular niche has also been implicated as an area for preferential homing and engraftment of malignant cells. This article aims to provide an overview of the dynamic interactions between cellular and molecular components of the bone marrow vascular niche and the potential role of megakaryocytes in bone marrow malignancy.

  7. [Changes in the bone marrow in cancer patients. 61 bone marrow biopsies].

    PubMed

    Marsan, C; Henon, P; Cywiner-Golenzer, C; Zitouna, M M; Girardi, P

    1976-01-01

    The authors studied 61 bone marrow biopsies carried out in cancerous patients, presumably suffering from a bone metastasis and before any treatment. They feel that quantitative and qualitative changes in the bone marrow may be considered to be an indirect diagnostic indication of metastatic spread.

  8. Bone Marrow Stress Decreases Osteogenic Progenitors.

    PubMed

    Ng, Adeline H; Baht, Gurpreet S; Alman, Benjamin A; Grynpas, Marc D

    2015-11-01

    Age-related bone loss may be a result of declining levels of stem cells in the bone marrow. Using the Col2.3Δtk (DTK) transgenic mouse, osteoblast depletion was used as a source of marrow stress in order to investigate the effects of aging on osteogenic progenitors which reside in the marrow space. Five-month-old DTK mice were treated with one or two cycles of ganciclovir to conditionally ablate differentiated osteoblasts, whereas controls were saline-treated. Treatment cycles were two weeks in length followed by four weeks of recovery. All animals were sacrificed at 8 months of age; bone marrow stromal cells (BMSCs) were harvested for cell culture and whole bones were excised for bone quality assessment. Colony-forming unit (CFU) assays were conducted to investigate the osteogenic potential of BMSC in vitro, and RNA was extracted to assess the expression of osteoblastic genes. Bone quality assessments included bone histomorphometry, TRAP staining, microcomputed tomography, and biomechanical testing. Osteoblast depletion decreased CFU-F (fibroblast), CFU-ALP (alkaline phosphatase), and CFU-VK (von Kossa) counts and BMSC osteogenic capacity in cell culture. Ex vivo, there were no differences in bone mineral density of vertebrae or femurs between treatment groups. Histology showed a decrease in bone volume and bone connectivity with repeated osteoblast depletion; however, this was accompanied by an increase in bone formation rate. There were no notable differences in osteoclast parameters or observed bone marrow adiposity. We have developed a model that uses bone marrow stress to mimic age-related decrease in osteogenic progenitors. Our data suggest that the number of healthy BMSCs and their osteogenic potential decline with repeated osteoblast depletion. However, activity of the remaining osteoblasts increases to compensate for this loss in progenitor osteogenic potential.

  9. Bone marrow histology in monoclonal macroglobulinemia.

    PubMed

    Rywlin, A M; Civantos, F; Ortega, R S; Dominguez, C J

    1975-06-01

    Rywlin, Arkadi, M., Civantos, Francisco, Ortega, Rolando S., and Dominguez, Carlos J.: Bone marrow histology in monoclonal macroglobulinemiamam J Clin Pathol 63. 769-778, 1975. Histologic sections and smears of aspirated bone marrow particles in 26 cases of monoclonal macroglobulinemia were studied. The bone marrows did not show uniform histologic features. Twenty-two patients had various degrees of lymphoid infiltration of the marrow, including nodules of malignant lymphoma, diffuse lymphocytic infiltration, nodular lymphoid hyperplasia, and normal lymphoid nodules. Four patients had no demonstrable lymphoid collections in the marrow. Additional histologic features of the marrows are summarized. A variant of a Dutcher body consisting of multiple PAS-positive inclusions that by light microscopy appear intranuclear is described. Even though the average macroglobulin levels were higher in patients with abnormal lymphoid infiltrates than in patients with noraml or no lymphoid collections, there was considerable overlap between individual patients values in the different groups. Similarly, no correlation between macroglobulin levels and other histologic features could be established. Patients with monoclonal macroglobulinemia represent a spectrum including benign monoclonal gammopathy, lymphoproliferative disorders of the marrow, nodal or extranodal lymphomas. The separation of Waldenström's macroglobulinemia by arbitrary criteria does not appear justified. (key words: Bone marrow; Monoclonal macroglobulinemia.

  10. LD Typing for Bone Marrow Transplantation.

    DTIC Science & Technology

    1977-06-15

    marrow transplantation will be required for treatment of patients who suffer damage to marrow either through exposure to radiation or to drugs being used...which could be used in various test systems to identify the tissue typ ing antigens of the fourth locus of the human histocompatibility system. Bone

  11. Psycholegal issues in sibling bone marrow donation.

    PubMed

    Weisz, Victoria

    1992-01-01

    The only hope of survival for children with a number of life-threatening illnesses is a successful bone marrow transplant (BMT). Unlike the treatment source for most therapies, the raw material for transplant therapy comes from a human being. Although many BMTs are autologous, utilizing the patient's own bone marrow, a large percentage of childhood BMTs rely on bone marrow from children or adolescents who are biological siblings to the sick child. Medical and legal systems are confronted with a dilemma when healthy children are needed to undergo minimally risky, yet somewhat painful, procedures for the benefit of their critically ill siblings. This article reviews legal issues involved in sibling bone marrow donation and psychological research that is relevant to those issues. The article concludes with proposed directions for future psycholegal research and a discussion of ethical issues that are not amenable to empirical investigation.

  12. Redox Regulation in Bone Marrow Failure

    DTIC Science & Technology

    2012-06-01

    aplastic anemia patients with a p38 MAPK inhibitor can restore defective hematopoietic activity, suggesting the critical role of p38 in bone marrow...hematopoietic stem cells, and eventually leading to bone marrow failure [7, 8] [9] [10]. On the other hand, treating aplastic anemia patients with a p38...in aplastic anemia . J Immunol, 2002. 168(12): p. 5984-8. 12. Ikebuchi, K., et al., Interleukin 6 enhancement of interleukin 3-dependent

  13. Bone marrow lesions: A systematic diagnostic approach

    PubMed Central

    Grande, Filippo Del; Farahani, Sahar J; Carrino, John A; Chhabra, Avneesh

    2014-01-01

    Bone marrow lesions on magnetic resonance (MR) imaging are common and may be seen with various pathologies. The authors outline a systematic diagnostic approach with proposed categorization of various etiologies of bone marrow lesions. Utilization of typical imaging features on conventional MR imaging techniques and other problem-solving techniques, such as chemical shift imaging and diffusion-weighted imaging (DWI), to achieve accurate final diagnosis has been highlighted. PMID:25114392

  14. Comparative evaluation of simultaneous bone marrow aspiration and bone marrow biopsy: an institutional experience.

    PubMed

    Toi, Pampa Ch; Varghese, Renu G'boy; Rai, Ramji

    2010-06-01

    Bone marrow aspirations and bone marrow biopsies are important diagnostic procedures. A comparative study of both the procedures done simultaneously was retrospectively reviewed in 160 cases where the clinical history is correlated with BMA and BMB results. The advantage of each method is analyzed. Correlation of our findings with that given in the literature is done to give a guideline for both techniques. We have found that 61.25% of the cases showed a positive correlation between bone marrow aspiration and bone marrow biopsy. However, we found that tuberculous granulomas and Hodgkin disease involvement of the marrow were detected better in bone marrow biopsies. The advantage of both the procedures done together provided more material and enabled us to study the cytomorphology of the cells, with the pattern of distribution of the cells depending on the cases. However, when both the procedures are done simultaneously, a proper technique is required so as to yield good diagnostic material.

  15. The pathology of bone marrow failure.

    PubMed

    Leguit, Roos J; van den Tweel, Jan G

    2010-11-01

    An important indication for bone marrow investigation is the presence of bone marrow failure, which manifests itself as (pan)cytopenia. The causes of cytopenia are varied and differ considerably between childhood and adulthood. In the paediatric age group inherited bone marrow failure syndromes are important causes of bone marrow failure, but they play only a minor role in later life. This review gives a comprehensive overview of bone marrow failure disorders in children and adults. We classified the causes of bone marrow failure according to the main presenting haematological abnormality, i.e. anaemia, neutropenia, thrombocytopenia or pancytopenia. The following red cell disorders are discussed: red cell aplasia, sideroblastic anaemia, congenital dyserythropoietic anaemia, haemolytic anaemia, paroxysmal nocturnal haemoglobinuria, iron deficiency anaemia, anaemia of chronic disease and megaloblastic anaemia. The neutropenias occur in the context of Shwachman-Diamond syndrome (SDS), severe congenital neutropenia, cyclic neutropenia, immune-related neutropenia and non-immune neutropenia. In addition, the following causes of thrombocytopenia are discussed: congenital amegakaryocytic thrombocytopenia, thrombocytopenia with absent radii, immune-related thrombocytopenia and non-immune thrombocytopenia. Finally, we pay attention to the following pancytopenic disorders: Fanconi anaemia, dyskeratosis congenita, aplastic anaemia, myelodysplastic syndromes and human immunodeficiency virus (HIV) infection.

  16. Murine Hind Limb Long Bone Dissection and Bone Marrow Isolation.

    PubMed

    Amend, Sarah R; Valkenburg, Kenneth C; Pienta, Kenneth J

    2016-04-14

    Investigation of the bone and the bone marrow is critical in many research fields including basic bone biology, immunology, hematology, cancer metastasis, biomechanics, and stem cell biology. Despite the importance of the bone in healthy and pathologic states, however, it is a largely under-researched organ due to lack of specialized knowledge of bone dissection and bone marrow isolation. Mice are a common model organism to study effects on bone and bone marrow, necessitating a standardized and efficient method for long bone dissection and bone marrow isolation for processing of large experimental cohorts. We describe a straightforward dissection procedure for the removal of the femur and tibia that is suitable for downstream applications, including but not limited to histomorphologic analysis and strength testing. In addition, we outline a rapid procedure for isolation of bone marrow from the long bones via centrifugation with limited handling time, ideal for cell sorting, primary cell culture, or DNA, RNA, and protein extraction. The protocol is streamlined for rapid processing of samples to limit experimental error, and is standardized to minimize user-to-user variability.

  17. [Characterization of bone marrow mesenchymal stem cells.

    PubMed

    Mizoguchi, Toshihide

    Bones support the body as part of the human musculoskeletal system. They also contain bone marrow, which is a site of hematopoiesis. Bone marrow mesenchymal stem cells play a vital role by regulating skeletal tissue formation and maintaining hematopoiesis. While the presence of bone marrow-derived mesenchymal stem cells has been indicated, they have yet to be fully understood in vivo. Recent studies using genetic mouse models revealed that perivascular stromal cells function as mesenchymal stem cells, and their differentiation status may vary during the early stage of life to adulthood. Furthermore, studies have investigated the underlying mechanisms that regulate the cell fate decision of mesenchymal stem cells. These findings could lead to the design of new therapeutic approaches for metabolic bone disease and hematopoietic disease.

  18. Common Cold Can Be Dangerous After Bone Marrow Transplant

    MedlinePlus

    ... 164206.html Common Cold Can Be Dangerous After Bone Marrow Transplant Rhinovirus far more worrisome in those with ... cold can be deadly for patients recovering from bone marrow transplants, a new study warns. After a bone ...

  19. [Bone and Stem Cells. Intravital imaging of bone marrow microenvironment].

    PubMed

    Mizuno, Hiroki; Kikuta, Junichi; Ishii, Masaru

    2014-04-01

    Various kinds of cell types, such as osteoclasts, osteoblasts, hematopoietic cells, and mesenchymal cells, have been reported to exist in the bone marrow and communicate with each other. Although there have been many previous studies about bone marrow microenvironment, most of them were analyzed by conventional methods such as histological analysis and flow cytometry. These methods could not observe the dynamic cell movement in living bone marrow. Recently rapid development of fluorescent imaging techniques enables us to understand the cellular dynamics in vivo . That's why we have originally established an advanced imaging system for visualizing living bone tissues with intravital two-photon microscopy. Here we show the latest data and the detailed methodology of intravital imaging of bone marrow microenvironment, and also discuss its further application.

  20. Allogenous bone grafts improved by bone marrow stem cells and platelet growth factors: clinical case reports.

    PubMed

    Filho Cerruti, Humberto; Kerkis, Irina; Kerkis, Alexandre; Tatsui, Nelson Hidekazu; da Costa Neves, Adriana; Bueno, Daniela Franco; da Silva, Marcelo Cavenaghi Pereira

    2007-04-01

    In order to increase the amount of available bone where dental implants must be placed, the present study has associated platelet-rich plasma (PRP) and mononuclear cells (MNCs) from bone marrow aspirate and bone scaffold (BS) in 32 patients aged between 45 and 75 years old. The MNC attainment and the adherence to the BS were confirmed through histology, cell culture, and scanning electron microscopy. The clinical results, analyzed by computed tomography, have showed that the scaffolds were well integrated and adapted to the cortical bone. We can conclude that the process of healing observed in the patients was due to the presence of mesenchymal stem cell in MNC fraction in the bone grafts.

  1. 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

  2. Radionuclide imaging of bone marrow disorders.

    PubMed

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

    2011-01-01

    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 (99m)Tc-nanocolloid, (99m)Tc-sulphur colloid, (111)In-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 (18)F-FDG and (18)F-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.

  3. Tracking Mouse Bone Marrow Monocytes In Vivo

    PubMed Central

    Hamon, Pauline; Rodero, Mathieu Paul; Combadière, Christophe; Boissonnas, Alexandre

    2015-01-01

    Real time multiphoton imaging provides a great opportunity to study cell trafficking and cell-to-cell interactions in their physiological 3-dimensionnal environment. Biological activities of immune cells mainly rely on their motility capacities. Blood monocytes have short half-life in the bloodstream; they originate in the bone marrow and are constitutively released from it. In inflammatory condition, this process is enhanced, leading to blood monocytosis and subsequent infiltration of the peripheral inflammatory tissues. Identifying the biomechanical events controlling monocyte trafficking from the bone marrow towards the vascular network is an important step to understand monocyte physiopathological relevance. We performed in vivo time-lapse imaging by two-photon microscopy of the skull bone marrow of the Csf1r-Gal4VP16/UAS-ECFP (MacBlue) mouse. The MacBlue mouse expresses the fluorescent reporters enhanced cyan fluorescent protein (ECFP) under the control of a myeloid specific promoter 1, in combination with vascular network labelling. We describe how this approach enables the tracking of individual medullar monocytes in real time to further quantify the migratory behaviour within the bone marrow parenchyma and the vasculature, as well as cell-to-cell interactions. This approach provides novel insights into the biology of the bone marrow monocyte subsets and allows to further address how these cells can be influenced in specific pathological conditions. PMID:25867540

  4. Performance of a gravitational marrow separator, multidirectional bone marrow aspiration needle, and repeated bone marrow collections on the production of concentrated bone marrow and separation of mesenchymal stem cells in horses.

    PubMed

    Ishihara, Akikazu; Helbig, Holly J; Sanchez-Hodge, Rebekah B; Wellman, Maxey L; Landrigan, Matthew D; Bertone, Alicia L

    2013-06-01

    Objective-To determine the efficiency of a novel point-of-care gravitational marrow separator and bone marrow aspiration needle for concentrated bone marrow production and bone marrow-derived mesenchymal stem cell (MSC) separation and assess the effect of repeated bone marrow collections in horses. Animals-8 healthy adult horses. Procedures-Bone marrow aspiration was performed twice (1 month apart) from sternebral bodies with a standard or prototype multidirectional needle. Concentrated bone marrow was obtained by gravitational marrow separation and evaluated for WBC and platelet counts, automated and cytomorphologic cell differential counts, MSCs, and cell viability. Results-Concentrated bone marrow samples obtained with the marrow separator had 5- to 19-fold bone marrow-derived MSC, WBC, and platelet counts, compared with original bone marrow samples. Use of a multidirectional needle increased the frequency of obtaining MSC-richer concentrated bone marrow. Repeating bone marrow aspiration at 1 month yielded greater MSC numbers but slightly lower cell viability after processing. Conclusions and Clinical Relevance-The gravitational bone marrow separator and multidirectional needle were used to effectively harvest bone marrow and improve the quality of concentrated bone marrow. Comparable, or even greater, numbers of bone marrow-derived MSCs were collected by repeated bone marrow aspiration after a 1-month interval from the same aspiration sites. Use of the marrow separator and multidirectional bone marrow aspiration needle can facilitate a 1-step, point-of-care, nonlaboratory method to obtain concentrated bone marrow as a mixture of bone marrow-derived MSCs and growth factors from platelets and plasma.

  5. Bone marrow osteoblast vulnerability to chemotherapy.

    PubMed

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

    2013-06-01

    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. As 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.

  6. Bone marrow cells and myocardial regeneration.

    PubMed

    Wang, Fu-Sheng; Trester, Cathy

    2004-05-01

    Hematopoietic stem cell (HSC) plasticity and its clinical application have been studied profoundly in the past few years. Recent investigations indicate that HSC and other bone marrow stem cells can develop into other tissues. Because of the high morbidity and mortality of myocardial infarction and other heart disorders, myocardial regeneration is a good example of the clinical application of HSC plasticity in regenerative medicine. Preclinical studies in animals suggest that the use of this kind of treatment can reconstruct heart blood vessels, muscle, and function. Some clinical study results have been reported in the past 2 years. In 2003, reports of myocardial regeneration treatment increased significantly. Other studies include observations on the cell surface markers of transplanted cells and treatment efficacy. Some investigations, such as HSC testing, have focused on clinical applications using HSC plasticity and bone marrow transplantation to treat different types of disorders. In this review, we focus on the clinical application of bone marrow cells for myocardial regeneration.

  7. [Method for concentrating marrow stem cells using the IBM 2991 washer. Necessary preparation before in vitro treatment of bone marrow by pharmacologic or immunologic means].

    PubMed

    Hervé, P; Coffe, C; Peters, A

    1983-04-01

    The technique using the IBM 2991 blood cell processor is an effective technique for the concentration of mononuclear cells from large volumes of bone marrow. The marrow cells are layered on to Ficoll Metrizoate using the IBM processing set. The mononuclear cells and CFU-GM recoveries are in close relationship with the hematocrit of the cell suspension processed. Twenty two bone marrows have been collected and purified according to this protocol. The mononuclear cell recovery is an average of 78,3% (range: 44-92%) and the CFU-GM recovery is in average of 67,5% (range: 40-89%). At the end of the procedure the cell viability is satisfying (97,1% +/- 1,7 are trypan blue negatives). When it is necessary to remove from the bone marrow collected either malignant cells prior autologous bone marrow graft or T lymphocytes in an attempt to prevent GVHD in allogeneic BMT, the purity of marrow cell suspension become a fundamental parameter.

  8. To evaluate the role of bone marrow aspiration and bone marrow biopsy in pancytopenia.

    PubMed

    Desalphine, Melina; Bagga, Permeet Kaur; Gupta, Parmod Kumar; Kataria, Amarjit Singh

    2014-11-01

    Pancytopenia is not a disease entity but a triad of findings that may result from various disease processes, primarily or secondarily involving the bone marrow. Bone marrow aspiration and biopsy evaluation along with good clinical correlation is of utmost importance to evaluate the causes of pancytopenia and planning further investigations. The present study was a prospective clinicohaematological study undertaken to analyse the various causes of pancytopenia by evaluating bone marrow aspiration and biopsy and correlating with clinical findings, complete blood counts and peripheral blood picture. Fifty patients of pancytopenia were included in the study in which relevant history and physical examination findings were recorded. Bone marrow aspiration and biopsy were performed simultaneously in all cases. Perl's stain was done in all cases and special stains like MPO, PAS and reticulin were also done wherever necessary. The maximum cases of pancytopenia were in the age group of 10 to 30 y with male preponderance. Aplastic anaemia was found to be the most common aetiology of pancytopenia followed by normoblastic erythroid hyperplasia, megaloblastic anaemia, acute leukemias, myelofibrosis, lymphoid neoplasia and iron deficiency anaemia. It was concluded from the study that although the advantages of bone marrow aspiration and biopsy differ, both are complimentary to each other and should be performed simultaneously for a complete bone marrow work up and evaluation. It is only through the correlation of clinical, hematological and bone marrow examination findings that proper evaluation and management of patients of pancytopenia can be made.

  9. To Evaluate the Role of Bone Marrow Aspiration and Bone Marrow Biopsy in Pancytopenia

    PubMed Central

    Desalphine, Melina; Gupta, Parmod Kumar; Kataria, Amarjit Singh

    2014-01-01

    Background: Pancytopenia is not a disease entity but a triad of findings that may result from various disease processes, primarily or secondarily involving the bone marrow. Bone marrow aspiration and biopsy evaluation along with good clinical correlation is of utmost importance to evaluate the causes of pancytopenia and planning further investigations. Aims: The present study was a prospective clinicohaematological study undertaken to analyse the various causes of pancytopenia by evaluating bone marrow aspiration and biopsy and correlating with clinical findings, complete blood counts and peripheral blood picture. Materials and Methods: Fifty patients of pancytopenia were included in the study in which relevant history and physical examination findings were recorded. Bone marrow aspiration and biopsy were performed simultaneously in all cases. Perl’s stain was done in all cases and special stains like MPO, PAS and reticulin were also done wherever necessary. Results and Conclusion: The maximum cases of pancytopenia were in the age group of 10 to 30 y with male preponderance. Aplastic anaemia was found to be the most common aetiology of pancytopenia followed by normoblastic erythroid hyperplasia, megaloblastic anaemia, acute leukemias, myelofibrosis, lymphoid neoplasia and iron deficiency anaemia. It was concluded from the study that although the advantages of bone marrow aspiration and biopsy differ, both are complimentary to each other and should be performed simultaneously for a complete bone marrow work up and evaluation. It is only through the correlation of clinical, hematological and bone marrow examination findings that proper evaluation and management of patients of pancytopenia can be made. PMID:25584228

  10. HIV infection presenting as bone marrow cryptococcosis

    PubMed Central

    Dharwadkar, Arpana; Vimal, Shruti; Buch, Archana C.; Panicker, N. K.

    2014-01-01

    Disseminated cryptococcal infection is an uncommon initial manifestation in immunocompromised patients. We report a rare case of a 40-year-old female presenting with fever and burning epigastrium. Peripheral blood film revealed a leukoerythroblastic picture with thrombocytopenia. Bone marrow aspiration showed granulomas along with cryptococcal yeast forms. The ELISA test for detection of human immunodeficiency virus (HIV) antigen was positive. Disseminated cryptococcosis can develop as the first manifestation of HIV infection in previously healthy individuals and granulomas in such bone marrow aspiration smears are a valuable clue to an underlying opportunistic infection. PMID:25161991

  11. Blood and Bone Marrow Evaluation for Eosinophilia.

    PubMed

    Boyer, Daniel F

    2016-10-01

    Evaluation of peripheral blood and bone marrow for an indication of persistent eosinophilia can be a challenging task because there are many causes of eosinophilia and the morphologic differences between reactive and neoplastic causes are often subtle or lack specificity. The purpose of this review is to provide an overview of the differential diagnosis for eosinophilia, to recommend specific steps for the pathologist evaluating blood and bone marrow, and to emphasize 2 important causes of eosinophilia that require specific ancillary tests for diagnosis: myeloproliferative neoplasm with PDGFRA rearrangement and lymphocyte-variant hypereosinophilic syndrome.

  12. Effect of peripheral lymphoid cells on the incidence of lethal graft versus host disease following allogeneic mouse bone marrow transplantation

    SciTech Connect

    Almaraz, R.; Ballinger, W.; Sachs, D.H.; Rosenberg, S.A.

    1983-02-01

    Experiments were performed to study the role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation-induced fully allogeneic mouse chimeras. The incidence of GVHD was reduced significantly in BALB/c leads to C57BL/6 radiation chimeras if bone marrow donors were exsanguinated immediately prior to marrow harvest. Chimeras resulting from the injection of bone marrow from bled donors exhibited only donor cells in spleen, bone marrow and peripheral blood and normal levels of Thy 1+ and Ia+ cells were found in each of these lymphoid compartments. The addition of as few as 3 X 10(4) peripheral mononuclear cells to the marrow from exsanguinated donors uniformly led to lethal GVHD. /sup 51/Cr-labeled cell traffic studies revealed that prior exsanguination of marrow donors led to about a 70% reduction in the number of circulating mononuclear cells contaminating the bone marrow at the time of marrow harvest. This decrease in contaminating peripheral cells was calculated to be in the appropriate range to account for the decreased GVHD seen when marrow from exsanguinated donors was used. It thus appears that peripheral cells contaminating marrow can be an important factor in causing lethal GVHD in allogeneic radiation chimeras.

  13. Human bone marrow-derived IgA is produced by IgA-committed B cells in vitro.

    PubMed

    Alley, C D

    1987-03-01

    Although human bone marrow has been implicated in the production of serum immunoglobulins, little information is available concerning the kinetics of antibody production (primary- or secondary-type humoral response) or the cells that are responsible for antibody production in human bone marrow. In this study, the kinetics of and cells responsible for antibody production in the bone marrow were investigated. Previous studies have demonstrated that human bone marrow mononuclear cells secrete a significant amount of IgA in vitro. This finding led to the focus of the present investigation on bone marrow IgA production. The results reported here demonstrate that IgA was synthesized de novo in cultures of bone marrow mononuclear cells; its peak concentration in the culture supernatants preceded that of IgM; its production was totally inhibited by the addition of microgram quantities of anti-alpha-chain antiserum, while milligram quantities of anti-mu-chain antiserum were required for even partial inhibition of IgA production; and the culture of isolated IgA-bearing cells resulted in a greater than 13-fold increase in IgA concentration in the culture supernatants as compared with those from unseparated bone marrow mononuclear cells. From this study, it was concluded that bone marrow produces IgA as a secondary or anamnestic response to some undetermined stimulus and that IgA-committed B cells residing in, although probably not stimulated in, the bone marrow compartment were responsible for the IgA synthesis and secretion in vitro.

  14. Androgen, Estrogen and the Bone Marrow Microenvironment

    DTIC Science & Technology

    2009-12-01

    vivo in osteoblasts, BM stromal cells, and endothelial cells. Primary human bone marrow stromal cell cultures secrete IGFBP5. In vitro, treatment of...immortalized prostate epithelial cells. Treatment of mice with DES for 3 weeks had a dramatic effect on the bone. 518 genes were upregulated by...DES by at least 1.5 fold with a false discovery rate of < 5%. The genes that are 5-fold or greater overexpressed after DES treatment are: procollagen

  15. The effect of peripheral lymphoid cells on the incidence of lethal graft versus host disease following allogeneic mouse bone marrow transplantation

    SciTech Connect

    Almaraz, R.; Ballinger, W.; Sachs, D.H.; Rosenberg, S.A.

    1983-02-01

    Experiments were performed to study the role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation-induced fully allogeneic mouse chimeras. The incidence of GVHD was reduced significantly in BALB/c leads to C57BL/6 radiation chimeras if bone marrow donors were exsanguinated immediately prior to marrow harvest. Chimeras resulting from the injection of bone marrow from bled donors exhibited only donor cells in spleen, bone marrow and peripheral blood and normal levels of Thy 1+ and Ia+ cells were found in each of these lymphoid compartments. The addition of as few as 3 X 10(4) peripheral mononuclear cells to the marrow from exsanguinated donors uniformly led to lethal GVHD. /sup 51/Cr-labeled cell traffic studies revealed that prior exsanguination of marrow donors led to about a 70% reduction in the number of circulating mononuclear cells contaminating the bone marrow at the time of marrow harvest. This decrease in contaminating peripheral cells was calculated to be in the appropriate range to account for the decreased GVHD seen when marrow from exsanguinated donors was used. It thus appears that peripheral cells contaminating marrow can be an important factor in causing lethal GVHD in allogeneic radiation chimeras. These results raise the possibility that the fulminant GVHD seen in human marrow transplantation is in part due to the major contamination of bone marrow with peripheral blood that results from the techniques currently used for human bone marrow harvest.

  16. Intracranial extramedullary hematopoiesis. CT and bone marrow scan findings

    SciTech Connect

    Urman, M.; O'Sullivan, R.A.; Nugent, R.A.; Lentle, B.C. )

    1991-06-01

    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.

  17. Gelatinous bone marrow in an HIV-positive patient

    PubMed Central

    Stephens, Johnny R.; Baker, Damon L.

    2007-01-01

    Gelatinous bone marrow transformation has been identified in patients with anorexia, malignancy, malabsorption, and HIV/AIDS. This represents a deposition of gelatinous material within the bone marrow, along with atrophy. We report the case of an HIV-seropositive man who presented with low back pain related to his gelatinous bone marrow changes. PMID:17637880

  18. Gelatinous bone marrow in an HIV-positive patient.

    PubMed

    Stroup, Jeffrey S; Stephens, Johnny R; Baker, Damon L

    2007-07-01

    Gelatinous bone marrow transformation has been identified in patients with anorexia, malignancy, malabsorption, and HIV/AIDS. This represents a deposition of gelatinous material within the bone marrow, along with atrophy. We report the case of an HIV-seropositive man who presented with low back pain related to his gelatinous bone marrow changes.

  19. Bone marrow-derived lung epithelial cells.

    PubMed

    Krause, Diane S

    2008-08-15

    Bone marrow-derived cells can take on the phenotype of epithelial cells and express epithelial-specific genes in multiple organs. Here, we focus on recent data on the appearance of marrow-derived epithelial cells in the adult lung. These findings have garnered significant skepticism because in most cases marrow-derived epithelial cells are very rare, the marrow cell of origin is not known, the techniques for detection have needed improvement, and there seem to be multiple mechanisms by which this occurs. Recent studies have focused on these concerns. Once these important concerns are addressed, further studies on the function(s) of these cells will need to be performed to determine whether this engraftment has any clinical significance-either beneficial or detrimental.

  20. Future of bone marrow transplantation in oncology

    SciTech Connect

    Fefer, A.

    1982-05-01

    The editorial presents an assessment of the current status of bone marrow transportation (BMT) for treatment of leukemia and the problems that must be resolved to render the approach more widely applicable. Studies are in progress which may show that the patient's autologous bone marrow, cryopreserved when it has no detectable tumor and reinfused after supralethal chemoradiotherapy, is associated with long-term, tumor-free survival. Effective chemoradiotherapy regimens may be identified from studies of twin BMT and the potential problem of tumor contamination of infused autologous marrow resolved by using monoclonal antibodies directed to tumor cells. Solving the problems associated with syngeneic, allogenic or autologous BMT may make it possible to use BMT for patients with nonhematologic malignancies sensitive to high doses of chemoradiotherapy. (JMT)

  1. Translational Control in Bone Marrow Failure

    DTIC Science & Technology

    2015-05-01

    HCLS1 associated protein X-1 (HAX1), cause hereditary forms of neutropenia. Previously, competing hypotheses have posited that mutant forms of...common pathways in different forms of hereditary neutropenia, and better understand how different types of mutations result in pathogenesis. Specific... hereditary forms of neutropenia and other bone marrow failure syndromes, including myelodysplasia (which is a complication of hereditary neutropenia) by

  2. The diagnostic value of bone marrow iron.

    PubMed

    Wulfhekel, U; Düllmann, J

    1990-01-01

    The light and electronmicroscopic representation of non-haemiron in the bone-marrow provides the unique opportunity of extensively evaluating the iron metabolism. In the bone-marrow, macrophages represent the physiological place of iron storage. The iron in the cytoplasma is stored in them in the form of free ferritin molecules and lysomally as aggregated ferritin and/or haemosiderin in siderosomes. In an equal iron balance and unimpaired internal iron exchange only erythroblasts (sideroblasts) and erythrocytes (siderocytes) of the bone-marrow besides macrophages possess siderosomes. In addition to this physiological or orthotopic iron storage a heterotopic iron storage can be observed under pathological conditions, particularly with iron overloading of the organism, in the endothelial cells of sinusoids and plasma cells. In detail, the patterns of iron storage in the bone-marrow are described in the different stages of iron deficiency, disturbance of iron utilization in chronically inflammatory processes or tumour diseases, condition after intravenous iron administration, transfusion siderosis, hereditary haemochromatosis and sideroblastic anaemia.

  3. [Genetic diversity and bone marrow transplantation].

    PubMed

    Marry, E

    2012-05-01

    The genetic origin of the patients, for whom a bone marrow transplantation has been proposed, is a key determinant in the possibility of identifying or not a compatible unrelated donor, and consequently in the possibility of performing the bone marrow transplantation. The required strict HLA compatibility, in the context of a bone marrow transplantation, increases the difficulty. A patient has one chance over four to have a compatible donor within his brothers and sisters, if any. This chance becomes one over a million, as an average, in the context of unrelated donor search. Taking into consideration the genetic history of the populations, their evolution and the large actual HLA diversity, the probability of finding an unrelated donor for a defined patient varies according to the frequency and the combination of the patient's HLA antigens, genetic markers inherited not only from his parents, but also from his ancestries. In the unrelated context, the HLA compatible donor most probably shares the same genetic history than the patient, and consequently belongs to the same population group. The study of the genetic of populations explains the difficulties in finding an unrelated compatible donor in the migrant populations, particularly those originated from Africa and from the middle east, due to their HLA specificities and to the small number of donors sharing the same origins registered on a volunteer bone marrow donors' file worldwide.

  4. The mechanism of thymus-dependent antibody formation in bone marrow.

    PubMed

    Koch, G; Osmond, D G; Julius, M H; Benner, R

    1981-04-01

    During the primary immune response of mice to i.v. administered thymus-dependent antigens the spleen is the major site of localization of antibody-producing plaque-forming cells (PFC). During the secondary response, on the other hand, large numbers of PFC not only appear in the spleen, but also in the bone marrow. By inducing B memory cells with a DNP-carrier complex and activating the DNP-specific B memory cells with the same hapten conjugated to a heterologous carrier, we show in this paper that B memory cells, but not necessarily T memory cells, must be present before booster immunization for PFC to appear in the bone marrow. The origin of the PFC that appear in the bone marrow during secondary type immune response was studied in parabiotic mice consisting of members congenic for the Igh-1 locus. From analysis of the allotype of antibodies produced by PFC in the marrow of such pairs of parabionts it appeared that antibody formation in bone marrow is dependent on the immigration into the marrow of B memory cells activated in peripheral lymphoid organs. Consistent with such a migration of activated cells, radioautographic studies in guinea pigs demonstrated an influx of newly formed mononuclear cells into the bone marrow via the blood stream during the first 3 days after intravascular antigen administration.

  5. Bone marrow concentrate with allograft equivalent to autograft in lumbar fusions.

    PubMed

    Johnson, Robert G

    2014-04-20

    Prospective randomized study. To compare autologous bone marrow concentrate mixed with allograft cancellous bone to iliac crest autograft in lumbar fusions. Bone marrow has been shown to be a rich source of osteoprogenitor cells. Osteoprogenitor cells have been shown in animals, and some human studies, to have potential in use as a bone graft substitute. Twenty-five patients underwent from 1- to 3-level lumbar fusions. One patient was lost to follow-up. On one half of the spine, allograft plus autologous bone marrow concentrate was used, whereas on the other half, autologous iliac crest bone was used. Cellular analysis, consisting of nucleated cell count, mononuclear cell count, CD34+ count, and colony-forming-units-fibroblast count, was done on marrow aspirates and concentrates. At 1 year postoperation, computed tomographic scans of the fusions were evaluated on a blinded basis by 2 neuroradiologists independent of each other. Radiographical fusion was the primary outcome measure. There was no statistical difference in fusion scores between allograft and autograft in the lateral gutters, interbody cages, or facet joints. There was a positive trend between CD34+ counts and radiographical fusion. The study shows equivalence between cancellous allograft mixed with bone marrow concentrate and autologous iliac crest bone for lumbar fusions. 2.

  6. Value of bone marrow imprint smears in early diagnosis of bone marrow pathologies.

    PubMed

    Tilak, Vijai; Das, Subhajit; Bundhun, Soobashchan

    2014-11-01

    Examination of bone marrow plays a pivotal role in the practice of haematology. It can be evaluated by three ways-bone marrow aspiration (BMA), bone marrow touch imprints (BMI) and bone marrow biopsy (BMBx). To study the efficacy and reliability of BMI smears in comparison to BMA smears, in making a diagnosis of diseases involving bone marrow. Setting and Designs: This study was carried out in the Department of Pathology, Institute of Medical Sciences, Varanasi over a period of 26 months. A total number of 182 cases, with their BMA, BMI and BMBx samples (from each and every case), were evaluated and their findings even compared. All the observations were evaluated using simple and basic statistical tool, i.e. percentage. The cellularity or cell density on BMI correlated with the cellularity of BMBx in 78.6% cases, which was higher than the value observed with BMA smears (71.4%). The spreading quality was better and cytological details were better appreciated in BMI as compared to BMA. Also, the presence of lymphoglandular bodies and particles on BMI were additive diagnostic clues. All of those findings were reflected in the higher diagnostic accuracy of BMI than BMA. BMI should be a standard practice and be considered as an early and reliable diagnostic tool for evaluating bone marrow pathologies.

  7. Comparison of bone marrow aspiration and bone marrow biopsy in neoplastic diseases.

    PubMed

    Hamid, G A; Hanbala, N

    2009-07-01

    Naturally trephine biopsies have definitive advantages over aspirates in case of dry tap bone marrow aspirates as a result of fibrosis or densely packed bone marrow by tumour cells and may be informative independent of cytology especially in bone marrow involvement by lymphomas and carcinomas. In this prospective descriptive study we aimed to compare between the bone marrow trephine biopsy (BMTB) and bone marrow aspirates (BMAs) regarding the detection rate of solid tumours, lymphoma and myeloma involvement of the bone marrow. The study was carried out in the department of pathology and Haematology-Oncology of Al-Gamhouria Teaching Hospital/Aden during the period between Jan 2005 to Dec 2005. A total of 32 patients with suspected or confirmed malignancy undergone both BMTB and BMA from the posterior superior iliac crest and both results were compared. We divided them into three groups: those with solid tumours (21) patients, lymphoma (7) patients and with MM (4) patients. Our results showed that BMA had a 47.6% sensitivity, 100.0% specificity, with positive predictive value (100%), and negative predictive value (50.0%). In solid tumours alone it had a sensitivity of (40.0%), 100% specificity, with positive predictive value (100%), and negative predictive value (64.7%). This gives the BMA a lower sensitivity in detecting solid tumour metastasis and lymphoma involvement in comparison to BMTB. In conclusion, any patient with suspected or confirmed cancer should undergo BMTB because of its high sensitivity compared to BMA.

  8. [Significance of Simultaneous Analysis of Bone Marrow Smear and Bone Marrow Biopsy in the Diagnosis of Lymphoma].

    PubMed

    Zhao, Juan; Yuan, Ting-Ting; Yang, Xuao-Liang; Guan, Jian-Hong

    2017-06-01

    To explore the value of bone marrow smear combined with biopsy in the diagnosis of lymphoma. Clinical data of 50 cases of lymphoma from our hospital were analyzed retrospectively, and the results of the bone marrow smear and the bone marrow biopsy were compared simultaneously. The decision for the degree of bone marrow hyperplasia in bone marrow biopsy slice was superior to that in smear, and the active or highly active hyperplasia of nucleated cells were observed in all the bone marrow biopsies; the lymphomatic cells were observed in bone marrow smear of the 12 patients(24%), but the bone marrow biopsies showed a higher detection rate of lymphomatic cells 44% in 22 patients(P<0.05); The hyperplasia of bone marrow fibrous tissue, mainly mild to moderate, were the common in cases with bone marrow involvement and the severity of bone marrow fibrosis positively correlated with the number of lymphomatic cells. Biopsy combined with aspiration can improve the accuracy of diagnosis in lymphoma with bone marrow involvement.

  9. 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.

  10. A clinical overview of bone marrow edema.

    PubMed

    Manara, M; Varenna, M

    2014-07-28

    Bone marrow edema (BME) is a descriptive term which identifies a specific magnetic resonance imaging (MRI) pattern that can be observed in a number of clinical entities, which are often characterized by pain as their main symptom, but show significant differences in terms of histopathological findings, causal mechanisms and prognosis. Bone marrow lesions in the subchondral bone of subjects with knee osteoarthritis (OA) seem to be associated with pain and progression of cartilage damage over time. Some histopathological studies of advanced OA have shown a prevalent fibrosis and bone marrow necrosis. BME of the subchondral bone in rheumatoid arthritis is associated with an infiltrate of inflammatory cells and osteoclasts and has a predictive value of further development of erosions. In spondyloarthritis, BME of the sacroiliac joints identifies an active sacroiliitis and is associated with histological inflammation and radiographic progression, whereas the relationship between BME lesions of the spine and syndesmophyte development is still controversial. BME syndromes (BMES), such as transient osteoporosis of the hip, regional migratory osteoporosis, and transient post-traumatic BMES, are characterized by a BME pattern on MRI and a self-limiting course. The potential evolution of BMES toward osteonecrosis is still controversial.

  11. Femoral bone marrow aspiration in live mice.

    PubMed

    Chung, Young Rock; Kim, Eunhee; Abdel-Wahab, Omar

    2014-07-05

    Serial sampling of the cellular composition of bone marrow (BM) is a routine procedure critical to clinical hematology. This protocol describes a detailed step-by-step technical procedure for an analogous procedure in live mice which allows for serial characterization of cells present in the BM. This procedure facilitates studies aimed to detect the presence of exogenously administered cells within the BM of mice as would be done in xenograft studies for instance. Moreover, this procedure allows for the retrieval and characterization of cells enriched in the BM such as hematopoietic stem and progenitor cells (HSPCs) without sacrifice of mice. Given that the cellular composition of peripheral blood is not necessarily reflective of proportions and types of stem and progenitor cells present in the marrow, procedures which provide access to this compartment without requiring termination of the mice are very helpful. The use of femoral bone marrow aspiration is illustrated here for cytological analysis of marrow cells, flow cytometric characterization of the hematopoietic stem/progenitor compartment, and culture of sorted HSPCs obtained by femoral BM aspiration compared with conventional marrow harvest.

  12. 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

  13. PECULIAR IMMUNOBIOLOGY OF BONE MARROW ALLOGRAFTS

    PubMed Central

    Cudkowicz, Gustavo; Bennett, Michael

    1971-01-01

    Mice are capable of rejecting H-2-incompatible bone marrow grafts after a single lethal exposure to X-rays. The onset of rejection begins 18–24 hr after transplantation and is completed by 96 hr. Maturation of this type of allograft reactivity does not occur until the 22nd day of life. In adult mice, the resistance to marrow allografts can be weakened by administration of cyclophosphamide or dead cultures of Corynebacterium parvum, but not heterologous anti-thymocyte serum. Sublethal exposures to X-rays 7 or 14 days before transplantation also weaken resistance. There is considerable interstrain variation in the ability of mice to resist allografts, even when H-2 differences between hosts and donor are kept identical. Although H-2 incompatibility is a necessary prerequisite for resistance, additional genetic factors influence the outcome of marrow allografts, presumably by controlling recognition. The regulator genes are determinant specific and the alleles for resistance or responder status appear to be dominant. The responder phenotype is expressed by hemopoietic cells and not by the environment. Accordingly, resistance is conferred to otherwise susceptible mice upon transfer of bone marrow cells but not of serum. The production and differentiation of effector cells for marrow graft rejection are thymus independent. In conclusion, bone marrow allografts elicit a particular transplantation reaction, previously unknown, in irradiated mice. Peculiar features of this reaction are the lack of proliferation of host lymphoid cells, tissue specificity, thymus independence, and regulation by genetic factors which apparently do not affect the fate of other grafts. PMID:4397663

  14. Comparison of bone marrow aspiration cytology with bone marrow trephine biopsy histopathology: An observational study.

    PubMed

    Gilotra, Meenu; Gupta, Monika; Singh, Sunita; Sen, Rajeev

    2017-01-01

    Bone marrow examination is a useful investigative tool for the diagnosis of many hematological and nonhematological disorders. Bone marrow aspiration (BMA) provides information about the numerical and cytological features of marrow cells, whereas bone marrow trephine biopsies (BMB) provide excellent appreciation of spatial relationships between cells and of overall bone marrow structure. We conducted this study with the objective of comparing the accuracy of BMA with BMB in the diagnosis of various hematological disorders. Both BMA and BMB were performed on a total of 130 cases and a comparative evaluation was performed in 100 cases to see the complementary role of both the procedures. However, 30 cases were excluded due to inadequate BMA, BMB, or both. Immunohistochemistry (IHC) was employed whenever required. In our study of 100 cases, 87% of cases were confirmed on bone marrow biopsy and in remaining 13% of cases final diagnosis was achieved with the help of other ancillary investigations. These cases were excluded for calculation of concordance rate between BMA and BMB. The concordance and disconcordance rate between BMA and BMB was 72.4% and 27.6%, respectively. BMA cytology and trephine biopsy histopathology complement each other and the superiority of one method over the other depended on the underlying disorder. Furthermore, application of ancillary techniques such as flow cytometery and IHC proved to be an additional advantage in further typing of various diseases.

  15. MR imaging of therapy-induced changes of bone marrow

    PubMed Central

    Henning, Tobias; Link, Thomas M.

    2006-01-01

    MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the bone marrow after radiation therapy and chemotherapy will be described. In addition, changes in bone marrow microcirculation and metabolism after anti-angiogenesis treatment will be reviewed. Finally, new specific imaging techniques for the depiction of regulatory events that control blood vessel growth and cell proliferation will be discussed. Future developments are directed to yield comprehensive information about bone marrow structure, function and microenvironment. PMID:17021706

  16. Sensitive fluorescent in situ hybridisation method for the characterisation of breast cancer cells in bone marrow aspirates.

    PubMed Central

    Forus, A; Høifødt, H K; Overli, G E; Myklebost, O; Fodstad, O

    1999-01-01

    AIM: The presence of malignant cells in the blood and bone marrow of patients with cancer at the time of surgery may be indicative of early relapse. In addition to their numbers, the phenotypes of the micrometastatic cells might be essential in determining whether overt metastases will develop. This study aimed to establish a sensitive method for the detection and characterisation of malignant cells present in bone marrow. METHODS: In spiking experiments, SKBR3 cells were mixed with mononuclear cells in known proportions to mimic bone marrow samples with micrometastatic cells. Tumour cells were extracted using SAM-M450 Dynabeads coupled to the MOC-31 anti-epithelial antibody, and were further analysed for amplification of erbB2 and int2 by fluorescent in situ hybridisation (FISH). erbB2 and int2 copy numbers were also determined in 15 primary breast cancers, and bone marrow samples from patients with amplification were analysed for micrometastatic cells by immunomagnetic enrichment and FISH. RESULTS: In model experiments, cells with amplification could be detected in bead selected fractions when ratios of tumour cells (SKBR3) to mononuclear cells were as low as 10:10(7). Among the tumour samples, eight showed increased copy numbers of erbB2 and/or int2, and three of these patients had detectable numbers of tumour cells in their bone marrow: 4000, 540, and 26 tumour cells/10(7) mononuclear cells, respectively. The patient with 540 tumour cells/10(7) mononuclear cells showed high level amplification of erbB2 and suffered from a particularly aggressive disease, whereas the patient with 4000 tumour cells/10(7) mononuclear cells had favourable disease progression. CONCLUSION: These results demonstrate the feasibility and advantage of combining immunomagnetic selection and FISH characterisation of cancer cells in bone marrow samples. It is possible that molecular characterisation of such cells could provide prognostically valuable information. PMID:10474684

  17. Molecular Mechanisms That Contribute to Bone Marrow Pain

    PubMed Central

    Ivanusic, Jason J.

    2017-01-01

    Pain associated a bony pathology puts a significant burden on individuals, society, and the health-care systems worldwide. Pathology that involves the bone marrow activates sensory nerve terminal endings of peripheral bone marrow nociceptors, and is the likely trigger for pain. This review presents our current understanding of how bone marrow nociceptors are influenced by noxious stimuli presented in pathology associated with bone marrow. A number of ion channels and receptors are emerging as important modulators of the activity of peripheral bone marrow nociceptors. Nerve growth factor (NGF) sequestration has been trialed for the management of inflammatory bone pain (osteoarthritis), and there is significant evidence for interaction of NGF with bone marrow nociceptors. Activation of transient receptor potential cation channel subfamily V member 1 sensitizes bone marrow nociceptors and could contribute to increased sensitivity of patients to noxious stimuli in various bony pathologies. Acid-sensing ion channels sense changes to tissue pH in the bone marrow microenvironment and could be targeted to treat pathology that involves acidosis of the bone marrow. Piezo2 is a mechanically gated ion channel that has recently been reported to be expressed by most myelinated bone marrow nociceptors and might be a target for treatments directed against mechanically induced bone pain. These ion channels and receptors could be useful targets for the development of peripherally acting drugs to treat pain of bony origin. PMID:28955292

  18. Molecular Mechanisms That Contribute to Bone Marrow Pain.

    PubMed

    Ivanusic, Jason J

    2017-01-01

    Pain associated a bony pathology puts a significant burden on individuals, society, and the health-care systems worldwide. Pathology that involves the bone marrow activates sensory nerve terminal endings of peripheral bone marrow nociceptors, and is the likely trigger for pain. This review presents our current understanding of how bone marrow nociceptors are influenced by noxious stimuli presented in pathology associated with bone marrow. A number of ion channels and receptors are emerging as important modulators of the activity of peripheral bone marrow nociceptors. Nerve growth factor (NGF) sequestration has been trialed for the management of inflammatory bone pain (osteoarthritis), and there is significant evidence for interaction of NGF with bone marrow nociceptors. Activation of transient receptor potential cation channel subfamily V member 1 sensitizes bone marrow nociceptors and could contribute to increased sensitivity of patients to noxious stimuli in various bony pathologies. Acid-sensing ion channels sense changes to tissue pH in the bone marrow microenvironment and could be targeted to treat pathology that involves acidosis of the bone marrow. Piezo2 is a mechanically gated ion channel that has recently been reported to be expressed by most myelinated bone marrow nociceptors and might be a target for treatments directed against mechanically induced bone pain. These ion channels and receptors could be useful targets for the development of peripherally acting drugs to treat pain of bony origin.

  19. Factors affecting mesenchymal stromal cells yield from bone marrow aspiration.

    PubMed

    Li, Jing; Wong, Wilfred Hing-Sang; Chan, Shing; Chim, James Chor-San; Cheung, Kenneth Man-Chee; Lee, Tsz-Leung; Au, Wing-Yan; Ha, Shau-Yin; Lie, Albert Kwok-Wei; Lau, Yu-Lung; Liang, Raymond Hin-Suen; Chan, Godfrey Chi-Fung

    2011-03-01

    This study was to investigate the variables in bone marrow harvesting procedure and individual donor factors which can potentially affect the yield of mesenchymal stromal cells (MSC). WE DETERMINED THE YIELD OF MSC FROM BONE MARROW UNDER DIFFERENT CLINICAL CONDITIONS BY COMPARING THE MSC COLONY NUMBERS FROM: (1) donors of different ages; (2) healthy donors and patients with leukemia; (3) bone marrow aspirated at different time points during marrow harvesting; (4) bone marrow harvested by different needles. During the process of harvesting, the number of MSC significantly decreased with increase number of aspiration, from 675/ml at the initial decreased to 60/ml after 100 ml bone marrow aspirated, and 50/ml after 200 ml bone marrow aspirated. The number of MSC retrieved from leukemia patients (99/ml bone marrow) was significantly lower than that of healthy donors (708/ml bone marrow). However, there was no significant difference in growth rate. There was no significant age-related difference of MSC yielded from donors <55 years. And there was no significant difference in MSC number between the samples from single end-holed needle and those from multiple-side-hole needle. The optimal bone marrow samples for MSC collection should be obtained earlier in the process of harvesting procedure. Bone marrow from donors <55 years was equally good as MSC sources. The autologous MSC from leukemia patients can be utilized for in-vitro MSC expansion.

  20. Prostaglandin E2 regulates macrophage colony stimulating factor secretion by human bone marrow stromal cells.

    PubMed

    Besse, A; Trimoreau, F; Faucher, J L; Praloran, V; Denizot, Y

    1999-07-08

    Bone marrow stromal cells regulate marrow haematopoiesis by secreting growth factors such as macrophage colony stimulating factor (M-CSF) that regulates the proliferation, differentiation and several functions of cells of the mononuclear-phagocytic lineage. By using a specific ELISA we found that their constitutive secretion of M-CSF is enhanced by tumour necrosis factor-alpha (TNF-alpha). The lipid mediator prostaglandin E2 (PGE2) markedly reduces in a time- and dose-dependent manner the constitutive and TNF-alpha-induced M-CSF synthesis by bone marrow stromal cells. In contrast, other lipid mediators such as 12-HETE, 15-HETE, leukotriene B4, leukotriene C4 and lipoxin A4 have no effect. EP2/EP4 selective agonists (11-deoxy PGE1 and 1-OH PGE1) and EP2 agonist (19-OH PGE2) inhibit M-CSF synthesis by bone marrow stromal cells while an EP1/EP3 agonist (sulprostone) has no effect. Stimulation with PGE2 induces an increase of intracellular cAMP levels in bone marrow stromal cells. cAMP elevating agents (forskolin and cholera toxin) mimic the PGE2-induced inhibition of M-CSF production. In conclusion, PGE2 is a potent regulator of M-CSF production by human bone marrow stromal cells, its effects being mediated via cAMP and PGE receptor EP2/EP4 subtypes.

  1. [One-step method of bone marrow aspiration and biopsy applied in diagnosis of the bone marrow metastatic cancer].

    PubMed

    Guan, Jian-Hong; Wang, Xiao-Ning; Ma, Kai

    2013-08-01

    This study was aimed to explore the value of one-step method of bone marrow aspiration and biopsy applied in diagnosis of the bone marrow metastatic cancer. The total of 46 cases of bone marrow metastatic cancer were analyzed retrospectively, and the results of the bone marrow smear and the bone marrow biopsies were compared. The results indicated that the success rate of one-step method of bone marrow aspiration and biopsy was 95.7%. Metastatic carcinoma cells in clumps or clusters with morphological changes were observed in the bone marrow biopsies of the 45 patients (97.8%), but the metastatic carcinoma cell clusters were observed only in bone marrow smears of the 25 patients (54.3%). There were mild to moderate hyperplasia of fibrous tissue in the patients with metastatic cancer. In addition to the 83.3% diagnostic rate of esophageal cancer, the rest diagnostic rate of bone marrow biopsy for metastatic carcinoma was 100%. The diagnostic rate of bone marrow smear for ovarian cancer, lung cancer, gastric cancer, thoracic tumor, sigmoid colon cancer, esophageal cancer and metastatic cancer of unknown primary cancers were 33.3%, 50%, 72.2%, 60%, 50%, 33.3% and 25%, respectively. The diagnostic rate of bone marrow biopsy was higher than that of bone marrow smear. It is concluded that the success rate of drawing specimen by one-step method of bone marrow aspiration and biopsy is high. The bone marrow biopsy is better than that of aspiration in diagnosis of metastatic cancer. Combining biopsy with aspiration can improve the accuracy of diagnosis.

  2. Late outgrowth endothelial cells resemble mature endothelial cells and are not derived from bone marrow.

    PubMed

    Tura, Olga; Skinner, Elizabeth M; Barclay, G Robin; Samuel, Kay; Gallagher, Ronald C J; Brittan, Mairi; Hadoke, Patrick W F; Newby, David E; Turner, Marc L; Mills, Nicholas L

    2013-02-01

    A decade of research has sought to identify circulating endothelial progenitor cells (EPC) in order to harness their potential for cardiovascular regeneration. Endothelial outgrowth cells (EOC) most closely fulfil the criteria for an EPC, but their origin remains obscure. Our aim was to identify the source and precursor of EOC and to assess their regenerative potential compared to mature endothelial cells. EOC are readily isolated from umbilical cord blood (6/6 donors) and peripheral blood mononuclear cells (4/6 donors) but not from bone marrow (0/6) or peripheral blood following mobilization with granulocyte-colony stimulating factor (0/6 donors). Enrichment and depletion of blood mononuclear cells demonstrated that EOC are confined to the CD34(+)CD133(-)CD146(+) cell fraction. EOC derived from blood mononuclear cells are indistinguishable from mature human umbilical vein endothelial cells (HUVEC) by morphology, surface antigen expression, immunohistochemistry, real-time polymerase chain reaction, proliferation, and functional assessments. In a subcutaneous sponge model of angiogenesis, both EOC and HUVEC contribute to de novo blood vessel formation giving rise to a similar number of vessels (7.0 ± 2.7 vs. 6.6 ± 3.7 vessels, respectively, n = 9). Bone marrow-derived outgrowth cells isolated under the same conditions expressed mesenchymal markers rather than endothelial cell markers and did not contribute to blood vessels in vivo. In this article, we confirm that EOC arise from CD34(+)CD133(-)CD146(+) mononuclear cells and are similar, if not identical, to mature endothelial cells. Our findings suggest that EOC do not arise from bone marrow and challenge the concept of a bone marrow-derived circulating precursor for endothelial cells. Copyright © 2012 AlphaMed Press.

  3. Autoimmune Encephalitis Following Bone Marrow Transplantation.

    PubMed

    Rathore, Geetanjali S; Leung, Kathryn S; Muscal, Eyal

    2015-09-01

    Neurological complications, especially encephalopathy and seizures, are commonly seen in bone marrow transplant patients. Infections, chemotoxicity, graft versus host disease, or secondary central nervous system malignancies are the most common underlying etiologies. There is increased awareness that autoimmune encephalitis may cause neurological dysfunction in immunocompetent children. The potential role of such a mechanism in children undergoing bone marrow transplantation is unknown. We report a boy who developed autoimmune encephalitis with voltage-gated potassium channel-associated and thyroid autoantibodies subsequent to transplantation. A 7-year-old boy presented with a change in behavior, poor attention, cognitive deficits, and abnormal movements 15 months after undergoing transplantation for idiopathic aplastic anemia. He had clinical and subclinical seizures and brain magnetic resonance imaging hyperintensities bilaterally in the uncal regions. His evaluation revealed high titers of voltage-gated potassium channel, leucine-rich glioma-inactivated 1 protein, and thyroglobulin antibodies suggestive of autoimmune limbic encephalitis. He showed significant improvement in behavior and neuropsychological testing and has remained seizure-free on levetiracetam after immunotherapy with corticosteroids and intravenous immunoglobulin. Systemic autoimmune manifestations in bone marrow transplant patients have been well-documented, but autoimmune encephalitis after transplantation has yet to be described in children. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Bone Marrow Stroma and Vascular Contributions to Myeloma Bone Homing.

    PubMed

    Moschetta, Michele; Kawano, Yawara; Sacco, Antonio; Belotti, Angelo; Ribolla, Rossella; Chiarini, Marco; Giustini, Viviana; Bertoli, Diego; Sottini, Alessandra; Valotti, Monica; Ghidini, Claudia; Serana, Federico; Malagola, Michele; Imberti, Luisa; Russo, Domenico; Montanelli, Alessandro; Rossi, Giuseppe; Reagan, Michaela R; Maiso, Patricia; Paiva, Bruno; Ghobrial, Irene M; Roccaro, Aldo M

    2017-09-09

    Herein we dissect mechanisms behind the dissemination of cancer cells from primary tumor site to the bone marrow, which are necessary for metastasis development, with a specific focus on multiple myeloma. The ability of tumor cells to invade vessels and reach the systemic circulation is a fundamental process for metastasis development; however, the interaction between clonal cells and the surrounding microenvironment is equally important for supporting colonization, survival, and growth in the secondary sites of dissemination. The intrinsic propensity of tumor cells to recognize a favorable milieu where to establish secondary growth is the basis of the "seed and soil" theory. This theory assumes that certain tumor cells (the "seeds") have a specific affinity for the milieu of certain organs (the "soil"). Recent literature has highlighted the important contributions of the vascular niche to the hospitable "soil" within the bone marrow. In this review, we discuss the crucial role of stromal cells and endothelial cells in supporting primary growth, homing, and metastasis to the bone marrow, in the context of multiple myeloma, a plasma cell malignancy with the unique propensity to primarily grow and metastasize to the bone marrow.

  5. Meeting report of the 2016 bone marrow adiposity meeting.

    PubMed

    van der Eerden, Bram; van Wijnen, André

    2017-04-05

    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.

  6. Magnetic resonance imaging of bone marrow disease in children

    SciTech Connect

    Cohen, M.D.; Klatte, E.C.; Baehner, R.; Smith, J.A.; Martin-Simmerman, P.; Carr, B.E.; Provisor, A.J.; Weetman, R.M.; Coates, T.; Siddiqui, A.

    1984-06-01

    Seven children underwent magnetic resonance imaging (MRI) of the bone marrow: results showed that it is technically feasible to obtain good MR images of marrow in children. MR has detected abnormality in the bone marrow of a child who had metastatic neuroblastoma. The extent of abnormality in the femur correlated well with findings of a bone marrow isotope scan. In one child who had idiopathic aplastic anemia, diseased marrow could not be distinguished from normal marrow on MR images. MRI identified abnormality of the marrow in osteogenic sarcoma, and demonstrated change in response to chemotherapy. It displayed marrow spread of tumors as well as CT. MRI showed marrow abnormality in four children who had leukemia.

  7. Bone marrow manifestations in multicentric Castleman disease.

    PubMed

    Ibrahim, Hazem A H; Balachandran, Kirsty; Bower, Mark; Naresh, Kikkeri N

    2016-03-01

    This study aimed to document the morphological and immunophenotypic features, and describe the diagnostic features of bone marrow (BM) involvement in human herpes virus 8 Multicentric Castleman disease (HHV8-MCD). BM trephine biopsy (BMTB) specimens from 28 patients were revisited. Samples were evaluated for expression of CD3, CD20, CD138, CD68R, glycophorin C, CD42b, HHV8-latency-associated nuclear antigen (LANA1), Epstein-Barr virus-encoded small RNA and light chains. Presence of significant numbers of HHV8-LANA1(+) lymphoid/plasmacytic cells, noted in 10/28 cases, was indicative of BM involvement and was associated with low CD4 and CD8 counts in peripheral blood. The characteristic morphological appearance of MCD seen in lymph nodes is a rare finding in BMTB. 4/5 cases with lymphoid aggregates were involved by MCD, whereas 6/23 cases without lymphoid aggregates were involved by MCD (P = 0·023). 9/18 cases with hypercellular marrow were involved by MCD, whilst only 1/8 cases with normo/hypocellular marrow showed involvement by MCD (P = 0·070). While 9/21 cases with increased marrow reticulin were involved by MCD, none of the cases with no increase in reticulin were involved by MCD (P = 0·080). Reactive plasmacytosis is a frequent finding. We conclude that bone marrow is involved in a significant proportion of patients with MCD (36%), and involvement can be identified by HHV8-LANA1 immunohistochemistry. © 2016 John Wiley & Sons Ltd.

  8. [Therapeutic potential of bone marrow stem cells in cerebral infarction].

    PubMed

    Sánchez-Cruz, Gilberto; Milián-Rodríguez, Lismary

    2015-05-16

    Introduccion. Las celulas madre constituyen una alternativa terapeutica que se encuentra en fase de experimentacion para el infarto cerebral. Objetivo. Mostrar la evidencia cientifica existente sobre el potencial terapeutico de las celulas madre de la medula osea en esta enfermedad. Desarrollo. El infarto cerebral representa el 80% de las enfermedades cerebrovasculares. La trombolisis constituye la unica terapia aprobada, pero, por su estrecha ventana terapeutica, solo se aplica a un bajo porcentaje de los pacientes. De manera alternativa, los tratamientos neurorrestauradores, como el de celulas madre, pueden aplicarse en periodos mas prolongados. Por esta razon se efectuo una busqueda bibliografica en PubMed con el empleo de las palabras clave 'stem cells', 'bone marrow derived mononuclear cells' y 'stroke'. Se encontraron evidencias de seguridad y eficacia de dichas celulas en diferentes momentos evolutivos del infarto cerebral. Se identificaron estudios que en clinica y preclinica las recolectaron por puncion medular y en sangre periferica, y las trasplantaron directamente en el area infartada o por via intravascular. El efecto terapeutico se relaciona con sus propiedades de plasticidad celular y liberacion de factores troficos. Conclusiones. El concentrado de celulas mononucleares autologas, obtenido en sangre periferica o por puncion de la medula osea, y trasplantado por via intravenosa, es una factible opcion metodologica que permitira rapidamente incrementar el numero de ensayos clinicos en diferentes etapas evolutivas del infarto cerebral. Esta terapia muestra seguridad y eficacia; sin embargo, deben ampliarse las evidencias que avalen su generalizacion en humanos.

  9. Bone Marrow Edema: Chronic Bone Marrow Lesions of the Knee and the Association with Osteoarthritis.

    PubMed

    Collins, Jason A; Beutel, Bryan G; Strauss, Eric; Youm, Thomas; Jazrawi, Laith

    2016-03-01

    Bone marrow edema of the knee occurs secondary to a myriad of causes. The hallmark of a bone marrow lesion (BML) is an area of decreased signal intensity on T1 weighted MRI with a corresponding area of increased signal intensity on a T2 weighted MRI. Recently, chronic bone marrow lesions have been correlated with knee pain and progression of osteoarthritis. These lesions have also been associated with other degenerative conditions such as meniscal tears, cartilage deterioration, subchondral cyst formation, mechanical malalignment, and ultimately progression to arthroplasty. Medical treatments, such as prostacyclin and bisphosphonate therapy, have shown promise. Alignment procedures, as well as core decompression and subchondroplasty, have been used as surgical treatments for chronic BMLs.

  10. Engineering bone grafts with enhanced bone marrow and native scaffolds.

    PubMed

    Hung, Ben P; Salter, Erin K; Temple, Josh; Mundinger, Gerhard S; Brown, Emile N; Brazio, Philip; Rodriguez, Eduardo D; Grayson, Warren L

    2013-01-01

    The translation of tissue engineering approaches to the clinic has been hampered by the inability to find suitable multipotent cell sources requiring minimal in vitro expansion. Enhanced bone marrow (eBM), which is obtained by reaming long bone medullary canals and isolating the solid marrow putty, has large quantities of stem cells and demonstrates significant potential to regenerate bone tissues. eBM, however, cannot impart immediate load-bearing mechanical integrity or maintain the gross anatomical structure to guide bone healing. Yet, its putty-like consistency creates a challenge for obtaining the uniform seeding necessary to effectively combine it with porous scaffolds. In this study, we examined the potential for combining eBM with mechanically strong, osteoinductive trabecular bone scaffolds for bone regeneration by creating channels into scaffolds for seeding the eBM. eBM was extracted from the femurs of adult Yorkshire pigs using a Synthes reamer-irrigator-aspirator device, analyzed histologically, and digested to extract cells and characterize their differentiation potential. To evaluate bone tissue formation, eBM was seeded into the channels in collagen-coated or noncoated scaffolds, cultured in osteogenic conditions for 4 weeks, harvested and assessed for tissue distribution and bone formation. Our data demonstrates that eBM is a heterogenous tissue containing multipotent cell populations. Furthermore, coating scaffolds with a collagen hydrogel significantly enhanced cellular migration, promoted uniform tissue development and increased bone mineral deposition. These findings suggest the potential for generating customized autologous bone grafts for treating critical-sized bone defects by combining a readily available eBM cell source with decellularized trabecular bone scaffolds.

  11. Bone marrow concentrate: a novel strategy for bone defect treatment.

    PubMed

    Jäger, Marcus; Jelinek, Eva M; Wess, Kai M; Scharfstädt, Axel; Jacobson, May; Kevy, Sherwin V; Krauspe, Rüdiger

    2009-01-01

    Although strong efforts have been made over the last decade to introduce stem cell and tissue engineering treatment strategies to the field of orthopaedics, only few clinical applications are currently available. The clinical outcomes of ten patients with volumetric bone deficiencies treated with mesenchymal stem cells and bone marrow aspirate are presented in this case series. Results were evaluated with radiographs. In addition to the in vivo data, we also presented in vitro data of BMC cultivated onto a porous collagen I scaffold and the technique of bone marrow aspiration via a commercially available system. Our results demonstrated that there is a rationale for a clinical application of BMC / bone aspirate in the treatment of osseous defects. The intraoperative harvest procedure is a safe method and does not significantly prolong the time of surgery. In addition, MSC isolated from the aspirate was able to adhere and proliferate onto a collagen scaffold in significant numbers after a 15 min incubation period. These cells were then able to allow osteogenic differentiation in vitro without any osteogenic stimuli. The local application of BMC / bone aspirate in the treatment of bone deficiencies may be a promising alternative to autogenous bone grafting and help reduce donor site morbidity.

  12. Periosteum and bone marrow in bone lengthening: a DEXA quantitative evaluation in rabbits.

    PubMed

    Guichet, J M; Braillon, P; Bodenreider, O; Lascombes, P

    1998-10-01

    We quantitatively studied the role of periosteum and bone marrow-endosteum during lengthening in 18 growing rabbits, comparing four surgical procedures: 1) periosteum and bone marrow preservation, 2) periosteum preservation, bone marrow destruction, 3) periosteum destruction, bone marrow preservation, 4) periosteum and bone marrow destruction. An external fixator was set on one femur, the other serving as a control. Distraction began on day 5 and stopped on day 25 (0.25 mm/12 hours). On day 30, femora were harvested with a layer of muscle. Area, bone mineral content and density were measured by dual-energy x-ray absorptiometry. Procedure 2 showed the highest increase in bone mineral content around the elongated callus (127%) compared to procedures: 1 (81%), 3 (25%) and 4 (-8%, i.e., resorption of bone ends). A statistically significant effect on bone formation was observed when preserving (vs. destroying): 1) periosteum, 2) bone marrow (effect observed only around the distraction gap), 3) periosteum and bone marrow in combination. Periosteum alone forms a larger callus, with more mineral content than bone marrow alone, and destruction of both results in the absence of bone formation around the distraction area. Careful preservation of periosteum is essential to bone healing. Formation of bone with a large mineral content does not require bone marrow preservation, but there is an interaction effect on healing between bone marrow and periosteum.

  13. [Fundamental study of blood and bone marrow].

    PubMed

    Miura, Ikuo

    2009-10-01

    The WHO classification incorporated recent advances of immunology, cytogenetics, and molecular biology, which developed from FAB classification based on cell morphology and cytochemistry. One of the most distinct changes was "AML with recurrent genetic abnormalities." The immunological and cytogenetic studies are required to apply the classification to hematopoietic and lymphoid neoplasms in addition to conventional examinations of the blood and bone marrow. The fundamentals of specimen collection, cell counts, morphologic analysis of blood cells, special stains and other laboratory studies were described in related to the management of myeloid leukemias.

  14. The inherited bone marrow failure syndromes.

    PubMed

    Chirnomas, S Deborah; Kupfer, Gary M

    2013-12-01

    Molecular pathogenesis may be elucidated for inherited bone marrow failure syndromes (IBMFS). The study and presentation of the details of their molecular biology and biochemistry is warranted for appropriate diagnosis and management of afflicted patients and to identify the physiology of the normal hematopoiesis and mechanisms of carcinogenesis. Several themes have emerged within each subsection of IBMFS, including the ribosomopathies, which include ribosome assembly and ribosomal RNA processing. The Fanconi anemia pathway has become interdigitated with the familial breast cancer syndromes. In this article, the diseases that account for most IBMFS diagnoses are analyzed. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Autologous bone marrow transplantation by photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Gulliya, Kirpal S.

    1992-06-01

    Simultaneous exposure of Merocyanine 540 dye containing cultured tumor cells to 514-nm laser light (93.6 J/cm2) results in virtually complete cell destruction. Under identical conditions, 40% of the normal progenitor (CFU-GM) cells survive the treatment. Laser- photoradiation treated, cultured breast cancer cells also were killed, and living tumor cells could not be detected by clonogenic assays or by anti-cytokeratin monoclonal antibody method. Thus, laser photoradiation therapy could be useful for purging of contaminating tumor cells from autologous bone marrow.

  16. Performing a Better Bone Marrow Aspiration.

    PubMed

    Friedlis, Mayo F; Centeno, Christopher J

    2016-11-01

    Bone marrow aspiration (BMA) is increasingly being used to harvest stem cells for use in regenerative medicine. The focus of BMA in interventional orthopedics is to maximize the yield of mesenchymal stem cells. The authors present an improved method for BMA that involves fluoroscope or ultrasound guidance combined with anesthesia; in the authors' experience, it produces the highest possible stem cell yield and is well tolerated by patients. The authors provide a step-by-step guide to the process, along with a discussion of technical and other considerations and quick reference guides for ultrasound- and fluoroscope-guided BMA. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Bone marrow-derived dendritic cells.

    PubMed

    Roney, Kelly

    2013-01-01

    While much is understood about dendritic cells and their role in the immune system, the study of these cells is critical to gain a more complete understanding of their function. Dendritic cell isolation from mouse body tissues can be difficult and the number of cells isolated small. This protocol describes the growth of large number of dendritic cells from the culture of mouse bone marrow cells. The dendritic cells grown in culture facilitate experiments that may require large number of dendritic cells without great expense or use of large number of mice.

  18. [Modified method for whole bone marrow adherent culture of human bone marrow mesenchymal stem cells].

    PubMed

    Wang, Xiao-Qing; Zhong, Zhao-Dong; Chen, Zhi-Chao; Zou, Ping

    2014-04-01

    This study was aimed to investigate a more convenient and efficient method to cultivate the human bone marrow mesenchymal stem cells by means of natural erythrocyte sedimentation principle, based on the whole bone marrow adherent method. The bone marrow was cultured with a six-well plate instead of the flasks.Firstly, the bone marrow specimen was cultivated with the MSC complete medium for 48 h, then the upper RBC-free supernatant layer was drawn and placed into the new wells to isolate MSC. Inverted microscope was used to observe the cell morphology and to record the adherent time of first cell passage, first passaging time. The traditional whole bone marrow adherent method was used as the control. The cell cycle and cell surface markers were detected by flow cytometry,and the differentiative capacity of MSC into osteocyte and adipocyte was identified by alkaline phosphatase kit and oil red O, respectively. Besides, the proliferative curve of P1,P3,P5 of BMSC was depicted by counting method. The results showed that MSC cultured by the modified method highly expressed CD90, CD105, CD13, CD44 and lowly expressed CD14, CD45, CD34. Concerning the cell cycle feature, it was found that most of the cells were in G0/G1 phase (88.76%) , followed by G2/M phase (3.04%) and S phase (8.2%), which was in accordance with stem cell cycle characteristics. The proliferative curve showed a typical "S" type, and both the oil red O and alkaline phosphatase staining of MSC were positive. Compared with the traditional method, the modified method had the advantage of high adherence rate (P = 0.0001) and shorter passaging time for the first passage (P = 0.001), with the statistically significant difference. It is concluded that there is a large number of adherent, active and suspended MSC in the RBC-free supernatant layer after the culture of bone marrow for 48 h. Isolating MSC by the modified method is more convenient and efficient than the traditional whole bone marrow adherent method.

  19. Marrow Fat and Bone: Review of Clinical Findings

    PubMed Central

    Schwartz, Ann V.

    2015-01-01

    With growing interest in the connection between fat and bone, there has been increased investigation of the relationship with marrow fat in particular. Clinical research has been facilitated by the development of non-invasive methods to measure bone marrow fat content and composition. Studies in different populations using different measurement techniques have established that higher marrow fat is associated with lower bone density and prevalent vertebral fracture. The degree of unsaturation in marrow fat may also affect bone health. Although other fat depots tend to be strongly correlated, marrow fat has a distinct pattern, suggesting separate mechanisms of control. Longitudinal studies are limited, but are crucial to understand the direct and indirect roles of marrow fat as an influence on skeletal health. With greater appreciation of the links between bone and energy metabolism, there has been growing interest in understanding the relationship between marrow fat and bone. It is well established that levels of marrow fat are higher in older adults with osteoporosis, defined by either low bone density or vertebral fracture. However, the reasons for and implications of this association are not clear. This review focuses on clinical studies of marrow fat and its relationship to bone. PMID:25870585

  20. [Significance of Simultaneous Analysis of Bone Marrow Smear and Bone Marrow Biopsy in the Diagnosis of Multiple Myloma].

    PubMed

    Liu, Ya-Lin; Wang, Wen-Juan; Liu, Hai-Bo

    2015-08-01

    To explore the value of bone marrow smear and biopsy simultaneously applied to diagnosis of multiple myloma (MM). Clinical data of 30 cases of multiple myloma were collected from our hospital in the year 2014 and analyzed retrospectively, and the results of the bone marrow smear and the simultaneous bone marrow biopsy were compared. Hyperplasia levels in bone marrow biopsy was significantly higher than that in bone marrow smears, and the active and highly active hyperplasia of nucleated cells were observed in all the bone marrow biopsies; the myeloma cells showed a focal or diffuse distribution, the binuclear or polynuclear myeloma cells were observed in 22 patients (73%), but the detection rate of abnormal myeloma cells was 40% in bone marrow smear (P < 0.05). There was mild to moderate hyperplasia of fibrous tissue in bone marrow biopsy, and the hyperplasia degeree of fibrous tissue strongly positively correlated with the myeloma cell ratio (r = 0.412). The bone marrow smear and aspiration biopsy can complement each other so as to reduce the misdiagnosis rate, therefore contributes to the early diaglosis and treatment.

  1. Schwann cells induce neuronal differentiation of bone marrow stromal cells.

    PubMed

    Zurita, Mercedes; Vaquero, Jesús; Oya, Santiago; Miguel, Miriam

    2005-04-04

    Bone marrow stromal cells are multipotent stem cells that have the potential to differentiate into bone, cartilage, fat and muscle. Recently, bone marrow stromal cells have been shown to have the capacity to differentiate into neurons under specific experimental conditions, using chemical factors. We now describe how bone marrow stromal cells can be induced to differentiate into neuron-like cells when they are co-cultured with Schwann cells. When compared with chemical differentiation, expression of neuronal differentiation markers begins later, but one week after beginning co-culture, most bone marrow stromal cells showed a typical neuronal morphology. Our present findings support the transdifferentiation of bone marrow stromal cells, and the potential utility of these cells for the treatment of degenerative and acquired disorders of the nervous system.

  2. Effects of the bone marrow microenvironment on hematopoietic malignancy.

    PubMed

    Askmyr, Maria; Quach, Julie; Purton, Louise E

    2011-01-01

    The bone marrow (BM) is contained within the bone cavity and is the main site of hematopoiesis, the continuous development of blood cells from immature hematopoietic stem and progenitor cells. The bone marrow consists of developing hematopoietic cells and non-hematopoietic cells, the latter collectively termed the bone marrow microenvironment. These non-hematopoietic cells include cells of the osteoblast lineage, adipocytes and endothelial cells. For many years these bone marrow microenvironment cells were predicted to play active roles in regulating hematopoiesis, and recent studies have confirmed such roles. Importantly, more recent data has indicated that cells of the BM microenvironment may also contribute to hematopoietic diseases. In this review we provide an overview of the roles of the data suggesting that the cells of the bone marrow microenvironment may play an active role in the initiation and progression of hematopoietic malignancy.

  3. Investigation of effect of variations in bone fraction and red marrow cellularity on bone marrow dosimetry in radio-immunotherapy.

    PubMed

    Wilderman, S J; Roberson, P L; Bolch, W E; Dewaraja, Y K

    2013-07-21

    A method is described for computing patient-specific absorbed dose rates to active marrow which accounts for spatial variation in bone volume fraction and marrow cellularity. A module has been added to the 3D Monte Carlo dosimetry program DPM to treat energy deposition in the components of bone spongiosa distinctly. Homogeneous voxels in regions containing bone spongiosa (as defined on CT images) are assumed to be comprised only of bone, active (red) marrow and inactive (yellow) marrow. Cellularities are determined from biopsy, and bone volume fractions are computed from cellularities and CT-derived voxel densities. Electrons are assumed to deposit energy locally in the three constituent components in proportions determined by electron energy absorption fractions which depend on energy, cellularity, and bone volume fraction, and which are either taken from the literature or are derived from Monte Carlo simulations using EGS5. Separate algorithms are used to model primary β particles and secondary electrons generated after photon interactions. Treating energy deposition distinctly in bone spongiosa constituents leads to marrow dosimetry results which differ from homogeneous spongiosa dosimetry by up to 20%. Dose rates in active marrow regions with cellularities of 20, 50, and 80% can vary by up to 20%, and can differ by up to 10% as a function of bone volume fraction. Dose to bone marrow exhibits a strong dependence on marrow cellularity and a potentially significant dependence on bone volume fraction.

  4. Investigation of effect of variations in bone fraction and red marrow cellularity on bone marrow dosimetry in radio-immunotherapy

    NASA Astrophysics Data System (ADS)

    Wilderman, S. J.; Roberson, P. L.; Bolch, W. E.; Dewaraja, Y. K.

    2013-07-01

    A method is described for computing patient-specific absorbed dose rates to active marrow which accounts for spatial variation in bone volume fraction and marrow cellularity. A module has been added to the 3D Monte Carlo dosimetry program DPM to treat energy deposition in the components of bone spongiosa distinctly. Homogeneous voxels in regions containing bone spongiosa (as defined on CT images) are assumed to be comprised only of bone, active (red) marrow and inactive (yellow) marrow. Cellularities are determined from biopsy, and bone volume fractions are computed from cellularities and CT-derived voxel densities. Electrons are assumed to deposit energy locally in the three constituent components in proportions determined by electron energy absorption fractions which depend on energy, cellularity, and bone volume fraction, and which are either taken from the literature or are derived from Monte Carlo simulations using EGS5. Separate algorithms are used to model primary β particles and secondary electrons generated after photon interactions. Treating energy deposition distinctly in bone spongiosa constituents leads to marrow dosimetry results which differ from homogeneous spongiosa dosimetry by up to 20%. Dose rates in active marrow regions with cellularities of 20, 50, and 80% can vary by up to 20%, and can differ by up to 10% as a function of bone volume fraction. Dose to bone marrow exhibits a strong dependence on marrow cellularity and a potentially significant dependence on bone volume fraction.

  5. The Composite of Bone Marrow Concentrate and PRP as an Alternative to Autologous Bone Grafting

    PubMed Central

    Hakimi, Mohssen; Grassmann, Jan-Peter; Betsch, Marcel; Schneppendahl, Johannes; Gehrmann, Sebastian; Hakimi, Ahmad-Reza; Kröpil, Patric; Sager, Martin; Herten, Monika; Wild, Michael; Windolf, Joachim; Jungbluth, Pascal

    2014-01-01

    One possible alternative to the application of autologous bone grafts represents the use of autologous bone marrow concentrate (BMC). The purpose of our study was to evaluate the potency of autologous platelet-rich plasma (PRP) in combination with BMC. In 32 mini-pigs a metaphyseal critical-size defect was surgically created at the proximal tibia. The animals were allocated to four treatment groups of eight animals each (1. BMC+CPG group, 2. BMC+CPG+PRP group, 3. autograft group, 4. CPG group). In the BMC+CPG group the defect was filled with autologous BMC in combination with calcium phosphate granules (CPG), whereas in the BMC+CPG+PRP group the defect was filled with the composite of autologous BMC, CPG and autologous PRP. In the autograft group the defect was filled with autologous cancellous graft, whereas in the CPG group the defect was filled with CPG solely. After 6 weeks radiological and histomorphometrical analysis showed significantly more new bone formation in the BMC+CPG+PRP group compared to the BMC+CPG group and the CPG group. There were no significant differences between the BMC+CPG+PRP group and the autograft group. In the PRP platelets were enriched significantly about 4.7-fold compared to native blood. In BMC the count of mononuclear cells increased significantly (3.5-fold) compared to the bone marrow aspirate. This study demonstrates that the composite of BMC+CPG+PRP leads to a significantly higher bone regeneration of critical-size defects at the proximal tibia in mini-pigs than the use of BMC+CPG without PRP. Furthermore, within the limits of the present study the composite BMC+CPG+PRP represents a comparable alternative to autologous bone grafting. PMID:24950251

  6. A multiscale model of the bone marrow and hematopoiesis

    PubMed Central

    Silva, Ariosto S; Anderson, Alexander R.A.

    2013-01-01

    The bone marrow is necessary for renewal of all hematopoietic cells and critical for maintenance of a wide range of physiologic functions. Multiple human diseases result from bone marrow dysfunction. It is also the site in which “liquid” tumors, including leukemia and multiple myeloma, develop as well as a frequent site of metastases. Understanding the complex cellular and microenvironmental interactions that govern normal bone marrow function as well as diseases and cancers of the bone marrow would be a valuable medical advance. Our goal is the development of a spatially-explicit in silico model of the bone marrow to understand both its normal function and the evolutionary dynamics that govern the emergence of bone marrow malignancy. Here we introduce a multiscale computational model of the bone marrow that incorporates three distinct spatial scales, cell, hematopoietic subunit, whole marrow. Implemented as a fixed lattice 3D cellular automaton, it reproduces the spatial characteristics of the normal bone marrow and is validated against data from the daily production of mature blood cells and response of hematopoiesis after irradiation. The major mechanisms modeled in this work are: (1) replication, specialization and migration of hematopoietic cells, (2) optimized spatial configuration of sinuses and hematopoietic compartments and, (3) intravasation of mature hematopoietic cells into sinuses. Our results, using parameter estimates from literature, recapitulates normal bone marrow function and suggest an explanation for the fractal-like structure of trabeculae and sinuses in the marrow, which would be an optimization of the hematopoietic function in order to maximize the number of mature blood cells produced daily within the volumetric restrictions of the marrow. PMID:21631151

  7. Bone marrow aspirate concentrate used with bovine bone mineral to reconstruct vertical and horizontal mandibular defects: report of two techniques.

    PubMed

    Sauerbier, Sebastian; Giessenhagen, Bernd; Gutwerk, Wolfgang; Rauch, Petra; Xavier, Samuel P; Oshima, Toshiyuki; Nagursky, Heiner; Gutwald, Ralf; Schmelzeisen, Rainer

    2013-01-01

    Following initial positive reports of the use of bone marrow aspirate concentrate (BMAC) in combination with bovine bone mineral (BBM) in augmentation procedures, the technique was evaluated in patients with mandibular deficiency. Two adult patients required surgical correction of a deficient alveolar ridge (one patient showed horizontal deficiency only, and the other patient presented with horizontal and vertical deficiency) prior to dental implant placement. In both patients, the reconstruction was performed with BBM in combination with mononuclear cells concentrated by the BMAC method using different techniques. The patients recovered well from all surgical procedures. Histologically, there was uniform bone formation, which allowed placement of dental implants. The results suggest that the use of BMAC in combination with BBM, without autogenous bone, has the potential to restore horizontal and vertical mandibular alveolar defects, providing a functional bone structure and allowing dental implant placement for subsequent prosthetic rehabilitation.

  8. Enteral nutrition after bone marrow transplantation

    PubMed Central

    Papadopoulou, A; MacDonald, A; Williams, M; Darbyshire, P; Booth, I

    1997-01-01

    Accepted 16 April 1997
 Nutritional insult after bone marrow transplantation (BMT) is complex and its nutritional management challenging. Enteral nutrition is cheaper and easier to provide than parenteral nutrition, but its tolerance and effectiveness in reversing nutritional depletion after BMT is poorly defined. Nutritional status, wellbeing, and nutritional biochemistry were prospectively assessed in 21 children (mean age 7.5 years; 14 boys) who received nasogastric feeding after BMT (mean duration 17 days) and in eight children (mean age 8 years, four boys) who refused enteral nutrition and who received dietetic advice only.
 Enteral nutrition was stopped prematurely in eight patients. Greater changes in weight and mid upper arm circumference were observed in the enteral nutrition group, while positive correlations were found between the duration of feeds and increase in weight and in mid upper arm circumference. Vomiting and diarrhoea had a similar incidence in the two groups, while fever and positive blood cultures occurred more frequently in the dietetic advice group. Diarrhoea occurring during enteral nutrition was not associated with fat malabsorption, while carbohydrate malabsorption was associated with rotavirus infection only. Enteral feeding did not, however, affect bone marrow recovery, hospital stay, general wellbeing, or serum albumin concentrations. Hypomagnesaemia, hypophosphataemia, zinc and selenium deficiency were common in both groups. In conclusion, enteral nutrition, when tolerated, is effective in limiting nutritional insult after BMT. With existing regimens nutritional biochemistry should be closely monitored in order to provide supplements when required.

 PMID:9301351

  9. Aerobic nitroreduction of dehydrochloramphenicol by bone marrow.

    PubMed

    Isildar, M; Abou-Khalil, W H; Jimenez, J J; Abou-Khalil, S; Yunis, A A

    1988-06-30

    It has been previously demonstrated that dehydrochloramphenicol (DH-CAP), a bacterial metabolite of chloramphenicol, induces DNA single strand breaks in intact cells and is profoundly more cytotoxic than chloramphenicol (CAP). In view of previous observations relating genotoxicity of nitrocompounds to their nitroreduction by the target tissue, we studied the nitroreduction of DH-CAP by human and rabbit bone marrow. Nitroreduction by tissue homogenates was determined by the Bratton Marshall colorimetric assay and by high-performance liquid chromatography (HPLC). Nitroreduction of DH-CAP by bone marrow cell homogenates was observed under aerobic conditions and the reduction was both cell concentration- and time-dependent. The formation of the amino product aminodehydrochloramphenicol was confirmed by HPLC. Reduction by other tissues including human liver, Raji cells, and HL-60 tumors was also observed. These results suggest that genotoxicity of DH-CAP may be related to its nitroreduction by the target tissue with in situ production of toxic intermediates. Together with previous studies, these observations lend support to the thesis that the p-NO2 group may be the structural feature underlying aplastic anemia from CAP.

  10. [Frontiers in Live Bone Imaging Researches. In vivo imaging of bone marrow microenvironment].

    PubMed

    Mizuno, Hiroki; Ishii, Masaru

    2015-06-01

    The function of hematopoietic stem cells and leukemia stem cells depends on their interaction with complex microenvironment within the bone marrow. Conventional methods could not observe the dynamic cell movement in living bone marrow. Recently rapid development of live imaging techniques enables us to understand the cellular interaction. Intravital two-photon imaging is the ideal method to understand the nature of bone marrow because of visualizing the cellular dynamics in vivo and observing the bone marrow long time. Here we show the latest reports about bone marrow microenvironment by intravital imaging, and also discuss its further application.

  11. Autologous Bone Marrow Transplantation for Poor-Prognosis Neuroblastoma

    DTIC Science & Technology

    1987-01-01

    Recent pilot studies of intensive chemotherapy and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) or...autologous bone marrow transplantation (ABMT) have produced encouraging results. In this report, we update our original study in which 20 patients with

  12. The Procuring and Processing of Human Cadaveric Bone Marrow

    DTIC Science & Technology

    1990-01-01

    PROCESSING OF HUMAN CADAVERIC BONE MARROW 12. PERSONAL AUTHOR(S) Timothy R. Faloon 13a. TYPE OF REPORT 13b. TIMECiOVED 14. DATE OF REPORT (Year, Month, Day) S...CADAVERIC BONE MARROW PROCESSING PROTOCOL ................ 15 Procedure for processing and freezing . .................................. 15 CELL VIABILITY...18 Procedure . ....................................................... 18 USING THE COULTER COUNTER

  13. Vertebral hyperemia associated with bone marrow insult and recovery

    SciTech Connect

    Klein, H.A.; Bolden, R.O.; Simone, F.J.

    1984-06-01

    A 15-year-old boy with rhabdoid sarcoma received chemotherapy, which was followed by bone marrow depression, massive nosebleeds and, finally, hematologic recovery. On both hepatobiliary and renal scintigraphy, prominent vertebral activity was present in early images. Correlation with his clinical course suggests that the findings reflect hyperemia due to marrow insult and recovery. Radionuclide imaging to detect hyperemia may be a useful probe for drug effects on hematopoietic bone marrow.

  14. Bone marrow necrosis complicating post-transplant lymphoproliferative disorder: resolution with rituximab.

    PubMed

    Rossi, Davide; Ramponi, Antonio; Franceschetti, Silvia; Stratta, Piero; Gaidano, Gianluca

    2008-05-01

    Bone marrow necrosis is a rare cause of bone marrow failure. Malignancy is the most frequent cause of bone marrow necrosis. Among malignancies, non-Hodgkin lymphoma (NHL) accounts for 10% of cases of bone marrow necrosis. Virtually all reported cases of NHL-associated bone marrow necrosis have developed in immunocompetent hosts. We report on a case of bone marrow necrosis complicating post-transplant lymphoproliferative disorder (PTLD) and resolving after rituximab monotherapy. This case report provides the first evidence of (i) bone marrow necrosis as a complication of PTLD; (ii) rapid resolution of NHL-associated bone marrow necrosis after rituximab treatment.

  15. [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.

  16. Engineering injectable bone using bone marrow stromal cell aggregates.

    PubMed

    Ma, Dongyang; Zhong, Cuiping; Yao, Hong; Liu, Yanpu; Chen, Fulin; Li, Jianxue; Zhao, Jinlong; Mao, Tianqiu; Ren, Liling

    2011-06-01

    With the increasing popularity of minimally invasive surgery, to develop an injectable bone would be highly preferable for the repair of bone nonunions and defects. However, the use of dissociated cells and exogenous carriers to construct injectable bone faces several drawbacks. To circumvent these limitations, we first harvested a cell sheet from rabbit bone marrow stromal cells using a continuous culture method and a scraping technique. The obtained sheet was then cut into fragments of multicellular aggregates, each of which was composed of a certain number of cells, extracellular matrix, and intercellular connections. The aggregates showed apparent mineralization properties, high alkaline phosphatase activity, increased osteocalcin content, and upregulated bone markers, implying their in vitro osteogenic potential. Then, serum-free medium (the control group), dissociated cell suspension (the cell group), and suspension of multicellular aggregates (the aggregate group) were injected subcutaneously on the back of the nude mice to evaluate ectopic bone formation. The results revealed that the aggregate group showed significantly larger and denser bone at the injection sites than the cell group, whereas bone formation did not occur in the control group. Additionally, when injecting them locally into the mandibular fracture gap of delayed healing in a rabbit model, we observed the most improved bone healing in the aggregate group. More cells survive and retain at the injection sites in the aggregate group than that in the cell group postoperatively. Our study indicates that the multicellular aggregates might be considered a promising strategy to generate injectable bone tissue and improve the efficacy of cell therapy.

  17. Bone marrow lesions and subchondral bone pathology of the knee.

    PubMed

    Kon, Elizaveta; Ronga, Mario; Filardo, Giuseppe; Farr, Jack; Madry, Henning; Milano, Giuseppe; Andriolo, Luca; Shabshin, Nogah

    2016-06-01

    Bone marrow lesions (BMLs) around the knee are a common magnetic resonance imaging (MRI) finding. However, despite the growing interest on BMLs in multiple pathological conditions, they remain controversial not only for the still unknown role in the etiopathological processes, but also in terms of clinical impact and treatment. The differential diagnosis includes a wide range of conditions: traumatic contusion and fractures, cyst formation and erosions, hematopoietic and infiltrated marrow, developmental chondroses, disuse and overuse, transient bone marrow oedema syndrome and, lastly, subchondral insufficiency fractures and true osteonecrosis. Regardless the heterogeneous spectrum of these pathologies, a key factor for patient management is the distinction between reversible and irreversible conditions. To this regard, MRI plays a major role, leading to the correct diagnosis based on recognizable typical patterns that have to be considered together with coexistent abnormalities, age, and clinical history. Several treatment options have been proposed, from conservative to surgical approaches. In this manuscript the main lesion patterns and their management have been analysed to provide the most updated evidence for the differential diagnosis and the most effective treatment.

  18. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration.

    PubMed

    Colnot, Céline

    2009-02-01

    Bone repair requires the mobilization of adult skeletal stem cells/progenitors to allow deposition of cartilage and bone at the injury site. These stem cells/progenitors are believed to come from multiple sources including the bone marrow and the periosteum. The goal of this study was to establish the cellular contributions of bone marrow and periosteum to bone healing in vivo and to assess the effect of the tissue environment on cell differentiation within bone marrow and periosteum. Results show that periosteal injuries heal by endochondral ossification, whereas bone marrow injuries heal by intramembranous ossification, indicating that distinct cellular responses occur within these tissues during repair. [corrected] Next, lineage analyses were used to track the fate of cells derived from periosteum, bone marrow, and endosteum, a subcompartment of the bone marrow. Skeletal progenitor cells were found to be recruited locally and concurrently from periosteum and/or bone marrow/endosteum during bone repair. Periosteum and bone marrow/endosteum both gave rise to osteoblasts, whereas the periosteum was the major source of chondrocytes. Finally, results show that intrinsic and environmental signals modulate cell fate decisions within these tissues. In conclusion, this study sheds light into the origins of skeletal stem cells/progenitors during bone regeneration and indicates that periosteum, endosteum, and bone marrow contain pools of stem cells/progenitors with distinct osteogenic and chondrogenic potentials that vary with the tissue environment.

  19. Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies.

    PubMed

    Hu, Wenyue; Sung, Tae; Jessen, Bart A; Thibault, Stephane; Finkelstein, Martin B; Khan, Nasir K; Sacaan, Aida I

    2016-04-15

    Palbociclib (PD-0332991) is the first selective cyclin-dependent kinase (CDK) 4/6 inhibitor approved for metastatic breast cancer. Hematologic effects, especially neutropenia, are dose-limiting adverse events for palbociclib in humans. Reversible hematologic effects and bone marrow hypocellularity have been identified in toxicology studies in rats and dogs after palbociclib treatment. To understand the mechanism by which the hematologic toxicity occurs, and to further differentiate it from the myelotoxicity caused by cytotoxic chemotherapeutic agents, anin vitroassay using human bone marrow mononuclear cells (hBMNC) was utilized. This work demonstrated that palbociclib-induced bone marrow suppression occurred through cell-cycle arrest, with no apoptosis at clinically relevant concentrations, was not lineage-specific, and was reversible upon palbociclib withdrawal. In contrast, treatment with chemotherapeutic agents (paclitaxel and doxorubicin) resulted in DNA damage and apoptotic cell death in hBMNCs. In the presence or absence of the antiestrogen, palbociclib-treated hBMNCs did not become senescent and resumed proliferation following palbociclib withdrawal, consistent with pharmacologic quiescence. The breast cancer cells, MCF-7, conversely, became senescent following palbociclib or antiestrogen treatment with additive effects in combination and remained arrested in the presence of antiestrogen. Palbociclib causes reversible bone marrow suppression, clearly differentiating it from apoptotic cell death caused by cytotoxic chemotherapeutic agents. This study also distinguished the cell-cycle arresting action of palbociclib on normal bone marrow cells from the senescent effects observed in breast cancer cells. These results shed light on the mechanism and support risk management of palbociclib-induced bone marrow toxicity in the clinic. ©2015 American Association for Cancer Research.

  20. Transcoronary sinus delivery of autologous bone marrow and angiogenesis in pig models with myocardial injury

    SciTech Connect

    Vicario, J.; Piva, J.; Pierini, A.; Ortega, H.H.; Canal, A.; Gerardo, L.; Pfeiffer, H.; Campos, C.; Fendrich, I.; Novero, R.; Monti, A

    2002-06-01

    Purpose: The aim of the investigation is to study myocardial injury on pig model with two objectives: (1) feasibility of stimulating angiogenesis with fresh autologous bone marrow; (2) administration of the same fresh autologous bone marrow via coronary sinus with transitory occlusion. Methods: A controlled study was done in animal model with three phases, in a study group of 12 pigs (bone marrow administration) as well as in control group of 4 pigs (saline administration). Phase 1--production of coronary stenosis and myocardial injury; Phase 2--two weeks later, administration of bone marrow through coronary sinus with 10 min occlusion in the study group and saline solution in the control group. Phase 3--two weeks later, histological staining with hematoxylin-eosin and inmunohistochemical staining with monoclonal antibody for smooth muscle {alpha}-actin were conducted on both study and control groups. Results: The percentage of angionenesis observed in the study group was 91% and 0% in control group. Counting of positive actin in affected and control areas showed statistically significant differences in relation to both groups: study group (1.37 vs. 0.79) and control group (0.47 vs. 0.51). The percentage of mononuclear immature cells observed in the myocardium in the study group was 25% and in the control group was 0%. There was no increment in the coronary collateral circulation when comparing coronary angiography. Conclusions: Autologous bone marrow in animal model with experimental myocardial injury enhances angiogenesis, as well as vessels with smooth muscles. The transitory occlusion of the coronary sinus might be an effective way to administer cells as those from the bone marrow.

  1. Retroviral-mediated transfer of the human glucocerebrosidase gene into cultured Gaucher bone marrow.

    PubMed Central

    Nolta, J A; Yu, X J; Bahner, I; Kohn, D B

    1992-01-01

    Gaucher disease, a lysosomal glycolipid storage disorder, results from the genetic deficiency of an acidic glucosidase, glucocerebrosidase (GC). The beneficial effects of allogeneic bone marrow transplantation (BMT) for Gaucher disease suggest that GC gene transduction and the transplantation of autologous hematopoietic stem cells (gene therapy) may similarly alleviate symptoms. We have constructed a retroviral vector, L-GC, produced by a clone of the amphotropic packaging cell line PA317, which transduces the normal human GC cDNA with high efficiency. Whole-marrow mononuclear cells and CD34-enriched cells from a 4-yr-old female with type 3 Gaucher disease were transduced by the L-GC vector and studied in long-term bone marrow culture (LTBMC). Prestimulation of marrow with IL-3 and IL-6, followed by co-cultivation with vector-producing fibroblasts, produced gene transfer into 40-45% of the hematopoietic progenitor cells. The levels of GC expression in progeny cells (primarily mature myelomonocytic) produced by the LTBMC were quantitatively analyzed by Northern blot, Western blot, and glucocerebrosidase enzyme assay. Normal levels of GC RNA, immunoreactive protein, and enzymatic activity were detected throughout the duration of culture. These studies demonstrate that retroviral vectors can efficiently transfer the GC gene into long-lived hematopoietic progenitor cells from the bone marrow of patients with Gaucher disease and express physiologically relevant levels of GC enzyme activity. Images PMID:1379609

  2. 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.

  3. Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications

    PubMed Central

    Piccinin, Meghan A; Khan, Zia A

    2014-01-01

    Diabetes leads to complications in select organ systems primarily by disrupting the vasculature of the target organs. These complications include both micro- (cardiomyopathy, retinopathy, nephropathy, and neuropathy) and macro-(atherosclerosis) angiopathies. Bone marrow angiopathy is also evident in both experimental models of the disease as well as in human diabetes. In addition to vascular disruption, bone loss and increased marrow adiposity have become hallmarks of the diabetic bone phenotype. Emerging evidence now implicates enhanced marrow adipogenesis and changes to cellular makeup of the marrow in a novel mechanistic link between various secondary complications of diabetes. In this review, we explore the mechanisms of enhanced marrow adipogenesis in diabetes and the link between changes to marrow cellular composition, and disruption and depletion of reparative stem cells. PMID:26317050

  4. A case of synovial sarcoma with bone metastasis identified by bone marrow scintigraphy

    SciTech Connect

    Otsuka, N.; Morita, R.; Yamamoto, T.; Muranaka, A.; Tomomitsu, T.; Yanagimoto, S.; Sone, T.; Fukunaga, M.

    1985-04-01

    In a patient with synovial sarcoma, routine bone survey showed no abnormality, while bone marrow scintigraphy with Tc-99m sulfur colloid revealed a defect in the fifth lumbar vertebra. At surgery, tumorous invasion was noted in the fifth lumbar vertebra and the surrounding tissues. It was suggested that the bone marrow scintigraphy was particularly useful in the detection of tumorous invasion into the bone marrow at the early stage before the destruction of skeletal tissue.

  5. Cells infected with Jaagsiekte sheep retrovirus are detected in the bone marrow of asymptomatic sheep.

    PubMed

    Borobia, Marta; Ortín, Aurora; Ferrer, Luis M; Ramos, Juán J; Lacasta, Delia; De Las Heras, Marcelo

    2014-07-01

    Ovine pulmonary adenocarcinoma (OPA) is a transmissible lung cancer caused by Jaggsiekte sheep retrovirus (JSRV). It is difficult to identify animals infected with JSRV but are clinically healthy. The virus does not induce a specific antibody response and, although proviral DNA sequences of JSRV can be found in mononuclear blood cells, the detection is inconsistent. The aim of this study was to investigate the presence of JSRV in the bone marrow of infected sheep and develop a more consistent screening method. Immunohistochemical examination of bone marrow samples from 8 asymptomatic JSRV-infected sheep revealed the presence of positively labelled cells. However, JSRV could not be detected by a highly sensitive polymerase chain reaction (PCR) in bone marrow aspirates periodically collected from these animals. Results suggest that JSRV-infected cells may be present in the bone marrow of symptomless animals, but the number is below the detectable level for PCR. Therefore, this technique does not seem to be helpful for preclinical diagnosis of OPA.

  6. Differentiation potential and GFP labeling of sheep bone marrow-derived mesenchymal stem cells.

    PubMed

    Czernik, Marta; Fidanza, Antonella; Sardi, Martina; Galli, Cesare; Brunetti, Dario; Malatesta, Daniela; Della Salda, Leonardo; Matsukawa, Kazutsugu; Ptak, Grazyna E; Loi, Pasqualino

    2013-01-01

    Mesenchymal stem cells (MSCs) are an important cell population in the bone marrow microenvironment. MSCs have the capacity to differentiate in vitro into several mesenchymal tissues including bone, cartilage, fat, tendon, muscle, and marrow stroma. This study was designed to isolate, expand, and characterize the differentiation ability of sheep bone marrow-derived MSCs and to demonstrate the possibility to permanently express a reporter gene. Bone marrow was collected from the iliac crest and mononuclear cells were separated by density gradient centrifugation. Sheep MSCs cell lines were stable characterized as CD44+ and CD34- and then transfected with a green fluorescent protein (GFP) reporter gene. The GFP expression was maintained in about half (46.6%) of cloned blastocysts produced by nuclear transfer of GFP+ sheep MSCs, suggesting the possibility to establish multipotent embryonic cells' lines carrying the fluorescent tag for comparative studies on the differentiation capacity of adult stem cells (MSCs) versus embryonic stem cells. We found that sheep MSCs under appropriate culture conditions could be induced to differentiate into adipocytes, chondrocytes, and osteoblast lineages. Our results confirm the plasticity of sheep MSCs and establish the foundation for the development of a pre-clinical sheep model to test the efficiency and safety of cell replacement therapy. Copyright © 2012 Wiley Periodicals, Inc.

  7. Fetal RHD genotyping after bone marrow transplantation.

    PubMed

    Thurik, Florentine F; Page-Christiaens, Godelieve C M L; Ait Soussan, Aicha; Ligthart, Peter C; Cheroutre, Goedele M A F; Bossers, Bernadette; Veldhuisen, Barbera; van der Schoot, C Ellen; de Haas, Masja

    2016-08-01

    Fetal RHD genotyping allows targeted diagnostic testing, fetal surveillance, and eventually intrauterine treatment to D-alloimmunized pregnant women who carry an RHD+ fetus. However, false-positive and false-negative results of noninvasive prenatal fetal RHD genotyping have been described due to a variety of causes. In this case report we present two cases where noninvasive fetal RHD typing was complicated by a previous bone marrow transplantation (BMT). We describe two women with a history of allogeneic BMT in early childhood. Both were born D+ and received a transplant of their D- male sibling. Anti-D were detected during pregnancy in one of them. The biologic father of this pregnancy was D+. In both cases polymerase chain reaction procedures specific for RHD on maternal plasma DNA were positive whereas a D- neonate was born in one case (Case 1). False-positive results of noninvasive fetal RHD genotyping occur in D+ women transplanted with marrow of a D- donor, due to circulating cell-free DNA originating from nonhematopoietic tissue. The cases highlight that health care professionals and laboratories should be aware that allogeneic BMT can be a cause for false-positive results in fetal RHD genotyping with cell-free DNA in maternal plasma, and likewise the wrong fetal sex can be reported in the case of a male donor and a female fetus. Based on one of the cases we also recommend giving D- blood products to young female patients who receive a BMT of D- donors. © 2016 AABB.

  8. The Inherited Bone Marrow Failure Syndromes

    PubMed Central

    Chirnomas, S. Deborah; Kupfer, Gary M

    2013-01-01

    In spite of the rarity of inherited bone marrow failure syndromes (IBMFS), they represent diseases for which the molecular pathogenesis may be elucidated. Their study and presentation of the details of their molecular biology and biochemistry is warranted not only for appropriate diagnosis and management of afflicted patients but also because they lend clues to the normal physiology of the normal hematopoiesis and, in many cases, mechanisms of carcinogenesis. Several themes have emerged within each subsection of IBMFS, including the ribosomopathies that entail both ribosome assembly as well as ribosomal RNA processing. The Fanconi anemia (FA) pathway itself has become interdigitated with the familial breast cancer syndromes. The sections that follow present a more detailed analysis of the diseases that account for the majority of IBMFS diagnoses. PMID:24237972

  9. Mouse Models of Bone Marrow Transplantation

    PubMed Central

    Reddy, Pavan; Negrin, Robert; Hill, Geoffrey R.

    2010-01-01

    Over the last 50 years, mouse models of bone marrow transplantation have provided the critical links between graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) pathophysiology and clinical practice. The initial insight from mouse models that GVHD and GVL were T cell dependent has long been confirmed clinically. More recent translations from mouse models have included the important role of inflammatory cytokines in GVHD. Newly developed concepts relating to the ability of antigen presenting cell (APC) and T cell subsets to mediate GVHD now promise significant clinical advances. The ability to use knockout and transgenic approaches to dissect mechanisms of GVHD and GVL mean that mouse systems will continue as the predominant preclinical platform. The basic transplant approach in these models, coupled with modern “real-time” immunologic imaging of GVHD and GVL is discussed. PMID:18162233

  10. Non-myeloablative bone marrow transplantation.

    PubMed

    Ruiz-Argüelles, Guillermo J

    2003-01-01

    As a result of the evolution of knowledge in the area of allogeneic hematopoietic stem cells (HSC) transplantation, several dogmata have been broken. We now have the following information: a) successful engraftment if allogeneic HSC bone marrow ablation of the recipient is not required; b) HSC create their own space through graft-vs.-host reactions; c) several malignancies are eradicated by the graft-vs.-tumor effect; d) allografting can be conducted on an out-patient basis; e) allografting can be done in aged or debilitated individuals; f) allografting can be achieved without transfusion of blood products, and g) costs of the allografting procedures can be substantially diminished. Breaking all these dogmata has resulted in availability of HSC allografting to a larger number of individuals, thus offering true curative therapeutic options to patients who otherwise would not qualify to receive these opportunities.

  11. Bone Marrow Microenvironmental Control of Prostate Cancer Skeletal Localization

    DTIC Science & Technology

    2009-07-01

    approaches to alter the bone marrow microenvironment. The first is cyclophosphamide (CTX) treatment . Four to five weeks old male C57BL/6J mice and...cyclophosphamide pre- treatment increased metastatic PCa tumor growth in the bone. Closer observation of the data suggests that increase of tumor growth may be...a result of more tumor cells engrafted in the bone marrow space. This led us to hypothesize that cyclophosphamide pre- treatment increased

  12. Phase 1 Trial of Autologous Bone Marrow Stem Cell Transplantation in Patients with Spinal Cord Injury.

    PubMed

    Kakabadze, Zurab; Kipshidze, Nickolas; Mardaleishvili, Konstantine; Chutkerashvili, Gocha; Chelishvili, Irakli; Harders, Albrecht; Loladze, George; Shatirishvili, Gocha; Kipshidze, Nodar; Chakhunashvili, David; Chutkerashvili, Konstantine

    2016-01-01

    Introduction. A total of 18 patients, with complete motor deficits and paraplegia caused by thoracic and lumbar spine trauma without muscle atrophy or psychiatric problems, were included into this study. Materials and Methods. The bone marrow was aspirated from the anterior iliac crest under local anesthesia and the mononuclear fraction was isolated by density gradient method. At least 750 million mononuclear-enriched cells, suspended in 2 mL of saline, were infused intrathecally. Results and Discussion. The study reports demonstrated improvement of motor and sensory functions of various degrees observed in 9 of the 18 (50%) cases after bone marrow stem cell transplantation. Measured by the American Spinal Injury Association (ASIA) scale, 7 (78%) out of the 9 patients observed an improvement by one grade, while two cases (22%) saw an improvement by two grades. However, there were no cases in which the condition was improved by three grades. Conclusions. Analysis of subsequent treatment results indicated that the transplantation of mononuclear-enriched autologous BMSCs is a feasible and safe technique. However, successful application of the BMSCs in the clinical practice is associated with the necessity of executing more detailed examinations to evaluate the effect of BMSCs on the patients with spinal cord injury.

  13. Bone marrow modified acrylic bone cement for augmentation of osteoporotic cancellous bone.

    PubMed

    Arens, Daniel; Rothstock, Stephan; Windolf, Markus; Boger, Andreas

    2011-11-01

    The use of polymethylmethacrylate (PMMA) cement to reinforce fragile or broken vertebral bodies (vertebroplasty) leads to extensive bone stiffening. This might be one reason for fractures at the adjacent vertebrae following this procedure. PMMA with a reduced Young's modulus may be more suitable. The goal of this study was to produce and characterize PMMA bone cements with a reduced Young's modulus by adding bone marrow. Bone cements were produced by combining PMMA with various volume fractions of freshly harvested bone marrow from sheep. Porosity, Young's modulus, yield strength, polymerization temperature, setting time and cement viscosity of different cement modifications were investigated. The samples generated comprised pores with diameters in the range of 30-250 μm leading to porosity up to 51%. Compared to the control cement, Young's modulus and yield strength decreased from 1830 to 740 MPa and from 58 to 23 MPa respectively by adding 7.5 ml bone marrow to 23 ml premixed cement. The polymerization temperature decreased from 61 to 38 ∘C for cement modification with 7.5 ml of bone marrow. Setting times of the modified cements were lower in comparison to the regular cement (28 min). Setting times increased with higher amounts of added bone marrow from around 16-25 min. The initial viscosities of the modified cements were higher in comparison to the control cement leading to a lower risk of extravasation. The hardening times followed the same trend as the setting times. In conclusion, blending bone marrow with acrylic bone cement seems to be a promising method to increase the compliance of PMMA cement for use in cancellous bone augmentation in osteoporotic patients due to its modified mechanical properties, lower polymerization temperature and elevated initial viscosity.

  14. Bone marrow-derived osteoblast progenitor cells in circulating blood contribute to ectopic bone formation in mice

    SciTech Connect

    Otsuru, Satoru; Tamai, Katsuto . E-mail: tamai@gts.med.osaka-u.ac.jp; Yamazaki, Takehiko; Yoshikawa, Hideki; Kaneda, Yasufumi

    2007-03-09

    Recent studies have suggested the existence of osteoblastic cells in the circulation, but the origin and role of these cells in vivo are not clear. Here, we examined how these cells contribute to osteogenesis in a bone morphogenetic protein (BMP)-induced model of ectopic bone formation. Following lethal dose-irradiation and subsequent green fluorescent protein-transgenic bone marrow cell-transplantation (GFP-BMT) in mice, a BMP-2-containing collagen pellet was implanted into muscle. Three weeks later, a significant number of GFP-positive osteoblastic cells were present in the newly generated ectopic bone. Moreover, peripheral blood mononuclear cells (PBMNCs) from the BMP-2-implanted mouse were then shown to include osteoblast progenitor cells (OPCs) in culture. Passive transfer of the PBMNCs isolated from the BMP-2-implanted GFP-mouse to the BMP-2-implanted nude mouse led to GFP-positive osteoblast accumulation in the ectopic bone. These data provide new insight into the mechanism of ectopic bone formation involving bone marrow-derived OPCs in circulating blood.

  15. Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

    PubMed Central

    Mesentier-Louro, Louise A.; Zaverucha-do-Valle, Camila; Rosado-de-Castro, Paulo H.; Silva-Junior, Almir J.; Pimentel-Coelho, Pedro M.; Mendez-Otero, Rosalia; Santiago, Marcelo F.

    2016-01-01

    Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized. PMID:26649049

  16. Copper-64 labeled liposomes for imaging bone marrow.

    PubMed

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

    2016-12-01

    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 [(18)F]-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. Optimized liposomal formulations were prepared with succinyl PE, DSPC, cholesterol, and mPEG-DSPE (69:39:1:10:0.1) with diameters of 90 and 140nm, and were doped with DOTA-Bn-DSPE for stable (64)Cu incorporation into liposomes. PET imaging and biodistribution studies with (64)Cu-labeled liposomes indicate that accumulation in bone marrow was as high as 15.18±3.69%ID/g for 90nm liposomes and 7.01±0.92%ID/g for 140nm liposomes at 24h post-administration. In vivo biodistribution studies in tumor-bearing mice indicate that the uptake of 90nm 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. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Marrow stromal fibroblastic cell cultivation in vitro on decellularized bone marrow extracellular matrix.

    PubMed

    Dutra, Timothy F; French, Samuel W

    2010-02-01

    The in vitro biocompatibility of decellularized bone marrow extracellular matrix was evaluated. Following a freeze-thaw cycle, sectioned discs of fresh frozen rat metaphyseal bone were sequentially incubated in solutions of hypertonic, then hypotonic Ringer's solution, followed by deoxycholic acid, then DNAase I. The adequacy of decellularization of marrow stroma was examined by light microscopy. Marrow stromal fibroblastic cells were harvested by dispersion of rat long bone marrow, followed by concentration by discontinuous Ficoll-Paque gradient centrifugation. The fibroblastic cells were expanded by in vitro cultivation, and second passage cells were cryopreserved until needed. Cryopreserved marrow stromal cells were applied dropwise to sections of decellularized bone marrow extracellular matrix, and cultured in BJGb medium with 20% fetal bovine serum for ten days. Mature cultures were formalin fixed, decalcified, and embedded in paraffin. Light microscopy of hematoxylin and eosin stained sections showed individual spindle cells invading the upper portion of the decellularized extracellular matrix, and also a monolayer of spindle cells on the upper surfaces of exposed trabecular and cortical bone. This experiment showed that decellularized marrow extracellular matrix is a biocompatible three dimensional in vitro substrate for marrow stromal fibroblastic cells.

  18. Last marrow standing: bone marrow transplantation for acquired bone marrow failure conditions.

    PubMed

    Gerds, Aaron T; Scott, Bart L

    2012-12-01

    Paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome are a spectrum of acquired marrow failure, having a common pathologic thread of both immune dysregulation and the development of abnormal hematopoiesis. Allogeneic hematopoietic cell transplantation plays a critical role in the treatment of these disorders and, for many patients, is the only treatment modality with demonstrated curative potential. In recent years, there have been many breakthroughs in the understanding of the pathogenesis of these uncommon disorders. The subsequent advances in non-transplant therapies, along with concurrent improvement in outcomes after hematopoietic cell transplantation, necessitate continual appraisal of the indications, timing, and approaches to transplantation for acquired marrow failure syndromes. We review here contemporary and critical new findings driving current treatment decisions.

  19. Replacement of bone marrow by bone in rat femurs: the bone bioreactor.

    PubMed

    Zhang, Qing; Cuartas, Esteban; Mehta, Nozer; Gilligan, James; Ke, Hua-Zhu; Saltzman, W Mark; Kotas, Maya; Ma, Mandy; Rajan, Sonali; Chalouni, Cécile; Carlson, Jodi; Vignery, Agnès

    2008-02-01

    During development and repair of bone, two distinct yet complementary mechanisms, intramembranous and endochondral, mediate new bone formation via osteoblasts. Because mechanical bone marrow ablation leads to the rapid and transient formation of new bone in the marrow cavity, we postulated that parathyroid hormone (PTH), which is a bone anabolic hormone, enhances the formation of new bone that forms after marrow ablation. We subjected the left femur of rats to mechanical marrow ablation, or sham operation, and injected the animals daily with PTH or vehicle for 1, 2, or 3 weeks in a first experiment, then with PTH, parathyroid hormone-related peptide (PTHrP), or vehicle for 3 weeks in a second experiment. We subjected both femurs from each rat to soft X-ray, peripheral quantitative computed tomography, computed tomography on a microscale, and histological analysis, and determined the concentration of serum osteocalcin. In addition, in the second experiment, we determined the serum concentration of calcium, tartrate-resistant acid phosphatase (TRAP), and receptor activator of NF-kappaB ligand (RANKL) at 3 weeks, and subjected femurs to biomechanical testing. Following treatment with PTH or PTHrP for 3 weeks, bone filled the marrow cavity of the shafts whose marrow had been ablated. PTH increased trabecular density in the right femur, but failed to induce bone formation in the medullary region of the right unoperated femoral shafts. The newly formed bone endowed left femoral shafts with improved biomechanical properties when compared to those of right femurs and left femurs from control, sham-operated, and vehicle-treated rats. PTHrP, like PTH, increased serum osteocalcin, but neither increased serum calcium, TRAP, or RANKL at 3 weeks. Our results reveal that the newly formed bone that follows marrow ablation is responsive to PTH, expand the role of PTH in bone, and might open new avenues of investigations to the field of regenerative medicine and tissue engineering

  20. Primary Splenic Angiosarcoma Revealed by Bone Marrow Metastasis

    PubMed Central

    Anoun, Soumaya; Marouane, Sofia; Quessar, Asmae; Benchekroun, Said

    2014-01-01

    Primary splenic angiosarcomas are the most common malignant non-hematopoietic tumors of the spleen. Metastatic diseases were found in 69% of patients in a reported series but the incidence of bone marrow involvement is unclear. We report a rare case of a 25-years-old Moroccan woman with unsuspected primary splenic angiosarcoma revealed by bone marrow metastasis. She presented with serious anemia and splenomegaly. Bone marrow biopsy revealed proliferating spindle cells. Computed tomography scanning showed an enlarged spleen with heterogeneous lesions. Splenectomy was performed and retrospective histological study of the spleen confirmed the diagnosis. She died 1 year after splenectomy. PMID:25541659

  1. Primary splenic angiosarcoma revealed by bone marrow metastasis.

    PubMed

    Anoun, Soumaya; Marouane, Sofia; Quessar, Asmae; Benchekroun, Said

    2014-12-05

    Primary splenic angiosarcomas are the most common malignant non-hematopoietic tumors of the spleen. Metastatic diseases were found in 69% of patients in a reported series but the incidence of bone marrow involvement is unclear. We report a rare case of a 25-years-old Moroccan woman with unsuspected primary splenic angiosarcoma revealed by bone marrow metastasis. She presented with serious anemia and splenomegaly. Bone marrow biopsy revealed proliferating spindle cells. Computed tomography scanning showed an enlarged spleen with heterogeneous lesions. Splenectomy was performed and retrospective histological study of the spleen confirmed the diagnosis. She died 1 year after splenectomy.

  2. Bone and bone-marrow blood flow in chronic granulocytic leukemia and primary myelofibrosis

    SciTech Connect

    Lahtinen, R.; Lahtinen, T.; Romppanen, T.

    1982-03-01

    Blood flow in hematopoietic bone marrow and in nonhematopoietic bone has been measured with a Xe-133 washout method in 20 patients with chronic granulocytic leukemia (CGL) and in seven with primary myelofibrosis. Age-matched healthy persons served as controls. Bone-marrow blood flow in CGL was dependent upon the phase of the disease. In the metamorphosis phase, bone-marrow blood flow was high compared with that in the well-controlled phase. Apart from the initial phase, the mean values for bone blood flow in CGL were increased compared with the values of the healthy controls. In myelofibrosis the bone blood flow was also increased. Bone-marrow blood flow in these diseases was dependent upon the cellularity of bone marrow as measured morphometrically.

  3. Infections and immunodeficiency in bone marrow transplantation.

    PubMed

    Tutschka, P J

    1988-05-01

    After allogeneic bone marrow transplantation certain patterns of infectious complications emerge that follow the clinical course, are correlated to the immunobiology of transplantation and are almost predictable in their character and expression. The preparative regimen, designed to generate complete aplasia, will be associated with severe and sometimes life-threatening bacterial infections, predominantly with Gram-negative organisms derived from bowel flora, but also Gram-positive skin saprophytes. In this early aplastic phase, life-threatening viral infections are less common, consisting mainly of herpes simplex and possibly Epstein-Barr stomatitis and BK papovavirus cystitis. Systemic infections with invasive filamentous fungi are rare and are seen only when the induced aplasia is markedly prolonged. Once early marrow recovery has been achieved, systemic infections will generally disappear unless acute graft-vs.-host disease develops. This complication, which will lead to the breakdown of natural barriers such as skin and gastrointestinal epithelium and the marked impairment of all systemic defense mechanisms, can cause polymicrobial infections as well as set the stage for life-threatening viral infections. Such opportunistic viral infections, leading to either interstitial pneumonia or hemorrhagic gastroenteritis, are the major threat in the early recovery phase after engraftment has taken place. Usually caused by cytomegalovirus and rotavirus, respectively, these infections are the primary expression of the severe combined immunodeficiency post transplant, statistically associated with the presence of acute graft-vs.-host disease and amenable to immunologic manipulations. With the recovery of cellular and humoral immune function derived from transplanted donor lymphoid cells, the third phase of infectious complications is reached, covering 3 months to 2 years post grafting.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Floatation of decalcified bone marrow core biopsy - a clue to marrow hypocellularity.

    PubMed

    Tilak, Vijai; Das, Subhajit; Singh, Gyan Prakash

    2014-12-01

    Background : Examination of bone marrow plays a pivotal role in the practice of haematology. It can be evaluated by three ways - bone marrow aspiration smears (BMA), bone marrow touch imprints (BMI) and bone marrow biopsy (BMB). BMB sections are considered to be the gold standard for assessing overall marrow cellularity. To evaluate the correlation, if any, between bone marrow cellularity and floatation pattern of the core biopsy specimen, after proper decalcification. This study was carried out in the Department of Pathology, Institute of Medical Sciences, Varanasi over a period of 26 months. Specimens of BMA, BMI and BMB were collected from 182 cases. The core biopsy specimens were fixed in 10% buffered formalin for 24 hours, and were decalcified in 5% formic acid for 12 hours. The properly decalcified core biopsy samples were then put into adequate-sized container filled with 10% buffered formalin, and floatation pattern was documented. All the observations were evaluated using simple and basic statistical tools, i.e. sensitivity, specificity, positive predictive value. Chi square test was applied for obtaining statistical correlation i.e. p-value. Out of 182 core biopsy specimens, 32.4% (n=59) floated, while rests sank. Out of the 59 floating core biopsies, 57 were hypocellular. Seven core biopsies, among 123 specimens that sank, were hypocellular. The sensitivity and specificity of floatation pattern for hypocellular marrow were 89.2% and 99.1%, respectively. A strong correlation (p-value <0.001) between the floatation pattern and bone marrow cellularity was obtained. Assessment of floatation pattern of properly decalcified marrow core specimen is reliable for assessing marrow hypocellularity.

  5. 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.

  6. 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.

  7. Characterization of megakaryocyte development in the native bone marrow environment.

    PubMed

    Eckly, Anita; Strassel, Catherine; Cazenave, Jean-Pierre; Lanza, François; Léon, Catherine; Gachet, Christian

    2012-01-01

    Differentiation and maturation of megakaryocytes occur in close association with cellular and extracellular components in the bone marrow. Thus, direct examination of these processes in the native environment provides important information regarding the development of megakaryocytes. In this chapter, we present methods applied to mouse bone marrow to (1) examine the ultrastructure of megakaryocytes and their state of maturation in situ in fixed bone marrow sections and (2) study the dynamics of proplatelet formation by real-time observation of fresh bone marrow explants where megakaryocytes have matured in their natural physiological context. Combining these two approaches allows detailed investigation of in situ megakaryocyte differentiation, including proplatelet formation, which is the final maturation step before platelet release.

  8. Bone marrow infection with Mycobacterium fortuitum in a diabetic patient.

    PubMed

    Satti, Luqman; Abbasi, Shahid; Sattar, Abdul; Ikram, Aamer; Manzar, Muhammad Adnan; Khalid, Malik Muhammad

    2011-08-01

    Incidence and prevalence of Mycobacterium fortuitum infection vary greatly by location and death is very rare except in disseminated disease in immunocompromised individuals. We present what we believe is the first case of bone marrow infection with Mycobacterium fortuitum in an HIV negative patient. Bone marrow examination revealed presence of numerous acid fast bacilli which were confirmed as Mycobacterium fortuitum on culture and by molecular analysis. Patient was managed successfully with amikacin and ciprofloxacin.

  9. Memory T-cell competition for bone marrow seeding

    PubMed Central

    Di Rosa, Francesca; Santoni, Angela

    2003-01-01

    The presence in the bone marrow of memory CD8 T cells is well recognized. However, it is still largely unclear how T-cell migration from the lymphoid periphery to the bone marrow is regulated. In the present report, we show that antigen-specific CD4 T cells, as well as antigen-specific CD8 T cells, localize to the bone marrow of immunized mice, and are sustained there over long periods of time. To investigate the rules governing T-cell migration to the bone marrow, we generated chimeric mice in which the lymphoid periphery contained two genetically or phenotypically distinct groups of T cells, one of which was identical to the host. We then examined whether a distinct type of T cell had an advantage over the others in the colonization of bone marrow. Our results show that whereas ICAM1 and CD18 molecules are both involved in homing to lymph nodes, neither is crucial for T-cell bone marrow colonization. We also observed that memory-phenotype CD44high T cells, but not virgin-type CD44−/low T cells, preferentially home to the bone marrow upon adoptive transfer to normal young mice, but not to thymectomized old recipients where an existing memory T-cell pool precludes their free access. Thus, T-cell colonization of the bone marrow uses distinct molecules from those implicated in lymph node homing, and is regulated both by the properties of the T cell and by the competitive efficacy of other T cells inhabiting the same, saturable niche. This implies that the homing potential of an individual lymphocyte is not merely an intrinsic property of the cell, but rather a property of the lymphoid system taken as a whole. PMID:12603595

  10. Assessment of dysplastic hematopoiesis: lessons from healthy bone marrow donors.

    PubMed

    Parmentier, Stefani; Schetelig, Johannes; Lorenz, Kerstin; Kramer, Michael; Ireland, Robin; Schuler, Ulrich; Ordemann, Rainer; Rall, Gabi; Schaich, Markus; Bornhäuser, Martin; Ehninger, Gerhard; Kroschinsky, Frank

    2012-05-01

    According to WHO 2008 guidelines, the required percentage of cells manifesting dysplasia in the bone marrow to qualify as significant is 10% or over in one or more hematopoietic cell lineages, but this threshold is controversial. No 'normal' values have been established. Therefore, we investigated dyshematopoiesis in bone marrow aspirate squash preparations of 120 healthy bone marrow donors. Bone marrow squash slides of 120 healthy unrelated bone marrow donors were examined independently by 4 experienced morphologists. Samples were taken from the first aspiration during the harvest. Bone marrow preparation and assessment were performed according to WHO recommendations and ICSH guidelines. More than 10% dysmyelopoiesis could be detected in 46% of bone marrow aspirate squash preparations with 26% in 2 or more cell lineages and 7% in 3 cell lineages in healthy bone marrow donors. Donors under the age of 30 years exhibited more dysgranulopoietic changes and dysmegakaryopoietic changes (P<0.001) compared to the older donors. Female donors showed more dysgranulopoietic changes than male donors (P = 0.025). The concordance rate between the 4 investigators was modest in dysgranulopoiesis but poor in dyserythropoiesis and dysmegakaryopoiesis. The poor reliability of the 10% cut off was partly related to the proximity of the current criteria to the observed cut-off mean values of the normal population. These findings question the current WHO threshold of the 10% or over necessary for the percentage of cells manifesting dysplasia to be considered significant, and suggest that either a higher threshold would be more appropriate or different thresholds should be set for each lineage.

  11. Therapy with Bone Marrow-Derived Autologous Adult Stem Cells in Quadriparesis due to Motor Neuron Disease.

    PubMed

    Bansal, Himanshu; Singh, Lipi; Agrawal, Anupama; Leon, Jerry; Sundell, I Birgitta; Koka, Prasad S

    To report the safety and therapeutic effectiveness of application of concentrated bone marrow aspirate in three bedridden patients with weakness in both legs, and monitor potential improvement in neurological outcomes. Case report. Intervention: Five infusions of 3x10(8) mononuclear cells were administrated with 12 week intervals. Bone marrow (240ML) were obtained from the posterior superior iliac spine and Bone marrow mononuclear cells were enriched by standard manual close method under aseptic condition. During the follow-up study of one year after stem cell implantation, the conditions of all three patients were improved and were confirmed by physical assessment, muscle charting and Electromyography (EMG). One year after stem cell implantation patients who were bedridden before treatment could sit without support and walk with support up to 200 feet at a stretch. The local application of a cocktail of regenerative cell population found in an MNC fraction of bone marrow was safe and effective in improving quality of life and muscle strength in ALS patients. This case opens the need for further investigations on Autogenic stem cell transplant therapies for MND disease.

  12. 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.

  13. Benzene toxicokinetics in humans: exposure of bone marrow to metabolites.

    PubMed Central

    Watanabe, K H; Bois, F Y; Daisey, J M; Auslander, D M; Spear, R C

    1994-01-01

    A three compartment physiologically based toxicokinetic model was fitted to human data on benzene disposition. Two separate groups of model parameter derivations were obtained, depending on which data sets were being fitted. The model was then used to simulate five environmental or occupational exposures. Predicted values of the total bone marrow exposure to benzene and cumulative quantity of metabolites produced by the bone marrow were generated for each scenario. The relation between cumulative quantity of metabolites produced by the bone marrow and continuous benzene exposure was also investigated in detail for simulated inhalation exposure concentrations ranging from 0.0039 ppm to 150 ppm. At the level of environmental exposures, no dose rate effect was found for either model. The occupational exposures led to only slight dose rate effects. A 32 ppm exposure for 15 minutes predicted consistently higher values than a 1 ppm exposure for eight hours for the total exposure of bone marrow to benzene and the cumulative quantity of metabolites produced by the bone marrow. The general relation between the cumulative quantity of metabolites produced by the bone marrow and the inhalation concentration of benzene is not linear. An inflection point exists in some cases leading to a slightly S shaped curve. At environmental levels (0.0039-10 ppm) the curve bends upward, and it saturates at high experimental exposures (greater than 100 ppm). PMID:8044234

  14. CD38 and bone marrow microenvironment.

    PubMed

    Chillemi, Antonella; Zaccarello, Gianluca; Quarona, Valeria; Lazzaretti, Mirca; Martella, Eugenia; Giuliani, Nicola; Ferracini, Riccardo; Pistoia, Vito; Horenstein, Alberto L; Malavasi, Fabio

    2014-01-01

    This review summarizes the events ruled by CD38 shaping the bone marrow environment, recapitulating old and new aspects derived from the body of knowledge on the molecule. The disease models considered were myeloma and chronic lymphocytic leukemia (CLL). CD38 has been analyzed considering its twin function as receptor and enzyme, roles usually not considered in clinics, where it is used as a routine marker. Another aspect pertaining basic science concerns the role of the molecule as a member of an ectoenzyme network, potentially metabolizing soluble factors not yet analyzed (e.g., NAD+, ATP, NAM) or influencing hormone secretion (e.g., oxytocin). The last point is focused on the use of CD38 as a target of an antibody-mediated therapeutic approach in myeloma and CLL. A recent observation is that CD38 may run an escape circuit leading to the production of adenosine. The generation of local anergy may be blocked by using anti-CD38 antibodies. Consequently, not only might CD38 be a prime target for mAb-mediated therapy, but its functional block may contribute to general improvement in cancer immunotherapy and outcomes.

  15. Diffuse proliferative glomerulonephritis after bone marrow transplantation.

    PubMed

    Suehiro, T; Masutani, K; Yokoyama, M; Tokumoto, M; Tsuruya, K; Fukuda, K; Kanai, H; Katafuchi, R; Nagatoshi, Y; Hirakata, H

    2002-09-01

    A 15-year-old boy developed nephrotic syndrome and acute renal failure 4 years after allogenic bone marrow transplantation (BMT) for lymphoid crisis of chronic myelocytic leukemia. On admission, he presented with clinical features of chronic GVHD including transient exacerbation of cholestatic liver injury. Renal biopsy showed diffuse proliferative glomerulonephritis with cellular crescents. The patient was treated with methylprednisolone pulse therapy (1 g/day, for 3 days) followed by oral prednisolone. Renal function gradually improved but nephrotic state was persistent. A second renal biopsy showed improvement of acute tubular necrosis and endocapillary proliferation and transformation of crescents into a fibrous form. After tapering of oral prednisolone, cyclophosphamide was started, which resulted in a gradual improvement of proteinuria. Several cases of nephrotic syndrome occurring after BMT have already been reported, but most cases had membranous nephropathy. In our case, renal biopsy revealed diffuse proliferative glomerulonephritis with findings of active cellular immunity, and aggressive treatment resulted in attenuation of these findings. Moreover, chronic GVHD-related liver injury was noted at the time of this episode. Our findings suggest that chronic GVHD may be complicated with diffuse proliferative glomerulonephritis through unknown cellular immune mechanism.

  16. The separation of a mixture of bone marrow stem cells from tumor cells: an essential step for autologous bone marrow transplantation

    SciTech Connect

    Rubin, P.; Wheeler, K.T.; Keng, P.C.; Gregory, P.K.; Croizat, H.

    1981-10-01

    KHT tumor cells were mixed with mouse bone marrow to simulate a sample of bone marrow containing metastatic tumor cells. This mixture was separated into a bone marrow fraction and a tumor cell fraction by centrifugal elutriation. Elutriation did not change the transplantability of the bone marrow stem cells as measured by a spleen colony assay and an in vitro erythroid burst forming unit assay. The tumorogenicity of the KHT cells was similarly unaffected by elutriation. The data showed that bone marrow cells could be purified to less than 1 tumor cell in more than 10/sup 6/ bone marrow cells. Therefore, purification of bone marrow removed prior to lethal radiation-drug combined therapy for subsequent autologous transplantation appears to be feasible using modifications of this method if similar physical differences between human metastatic tumor cells and human bone marrow cells exist. This possibility is presently being explored.

  17. Vascularized bone marrow transplantation model in rats as an alternative to conventional cellular bone marrow transplantation: preliminary results.

    PubMed

    Zamfirescu, D; Popovicu, C; Stefanescu, A; Bularda, A; Popescu, M; Zegrea, I; Lanzetta, M; Lascar, I

    2011-11-01

    The aim of the study was to follow the development of microchimerism after allogeneic vascularized bone marrow transplantation (VBMT) versus conventional bone marrow transplantation (BMT). In one group, a VBMT model consisted of donor Brown Norway rat hind limb heterotopic transplanted on recipient Lewis rats. An intravenous infusion of donor bone marrow cells in suspension equivalent to that grafted in the vascularized femur limb was administered intravenously to recipient rats in the second group. Cellular microchimerism was investigated in recipients of VBMT versus BMT. Donor-derived cells could be detected in VBMT recipients at 30 and 60 days but not in recipients of intravenous suspension of BMC. VBMT provides a theoretical alternative to conventional cellular bone marrow transplantation by addressing crucial clinical problems such as failure of engraftment or graft-versus-host disease. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. In vivo longitudinal visualization of bone marrow engraftment process in mouse calvarium bone marrow with two-photon microscopy (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Le, Viet Hoan; Lee, Seunghun; Kim, Ki Hean; Lee, Seungwon; Lee, Seung-Woo

    2017-02-01

    Bone marrow transplantation became the standard choice for treatment of many leukemias, tumors and metabolic diseases. Understanding the dynamic behavior of bone marrow niches, especially in case of bone marrow transplantation is critical to improve the efficiency of the treatment. Intravital microscopy was demonstrated to be a powerful tool to study physiological structure of bone marrow niche. However, current method of intravital microscopy has difficulty in longitudinal monitoring the same bone marrow niche site due to the invasion of the prior-imaging surgery. In this study, we introduce a method to improve the bone marrow niche imaging process and enable the longitudinal imaging of murine calvarium bone marrow. Mouse model for calvarium bone marrow imaging was made by attaching cover glass window to the calvarium bone. Longitudinal imaging of whole bone marrow engraftment process was carried out to demonstrate the advantage of our mouse model. Qualitative and quantitative analysis were also executed on the image data. The result provided a dynamic and full visualization of the bone marrow engraftment process. The study was expected to provide helpful tool for bone marrow studies and useful information for bone marrow transplantation in future.

  19. Radioimmune imaging of bone marrow in patients with suspected bone metastases from primary breast cancer

    SciTech Connect

    Duncker, C.M.; Carrio, I.; Berna, L.; Estorch, M.; Alonso, C.; Ojeda, B.; Blanco, R.; Germa, J.R.; Ortega, V. )

    1990-09-01

    Radioimmune imaging of bone marrow was performed by technetium-99m- (99mTc) labeled antigranulocyte monoclonal antibody BW 250/183 (AGMoAb) scans in 32 patients with suspected bone metastases from primary breast cancer. AGMoAb scans showed bone marrow defects in 25/32 (78%) patients; bone invasion was subsequently confirmed in 23 (72%) patients. Conventional bone scans performed within the same week detected bone metastases in 17/32 (53%) patients (p less than 0.001). AGMoAb scans detected more sites indicating metastatic disease than bone scans in 12 of these 17 patients (71%). All patients with bone metastases in the axial skeleton had bone marrow defects at least at the sites of bone metastases. Of 15 patients with normal, or indicative of, benign disease bone scans, 8 patients (53%) presented with bone marrow defects in the AGMoAb scans. Bone invasion was confirmed in six of them. AGMoAb bone marrow scans provide a method for the early detection of bone metastatic invasion in patients with breast cancer and suspected bone metastases.

  20. Bone marrow evaluation in new-onset pancytopenia.

    PubMed

    Weinzierl, Elizabeth P; Arber, Daniel A

    2013-06-01

    The new onset of pancytopenia often creates a diagnostic dilemma to the treating physician and leads to bone marrow biopsy and aspiration. To determine the distribution of bone marrow findings in such cases of new-onset pancytopenia in a tertiary academic medical center, we evaluated 250 recent bone marrow aspirates and biopsies performed in the setting of new-onset pancytopenia in patients without previously diagnosed hematologic neoplastic disease. Of the 250 bone marrow studies, 193 were performed in adults and 57 were performed in children. In children, the most prevalent bone marrow finding was B-lymphoblastic leukemia, followed by nonspecific changes attributed clinically to a variety of factors including multifactorial, autoimmune, inflammatory, and infectious etiologies. In adults, hematologic neoplastic causes of pancytopenia were the most prevalent diagnoses, with the cases divided mostly between acute myeloid leukemia and myelodysplastic syndrome, with fewer numbers of cases of acute lymphoblastic leukemia, myeloproliferative neoplasms, and lymphomas. Many bone marrow findings demonstrated nonspecific changes that were attributed clinically to a variety of etiologies such as myelodysplastic syndrome, multifactorial causes, hypersplenism, drugs, and systemic disease. Overall, in both the pediatric and the adult population, new-onset pancytopenia was most commonly associated with neoplasia, although the neoplasm differed by age group. Although in most cases, a definitive diagnosis could be made based solely on bone marrow aspirate and biopsy interpretation, a significant fraction of cases in both children and adults demonstrated nonspecific marrow findings that required clinical follow-up and/or repeat biopsy for definitive diagnosis. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. 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.

  2. 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

  3. Detection of Bone Marrow Derived Lung Epithelial Cells

    PubMed Central

    Kassmer, Susannah H.; Krause, Diane S.

    2010-01-01

    Studies on the ability of bone marrow derived cells to adopt the morphology and protein expression of epithelial cells in vivo have expanded rapidly over the last decade, and hundreds of publications report that bone marrow derived cells can become epithelial cells of multiple organs including lung, liver, GI tract, skin, pancreas and others. In this review, we critically evaluate the literature related to engraftment of bone marrow derived cells as epithelial cells in the lung. Over 40 manuscripts focused on whether bone marrow cells can differentiate into lung epithelial cells have been published, nearly all of which claim to identify marrow derived epithelial cells. A few investigations have concluded that no such cells are present and that the phenomenon of marrow derived epithelial cells is based on detection artifacts. Here we discuss the problems that exist in published papers identifying marrow derived epithelial cells, and propose standards for detection methods that provide the most definitive data. Identification of BM derived epithelial cells requires reliable and sensitive techniques for their detection, which must include cell identification based on the presence of an epithelial marker and the absence of blood cell markers as well as a marker for donor BM origin. In order for these studies to be rigorous, they must also use approaches to rule out cell overlap by microscopy or single cell isolation. Once these stringent criteria for identification of marrow derived epithelial cells are used universally, then the field can move forward to address the critical questions regarding which bone marrow derived cells are responsible for engraftment as epithelial cells, the mechanisms by which this occurs, whether these cells play a role in normal tissue repair, and whether specific cell subsets can be used for therapeutic benefit. PMID:20447442

  4. Spinal nociceptive transmission by mechanical stimulation of bone marrow

    PubMed Central

    Tanaka, Satoshi; Sekiguchi, Takemi; Sugiyama, Daisuke; Kawamata, Mikito

    2016-01-01

    Background Since bone marrow receives innervation from A-delta and C-fibers and since an increase in intramedullary pressure in bone marrow may induce acute pain in orthopedic patients during surgery and chronic pain in patients with bone marrow edema, skeletal pain may partly originate from bone marrow. Intraosseous lesions, such as osteomyelitis and bone cancer, are also known to produce cutaneous hypersensitivity, which might be referred pain from bone. However, little is known about pain perception in bone marrow and referred pain induced by bone disease. Thus, we carried out an in vivo electrophysiological study and behavioral study to determine whether increased intraosseous pressure of the femur induces acute pain and whether increased intraosseous pressure induces referred pain in the corresponding receptive fields of the skin. Results Intraosseous balloon inflation caused spontaneous pain-related behavior and mechanical hyperalgesia and allodynia in the lumbosacral region. Single neuronal activities of spinal dorsal horn neurons were extracellularly isolated, and then evoked responses to non-noxious and noxious cutaneous stimuli and intraosseous balloon inflation were recorded. Ninety-four spinal dorsal horn neurons, which had somatic receptive fields at the lower back and thigh, were obtained. Sixty-two percent of the wide-dynamic-range neurons (24/39) and 86% of the high-threshold neurons (12/14) responded to intraosseous balloon inflation, while none of the low-threshold neurons (0/41) responded to intraosseous balloon inflation. Spinally administered morphine (1 µg) abolished balloon inflation-induced spontaneous pain-related behavior and mechanical hyperalgesia in awake rats and also suppressed evoked activities of wide-dynamic-range neurons to noxious cutaneous stimulation and intraosseous balloon inflation. Conclusions The results suggest that mechanical stimulation to bone marrow produces nociception, concomitantly producing its referred pain

  5. Diagnosis and quantification of bone marrow fibrosis are significantly biased by the pre-staining processing of bone marrow biopsies.

    PubMed

    Buesche, G; Georgii, A; Kreipe, H-H

    2006-01-01

    Marrow fibrosis (MF) is an unfavourable, often lethal complication of haematological neoplasms. Although biopsy technique and staining procedure are standardized, the prestaining processing of bone marrow biopsies (BMBs) varies markedly without any existing data on its significance for the diagnosis of MF. In this study on 712 BMBs from 296 patients with chronic idiopathic myelofibrosis (CIMF), chronic myeloid leukaemia (CML), or healthy bone marrow, MF was a characteristic complication of CML and CIMF. However, diagnosis and quantification of MF and detection of its prognostic significance were significantly biased by fixation, decalcification, embedding, marrow tissue shrinkage during biopsy processing and the thickness of marrow sections (P < 0.000005). The relevance of these influences was explained by their effect on the marrow volume to which the fibre content was related, whereas the stainability of fibres was not affected. Semiquantitative grading of fibrosis and measurements of fibre density could not be adjusted to various methods of processing of bone marrow biopsies (P < 0.003). Evaluations of MF and its prognostic significance should consider the bias due to the prestaining processing of BMBs and the necessity of an adjustment to the thickness of tissue sections and the degree of marrow tissue shrinkage.

  6. Hemorrhagic cytitis after bone marrow transplantation.

    PubMed

    Padilla-Fernandez, Barbara; Bastida-Bermejo, J M; Virseda-Rodriguez, A J; Labrador-Gomez, J; Caballero-Barrigon, D; Silva-Abuin, J M; San Miguel-Izquierdo, J F; Lorenzo-Gomez, M F

    2014-03-01

    Hemorrhagic cystitis (HC) presenting with gross hematuria, bladder pain and urinary frequency develops in 13-38% of patients following bone marrow transplantation (BMT). The objective of the study was to study the characteristics of patients suffering hemorrhagic cystitis after hematopoietic stem cell transplantation in our center. We conducted a retrospective chart review of all patients who underwent BMT at our institution between January 1996 and August 2012. We recorded the age, sex, diagnosis, conditioning regimen, interval between BMT and development of symptoms of cystitis and treatment instituted. Five hundred patients underwent BMT in the period of time studied. 52 of them developed hemorrhagic cystitis. The mean age of the affected patients was 39 years; there were 34 males and 18 females. The diagnoses include AML (n=11), ALL (n=8), CML (n=6), MDS (n=11), CLL (n=5), NHL (n=1), HD (n=5), MM (n=2), Medular aplasia((n=3). HC appeared 59.48 days after BMT. There were no differences between sexes. Mortality among the 52 patients was 51.14% but HC was not the cause of death in any patient. Polyomaviruses were detected in the urine of 78.94 % of survivors. Polyomavirus infection with BK and JC types is usually acquired in infancy and the virus remains latent in renal tissue. Immunosuppression facilitates reactivation of the renal infection and replication of the virus responsible for the clinical manifestations of HC. The differential diagnoses include other urinary infections, lithiasis, thrombocytopenia and adverse effects of pharmacological agents. The urologist plays a limited role in the management of this disease.

  7. 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.

  8. Ventricular arrhythmias following intracoronary bone marrow stem cell transplantation.

    PubMed

    Villa, Adolfo; Sanchez, Pedro L; Fernandez-Aviles, Francisco

    2007-12-01

    We describe the appearance of delayed episodes of ventricular arrhythmias in 4 patients out of 72 undergoing intracoronary transplantation of autologous bone marrow mononuclear cells (BMMC) following ST elevated myocardial infarction (STEMI). Two cases with severely depressed systolic function presented electrical storms with monomorphic sustained ventricular tachycardia (SVT) within 2 to 3 days following cell transplantation, even though there were no periprocedural complications. Both patients were implanted with an internal defibrillator (ICD) after ruling out coronary re-occlusion. The remaining 2 patients presented several asymptomatic episodes of non-sustained ventricular tachycardia within one month following cell transfer. Only one of the latter presented syncopal SVT through programmed ventricular stimulation, undergoing ICD implantation afterwards. Neither new arrhythmic episodes nor ICD interventions have occurred during later follow-up of the three ICD patients (639+/-59 days). Information from large multicenter databases and our historical cohort of STEMI patients indicates that the rate of VT occurring within the first weeks after the initial 48 hours of infarction is significantly lower than that observed in our cell-therapy experience. The lack of information regarding the appearance of malignant arrhythmias in patients with severe systolic dysfunction following this type of therapy after STEMI requires us to be extremely cautious. However, any claim of a mechanism related to cell transfer would be completely speculative with the available data. Therefore, our only aim when reporting our findings is to recommend a short but longer stay (2-3 days) following cell transplantation, particularly in patients with a natural tendency to develop arrhythmic events.

  9. Cell survival kinetics in peripheral blood and bone marrow during total body irradiation for marrow transplantation

    SciTech Connect

    Shank, B.; Andreeff, M.; Li, D.

    1983-11-01

    Cell survival kinetics in both peripheral blood and in bone marrow have been studied over the time course of hyperfractionated total body irradiation (TBI) for bone marrow transplantation. Our unique TBI regimen allows the study of the in vivo radiation effect uncomplicated by prior cyclophosphamide, since this agent is given after TBI in our cytoreduction scheme. Peripheral blood cell concentrations were monitored with conventional laboratory cell counts and differentials. Absolute bone marrow cell concentrations were monitored by measuring cell concentrations in an aspirate sample and correcting for dilution with blood by a cell cycle kinetic method using cytofluorometry. For lymphocytes in peripheral blood in patients in remission, the effective D/sub 0/ ranged from 373 rad in 10 children less than or equal to 10 y old, to 536 rad in the four patients between 11 to 17 y old, while n = 1.0 in all groups. There was no trend observed according to age. Granulocytes had a much higher effective D/sub 0/, approximately 1000 rad in vivo. Absolute nucleated cell concentration in marrow dropped slowly initially, due to an increased lymphocyte concentration in marrow during a concurrent drop in lymphocyte concentration in peripheral blood, but eventually fell on the last day of TBI ranging from 7 to 44% of the initial marrow nucleated cell concentration. Marrow myeloid elements, however, dropped continuously throughout the course of TBI.

  10. Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

    PubMed Central

    de Carvalho, Felipe Gonçalves; de Freitas, Gabriel Rodriguez

    2016-01-01

    Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field. PMID:27698671

  11. Characterization of the CD14++CD16+ monocyte population in human bone marrow.

    PubMed

    Mandl, Manuela; Schmitz, Susanne; Weber, Christian; Hristov, Michael

    2014-01-01

    Numerous studies have divided blood monocytes according to their expression of the surface markers CD14 and CD16 into following subsets: classical CD14(++)CD16(-), intermediate CD14(++)CD16(+) and nonclassical CD14(+)CD16(++) monocytes. These subsets differ in phenotype and function and are further correlated to cardiovascular disease, inflammation and cancer. However, the CD14/CD16 nature of resident monocytes in human bone marrow remains largely unknown. In the present study, we identified a major population of CD14(++)CD16(+) monocytes by using cryopreserved bone marrow mononuclear cells from healthy donors. These cells express essential monocyte-related antigens and chemokine receptors such as CD11a, CD18, CD44, HLA-DR, Ccr2, Ccr5, Cx3cr1, Cxcr2 and Cxcr4. Notably, the expression of Ccr2 was inducible during culture. Furthermore, sorted CD14(++)CD16(+) bone marrow cells show typical macrophage morphology, phagocytic activity, angiogenic features and generation of intracellular oxygen species. Side-by-side comparison of the chemokine receptor profile with unpaired blood samples also demonstrated that these rather premature medullar monocytes mainly match the phenotype of intermediate and partially of (non)classical monocytes. Together, human monocytes obviously acquire their definitive CD14/CD16 signature in the bloodstream and the medullar monocytes probably transform into CD14(++)CD16- and CD14(+)CD16(++) subsets which appear enriched in the periphery.

  12. Intracoronary bone marrow cell application for terminal heart failure in children.

    PubMed

    Rupp, Stefan; Jux, Christian; Bönig, Halvard; Bauer, Jürgen; Tonn, Torsten; Seifried, Erhard; Dimmeler, Stefanie; Zeiher, Andreas M; Schranz, Dietmar

    2012-10-01

    In spite of tremendous progress in the medical and surgical treatment of children with congenital heart disease and dilated cardiomyopathy achieved during the past few decades, for some children a heart transplant remains the only option. Clinically relevant benefits of intracoronary injection of autologous stem cells on cardiac function and remodelling have been demonstrated in adult patients with acute myocardial infarction. Experience with autologous stem cell therapy in children with severe congenital or acquired pump failure is limited to a small number of case reports. Between 2006 and 2010, nine severely ill children were treated with intracoronary infusion of autologous bone marrow-derived mononuclear cells as part of a compassionate therapy in our centre. No procedure-related unexpected adverse events occurred. There was one patient on extracorporeal membrane oxygenation who died of haemorrhage unrelated to the procedure; three patients proceeded to heart transplantation once a donor heart became available. The other five patients showed an improvement with respect to New York Heart Association classification (greater than or equal to 1), brain natriuretic peptide serum levels, and ejection fraction. Similar to adults, intracoronary injection of autologous bone marrow cell is technically feasible and safe for children. On the basis of our data, we propose to perform a pilot study for children with congestive heart failure, to formally assess the efficacy of intracoronary autologous bone marrow cell therapy.

  13. Long-term survival of murine allogeneic bone marrow chimeras: effect of anti-lymphocyte serum and bone marrow dose

    SciTech Connect

    Norin, A.J.; Emeson, E.E.; Veith, F.J.

    1981-02-01

    Graft-vs-host disease (GVHD) and failure of donor stem cells to engraft permanently are two major obstacles to successful bone marrow transplantation. The effect of a single large dose of anti-lymphocyte serum (ALS) on mice receiving various numbers of H-2 incompatible bone marrow cells was evaluated. Most animals receiving lethal total body irradiation (TBI) and allogeneic marrow died within 45 days due to GVHD. Mice that were given ALS 6 to 24 h before TBI and bone marrow 24 h after irradiation survived in good health for more than 200 days. These cell preparations caused lethal GVHD in third party mice indicating that the lack of alloreactivity was specific to the strain in which the unresponsiveness was originally induced.

  14. Safety of intramyocardial injection of autologous bone marrow cells to treat myocardial ischemia in pigs.

    PubMed

    Goodchild, Traci; Pang, Wenxin; Tondato, Fernando; Cui, Jianhua; Otsuka, Yoritaka; Frowein, Steve; Ungs, Mark; Robinson, Keith; Poznansky, Mark; Chronos, Nicolas

    2006-01-01

    The purpose of this study is to determine the potential adverse consequences of intracardiac injections of bone marrow mononuclear cells (BMCs) to facilitate the revascularization of ischemic myocardium. Bone marrow mononuclear cells are used to treat heart failure, though there are few studies that evaluated the safety of BMC transplantation for chronic myocardial ischemia. The pigs received coronary ameroid constrictors to induce chronic myocardial ischemia and left ventricular dysfunction. At 4 weeks, autologous BMCs were injected intramyocardially by Boston Scientific Stiletto catheter with low-dose (10(7) cells) or high-dose BMC (10(8)). Control animals received saline. Blood samples were collected for hematological and chemical indices, including cardiac enzyme levels at regular time intervals postinfarction. At 7 weeks, animals underwent electrophysiological study to evaluate the arrhythmic potential of transplanted BMC, followed by necropsy and histopathology. No mortalities were associated with intramyocardial delivery of BMC or saline. At Day 0, the total creatine phosphokinase (CPK) was in the normal range in all groups. All groups had significant elevations in CPK after ameroid placement, with no significant differences between groups. At 7 weeks, CPK in all groups had returned to pretreatment levels. Electrophysiological assessment revealed that one control animal had an inducible arrhythmia. No arrhythmias were induced in low- or high-dose BMC-treated pigs. There were no histopathological changes associated with BMC injection. This study showed, in a clinically relevant large-animal model, that catheter-based intramyocardial injection of autologous BMC into ischemic myocardium is safe.

  15. 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

  16. Usefulness of bone marrow imaging in childhood malignancies

    SciTech Connect

    Oseas, R.S.; Siddiqui, A.R.; Wellman, H.N.; Baehner, R.L.

    1982-08-01

    Two hundred six /sup 99m/Tc sulfur colloid bone marrow scans in 110 pediatrics patients were reviewed. The normal distribution of sulfur colloid in the lower extremities in various age groups was established. There was progressive loss of uptake with increasing age from less than two years to greater than ten years. Tumor replacement was seen as regions of decreased radioactivity, and the extent of the scan defect paralleled the response of the disease to therapy. Both chemotherapy and irradiation resulted in an extension of the /sup 99m/Tc SC to peripheral marrow sites. In irradiated areas, marrow scan defects were demonstrated and generally recovered normal activity by six months after the completion of therapy. Marrow scan abnormalities caused by tumor replacement were present in four patients despite normal bone scans and radiographs. Ultimate confirmation of tumor involvement was by needle aspiration or biopsy. Persistent marrow defects were seen in two patients with neuroblastoma who had remission of their disease: biopsy revealed myelofibrosis. /sup 99m/Tc sulfur colloid bone marrow scanning is a sensitive monitor of altered marrow activity associated with pediatric hematologic or oncologic diseases.

  17. Spatial mapping of functional pelvic bone marrow using FLT PET.

    PubMed

    McGuire, Sarah M; Menda, Yusuf; Boles Ponto, Laura L; Gross, Brandie; TenNapel, Mindi; Smith, Brian J; Bayouth, John E

    2014-07-08

    The purpose of this study was to determine the ability of regions identified with bony landmarks on CT imaging to accurately represent active bone marrow when compared to FLT PET imaging. These surrogate regions could then be used to create a bone marrow sparing radiation therapy plan when FLT PET imaging is not available. Whole body (WB) FLT PET images were obtained of 18 subjects prior to chemoradiation therapy. The FLT image of each subject was registered to a CT image acquired for that subject to obtain anatomic information of the pelvis. Seventeen regions were identified based on features of the pelvic bones, sacrum, and femoral heads. The probability of FLT uptake being located in each of 17 different CT-based regions of the bony pelvis was calculated using Tukey's multiple comparison test. Statistical analysis of FLT uptake in the pelvis indicated four distinct groups within the 17 regions that had similar levels of activity. Regions located in the central part of the pelvis, including the superior part of the sacrum, the inner halves of the iliac crests, and the L5 vertebral body, had greater FLT uptake than those in the peripheral regions (p-value < 0.05). We have developed a method to use CT-defined pelvic bone regions to represent FLT PET-identified functional bone marrow. Individual regions that have a statistically significant probability of containing functional bone marrow can be used as avoidance regions to reduce radiation dose to functional bone marrow in radiation therapy planning. However, because likely active bone marrow regions and pelvic targets typically overlap, patient-specific spatial detail may be advantageous in IMRT planning scenarios and may best be provided using FLT PET imaging.

  18. Bone Marrow Fat Changes After Gastric Bypass Surgery Are Associated With Loss of Bone Mass.

    PubMed

    Kim, Tiffany Y; Schwartz, Ann V; Li, Xiaojuan; Xu, Kaipin; Black, Dennis M; Petrenko, Dimitry M; Stewart, Lygia; Rogers, Stanley J; Posselt, Andrew M; Carter, Jonathan T; Shoback, Dolores M; Schafer, Anne L

    2017-08-09

    Bone marrow fat is a unique fat depot that may regulate bone metabolism. Marrow fat is increased in states of low bone mass, severe underweight, and diabetes. However, longitudinal effects of weight loss and improved glucose homeostasis on marrow fat are unclear, as is the relationship between marrow fat and bone mineral density (BMD) changes. We hypothesized that after Roux-en-Y gastric bypass (RYGB) surgery, marrow fat changes are associated with BMD loss. We enrolled 30 obese women, stratified by diabetes status. Before and 6 months after RYGB, we measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and vertebral marrow fat content by magnetic resonance spectroscopy. At baseline, those with higher marrow fat had lower BMD. Postoperatively, total body fat declined dramatically in all participants. Effects of RYGB on marrow fat differed by diabetes status (p = 0.03). Nondiabetic women showed no significant mean change in marrow fat (+1.8%, 95% confidence interval [CI] -1.8% to +5.4%, p = 0.29), although those who lost more total body fat were more likely to have marrow fat increases (r = -0.70, p = 0.01). In contrast, diabetic women demonstrated a mean marrow fat change of -6.5% (95% CI -13.1% to 0%, p = 0.05). Overall, those with greater improvements in hemoglobin A1c had decreases in marrow fat (r = 0.50, p = 0.01). Increases in IGF-1, a potential mediator of the marrow fat-bone relationship, were associated with marrow fat declines (r = -0.40, p = 0.05). Spinal volumetric BMD decreased by 6.4% ± 5.9% (p < 0.01), and femoral neck areal BMD decreased by 4.3% ± 4.1% (p < 0.01). Marrow fat and BMD changes were negatively associated, such that those with marrow fat increases had more BMD loss at both spine (r = -0.58, p < 0.01) and femoral neck (r = -0.49, p = 0.01), independent of age and menopause. Our findings suggest that glucose metabolism and

  19. Cells Derived from Young Bone Marrow Alleviate Renal Aging

    PubMed Central

    Yang, Hai-Chun; Rossini, Michele; Ma, Li-Jun; Zuo, Yiqin; Ma, Ji

    2011-01-01

    Bone marrow-derived stem cells may modulate renal injury, but the effects may depend on the age of the stem cells. Here we investigated whether bone marrow from young mice attenuates renal aging in old mice. We radiated female 12-mo-old 129SvJ mice and reconstituted them with bone marrow cells (BMC) from either 8-wk-old (young-to-old) or 12-mo-old (old-to-old) male mice. Transfer of young BMC resulted in markedly decreased deposition of collagen IV in the mesangium and less β-galactosidase staining, an indicator of cell senescence. These changes paralleled reduced expression of plasminogen activator inhibitor-1 (PAI-1), PDGF-B (PDGF-B), the transdifferentiation marker fibroblast-specific protein-1 (FSP-1), and senescence-associated p16 and p21. Tubulointerstitial and glomerular cells derived from the transplanted BMC did not show β-galactosidase activity, but after 6 mo, there were more FSP-1-expressing bone marrow-derived cells in old-to-old mice compared with young-to-old mice. Young-to-old mice also exhibited higher expression of the anti-aging gene Klotho and less phosphorylation of IGF-1 receptor β. Taken together, these data suggest that young bone marrow-derived cells can alleviate renal aging in old mice. Direct parenchymal reconstitution by stem cells, paracrine effects from adjacent cells, and circulating anti-aging molecules may mediate the aging of the kidney. PMID:21965376

  20. Cardiomyocyte regeneration from circulating bone marrow cells in mice.

    PubMed

    Kuramochi, Yukio; Fukazawa, Ryuji; Migita, Makoto; Hayakawa, Jun; Hayashida, Mari; Uchikoba, Yohko; Fukumi, Daichi; Shimada, Takashi; Ogawa, Shunichi

    2003-09-01

    We investigated the role of circulating bone marrow cells (BMC) in cardiomyocyte regeneration. BMC, isolated from transgenic mice expressing enhanced green fluorescent protein (GFP), were transplanted into lethally irradiated C57BL6 mice. Five weeks after bone marrow transplantation (BMT), flow cytometric analysis for GFP-positive cells confirmed reconstitution of transplanted bone marrow. Bone marrow transplant mice subsequently underwent left coronary artery ligation (myocardial infarction) or sham-operation, and were killed at 1 mo or 3 mo after operation. Infarct size was similar in bone marrow transplant mice at 1 mo (47.1 +/- 5.9%) and at 3 mo (45.3 +/- 7.8%), and echocardiography at 2 and 8 wk revealed decreasing left ventricular function. In infarcted heart, GFP-positive cells that expressed desmin and troponin T-C were identified by confocal microscopy. GFP and troponin T-C double-positive cells were predominantly in the peri-infarcted region (1 mo, 365 +/- 45 cells/50 sections; 3 mo: 458 +/- 100 cells/50 sections; p < 0.05 versus noninfarct, infarct, and sham-operated regions). Furthermore, BMC mobilization and differentiation into cardiomyocytes was found to be complete within 1 mo after myocardial infarction. These results demonstrate that circulating BMC undergo mobilization and differentiation in cardiac cells after myocardial infarction. Future studies are required to determine the molecular signaling mechanisms responsible for this phenomenon.

  1. Lasting engraftment of histoincompatible bone marrow cells in dogs

    SciTech Connect

    Vriesendorp, H.M.; Klapwijk, W.M.; van Kessel, A.M.C.; Zurcher, C.; van Bekkum, D.W.

    1981-05-01

    Conditioning protocols were tested for their efficacy in increasng the incidence of engraftment of histoincompatible dog bone marrow cells. Cyclophosphamide and total body irradiation (TBI), Corynebacterium parvum and TBI, a 3- or 5-day delayed transfusion of bone marrow cells after TBI, or an increase in the number of donor bone marrow cells or lymphocytes appeared to be ineffective. These protocols were previously reported to promote recovery of splenic hemopoiesis in mice in short-term assays. The noted discrepancy between studies with mice and dogs invalidated allogeneic resistance as measured in the mouse spleen assay as a model for bone marrow allograft rejection. Intravenous treatment with silica particles or L-asparaginase did improve the engraftment rate after 7.5 Gy TBI. Low efficiency and significant extra toxicity restrict the applicability of these procedures. The most promising conditioning schedule found appeared to be two fractions of 6.0 Gy TBI separated by a 72-h interval. Prolonged survival was noted after transplantation of bone marrow cells from a one-DLA haplotype-mismatched donor. Possibilities for further improvement of this protocol are discussed.

  2. Lasting engraftment of histoincompatible bone marrow cells in dogs

    SciTech Connect

    Vriesendorp, H.M.; Klapwijk, W.M.; van Kessel, A.M.; Zurcher, C.; van Bekkum, D.W.

    1981-05-01

    Conditioning protocols were tested for their efficacy in increasing the incidence of engraftment of histoincompatible dog bone marrow cells. Cyclophosphamide and total body irradation (TBI), Corynebacterium parvum and TBI, a 3- or 5-day delayed transfusion of bone marrow cells after TBI, or an increase in the number of donor bone marrow cells or lymphocytes appeared to be ineffective. These protocols were previously reported to promote recovery of splenic hemopoiesis in mice in short-term assays. The noted discrepancy between studies with mice and dogs invalidated allogeneic resistance as measured in the mouse spleen assay as a model for bone marrow allograft rejection. Intravenous treatment with silica particles or L-asparaginase did improve the engraftment rate after 7.5 Gy TBI. Low efficiency and significant extra toxicity restrict the applicability of these procedures. The most promising conditioning schedule found appeared to be two fractions of 6.0 Gy TBI separated by a 72-hr interval. Prolonged survival was noted after transplantation of bone marrow cells from a one-DLA haplo-type-mismatched donor. Possibilities for further improvement of this protocol are discussed.

  3. Bone marrow-derived T lymphocytes responsible for allograft rejection

    SciTech Connect

    Senjanovic, M.; Marusic, M.

    1984-08-01

    Lethally irradiated mice reconstituted with syngeneic bone marrow cells were grafted with allogeneic skin grafts 6-7 weeks after irradiation and reconstitution. Mice with intact thymuses rejected the grafts whereas the mice thymectomized before irradiation and reconstitution did not. Thymectomized irradiated mice (TIR mice) reconstituted with bone marrow cells from donors immune to the allografts rejected the grafts. Bone marrow cells from immunized donors, pretreated with Thy 1.2 antibody and C', did not confer immunity to TIR recipients. To determine the number of T lymphocytes necessary for the transfer of immunity by bone marrow cells from immunized donors, thymectomized irradiated mice were reconstituted with nonimmune bone marrow cells treated with Thy 1.2 antibody and C' and with various numbers of splenic T lymphocytes from nonimmune and immune donors. Allogeneic skin graft rejection was obtained with 10(6) nonimmune or 10(4) immune T cells. The effect of immune T cells was specific: i.e., immune T cells accelerated only rejection of the relevant skin grafts whereas against a third-party skin grafts acted as normal T lymphocytes.

  4. Cells derived from young bone marrow alleviate renal aging.

    PubMed

    Yang, Hai-Chun; Rossini, Michele; Ma, Li-Jun; Zuo, Yiqin; Ma, Ji; Fogo, Agnes B

    2011-11-01

    Bone marrow-derived stem cells may modulate renal injury, but the effects may depend on the age of the stem cells. Here we investigated whether bone marrow from young mice attenuates renal aging in old mice. We radiated female 12-mo-old 129SvJ mice and reconstituted them with bone marrow cells (BMC) from either 8-wk-old (young-to-old) or 12-mo-old (old-to-old) male mice. Transfer of young BMC resulted in markedly decreased deposition of collagen IV in the mesangium and less β-galactosidase staining, an indicator of cell senescence. These changes paralleled reduced expression of plasminogen activator inhibitor-1 (PAI-1), PDGF-B (PDGF-B), the transdifferentiation marker fibroblast-specific protein-1 (FSP-1), and senescence-associated p16 and p21. Tubulointerstitial and glomerular cells derived from the transplanted BMC did not show β-galactosidase activity, but after 6 mo, there were more FSP-1-expressing bone marrow-derived cells in old-to-old mice compared with young-to-old mice. Young-to-old mice also exhibited higher expression of the anti-aging gene Klotho and less phosphorylation of IGF-1 receptor β. Taken together, these data suggest that young bone marrow-derived cells can alleviate renal aging in old mice. Direct parenchymal reconstitution by stem cells, paracrine effects from adjacent cells, and circulating anti-aging molecules may mediate the aging of the kidney.

  5. Hematopoietic bone marrow recovery after radiation therapy: MRI evaluation

    SciTech Connect

    Casamassima, F.; Ruggiero, C.; Caramella, D.; Tinacci, E.; Villari, N.; Ruggiero, M. )

    1989-05-01

    Magnetic resonance imaging (MRI) is able to detect the increase of adipocytes in the hematopoietic bone marrow that occurs as a consequence of radiotherapy and is indicative of the loss of myeloid tissue. By monitoring this process, it is also possible to determine the recovery of the bone marrow. The amount of viable hematopoietic tissue plays a fundamental role in determining whether the patient is able to undergo further antineoplastic therapy, particularly chemotherapy. We examined 35 patients who had been treated with radiotherapy for Hodgkin's lymphoma (12), uterine cervix carcinoma (nine), ovarian dysgerminoma (six), testicular seminoma (four), and non-Hodgkin's lymphoma (four). We observed that radiation-induced modifications of the MRI pattern in the bone marrow are tightly linked to two parameters; the administered radiation dose and the length of time passed after the treatment. Bone marrow recovery was observed only when patients were treated with doses lower than 50 Gy. The earlier radiation-induced modifications of the bone marrow MRI pattern occurred 6 to 12 months after irradiation, and they were most evident 5 to 6 years after the treatment. From 2 to 9 years after radiotherapy, we observed partial recovery. Complete recovery, when it occurred, was observed only 10 to 23 years after the treatment. Our results indicate that MRI studies are likely to be useful in the assessment of radiation-induced injuries.

  6. Spine fusion using cell matrix composites enriched in bone marrow-derived cells.

    PubMed

    Muschler, George F; Nitto, Hironori; Matsukura, Yoichi; Boehm, Cynthia; Valdevit, Antonio; Kambic, Helen; Davros, William; Powell, Kimerly; Easley, Kirk

    2003-02-01

    Bone marrow-derived cells including osteoblastic progenitors can be concentrated rapidly from bone marrow aspirates using the surface of selected implantable matrices for selective cell attachment. Concentration of cells in this way to produce an enriched cellular composite graft improves graft efficacy. The current study was designed to test the hypothesis that the biologic milieu of a bone marrow clot will significantly improve the efficacy of such a graft. An established posterior spinal fusion model and cancellous bone matrix was used to compare an enriched cellular composite bone graft alone, bone matrix plus bone marrow clot, and an enriched bone matrix composite graft plus bone marrow clot. Union score, quantitative computed tomography, and mechanical testing were used to define outcome. The union score for the enriched bone matrix plus bone marrow clot composite was superior to the enriched bone matrix alone and the bone matrix plus bone marrow clot. The enriched bone matrix plus bone marrow clot composite also was superior to the enriched bone matrix alone in fusion volume and in fusion area. These data confirm that the addition of a bone marrow clot to an enriched cell-matrix composite graft results in significant improvement in graft performance. Enriched composite grafts prepared using this strategy provide a rapid, simple, safe, and inexpensive method for intraoperative concentration and delivery of bone marrow-derived cells and connective tissue progenitors that may improve the outcome of bone grafting.

  7. Bone marrow endothelium-targeted therapeutics for metastatic breast cancer.

    PubMed

    Mai, Junhua; Huang, Yi; Mu, Chaofeng; Zhang, Guodong; Xu, Rong; Guo, Xiaojing; Xia, Xiaojun; Volk, David E; Lokesh, Ganesh L; Thiviyanathan, Varatharasa; Gorenstein, David G; Liu, Xuewu; Ferrari, Mauro; Shen, Haifa

    2014-08-10

    Effective treatment of cancer metastasis to the bone relies on bone marrow drug accumulation. The surface proteins in the bone marrow vascular endothelium provide docking sites for targeted drug delivery. We have developed a thioaptamer that specifically binds to E-selectin that is overexpressed in the vasculature of tumor and inflammatory tissues. In this study, we tested targeted delivery of therapeutic siRNA loaded in the E-selectin thioaptamer-conjugated multistage vector (ESTA-MSV) drug carrier to bone marrow for the treatment of breast cancer bone metastasis. We evaluated tumor type- and tumor growth stage-dependent targeting in mice bearing metastatic breast cancer in the bone, and carried out studies to identify factors that determine targeting efficiency. In a subsequent study, we delivered siRNA to knock down expression of the human STAT3 gene in murine xenograft models of human MDA-MB-231 breast tumor, and assessed therapeutic efficacy. Our studies revealed that the CD31(+)E-selectin(+) population accounted for 20.8%, 26.4% and 29.9% of total endothelial cells respectively inside the femur of mice bearing early, middle and late stage metastatic MDA-MB-231 tumors. In comparison, the double positive cells remained at a basal level in mice with early stage MCF-7 tumors, and jumped to 23.9% and 28.2% when tumor growth progressed to middle and late stages. Accumulation of ESTA-MSV inside the bone marrow correlated with the E-selectin expression pattern. There was up to 5-fold enrichment of the targeted MSV in the bone marrow of mice bearing early or late stage MDA-MB-231 tumors and of mice with late stage, but not early stage, MCF-7 tumors. Targeted delivery of STAT3 siRNA in ESTA-MSV resulted in knockdown of STAT3 expression in 48.7% of cancer cells inside the bone marrow. Weekly systemic administration of ESTA-MSV/STAT3 siRNA significantly extended survival of mice with MDA-MB-231 bone metastasis. In conclusion, targeting the overexpressed E

  8. Percutaneous autologous bone marrow injections for delayed or non-union of bones.

    PubMed

    Singh, Ashok K; Shetty, Sanat; Saraswathy, Jayadeep J; Sinha, Amit

    2013-04-01

    To evaluate 12 patients with delayed or nonunion of bones treated with bone marrow injections. 6 men and 6 women aged 15 to 70 (mean, 45) years underwent bone marrow injections for delayed union (n=2) or atrophic non-union (n=10) of the ulna (n=6), femur (n=3), humerus (n=2), or metacarpal (n=1). Bone marrow was aspirated from the anterior iliac crest and injected to the delayed and non-union sites. Two injections were given for children and adolescents, and 3 for adults. The interval between the injections was 6 to 8 weeks. The amount of bone marrow injected was 30 to 40 ml for long bones and 20 ml for metacarpals. Ten of the 12 delayed or non-union of bones healed after bone marrow injections. The mean time for callus formation was 5.8 (range, 3-10) weeks, for clinical union was 7 (range, 4-12) weeks, and for radiological union was 16 (range, 10-24) weeks. Multiple injections of low-volume bone marrow can be used for treatment of delayed or non-union of bones.

  9. 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

    2017-09-13

    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.

  10. [Bone marrow transplantation in chronic myeloid leukemia].

    PubMed

    Milone, J H; Bordone, J; Etchegoyen, O; Napal, J; Prates, M V; Morales, V H

    1999-01-01

    Chronic Myelogenous Leukemia (CML) is an oncohematological disease characterized by a clonal proliferation concerning the primitive hematopoietic cell. A typical cytogenetic alteration known as Philadelphia Chromosome (Ph1), a 9:22 chromosomic translocation which produces a hybrid gene BCR/ABL, is present in 95% of the patients. Nineteen CML patients (9 female and 10 male) underwent Bone Marrow Transplantation (BMT). Median age was 32 years (range 9 to 47); 15 of them were in chronic phase (CP), and 4 in accelerated phase (AP). At diagnosis, all patients were Ph1+, BCR/ABL+. The conditioning regimen consisted of busulphan and cyclophosphamide while patients in AP received etoposide as well. Seventeen patients received cyclosporine A, methotrexate and methylprednisone as prophylaxis for Graft Versus Host Disease (GVHD) while 2 patients received only the first two drugs. The 9.22 translocation was determined by means of RT-PCT technique using the primers NB1+, Abl3, B2A, CA3 and A2. The sensitivity of the method was 1 x 10(-6). Among the 19 patients who entered the protocol, 14 are alive and in clinical, hematological and cytogenetic remission (Ph1-) and 3 patients died due to acute GVHD, 1 due to graft failure and 1 due to Hemolytic Uremic Syndrome. Of the 4 transplanted patients in AP, 3 are alive and in complete remission. The patients had a 74% survival, with a median follow-up of 655 days. Complete hematopoietic chimerism was demonstrated in 16 patients, with the study of 3 loci, D1S80, APO B and D17S30. No relationship was found between post BMT hybrid BCR/ABL (RT.PCR) persistence and disease relapse; the presence of acute and/or chronic GVHD did not influence the BCR/ABL positivity. In our experience, BMT has proved to be the only therapeutic alternative for CML with complete clinical, hematological and cytogenetic remission and a mean survival of 74%, comparable to the international experience.

  11. Alterations of the RANKL pathway in blood and bone marrow samples of prostate cancer patients without bone metastases.

    PubMed

    Todenhöfer, Tilman; Hennenlotter, Jörg; Schmiedel, Benjamin Joachim; Hohneder, Andrea; Grimm, Sabrina; Kühs, Ursula; Salih, Helmut Rainer; Bühring, Hans-Jörg; Fehm, Tanja; Gakis, Georgios; Blumenstock, Gunnar; Aufderklamm, Stefan; Schilling, David; Stenzl, Arnulf; Schwentner, Christian

    2013-01-01

    The receptor activator of the NF-kB ligand (RANKL) pathway is a key mediator of prostate cancer (PC)-induced bone disease. However, little is known about this pathway in patients with non-metastatic PC. We aimed to investigate whether changes of RANKL, its inhibitor osteoprotegerin (OPG) and bone marrow-mesenchymal stromal cells (BM-MSCs) occur in PC patients without manifest bone metastases. We determined OPG and soluble RANKL (sRANKL) in serum and corresponding bone marrow (BM) samples of 140 patients before radical prostatectomy by enzyme-linked immunosorbent assay (ELISA). As control serum samples of 50 patients with benign prostate hyperplasia were analyzed. BM mononuclear cells (BMNCs) of 16 PC patients were analyzed for expression of RANKL and CD271 (as marker for MSCs) by flow cytometry. PC patients had significantly lower serum levels of OPG compared to BPH patients (P = 0.007), whereas no differences were observed for serum sRANKL (P = 0.74). Both OPG and sRANKL concentrations of serum and corresponding BM samples correlated significantly (P < 0.0001 each). Interestingly, in PC patients, lower serum and BM OPG levels were associated with a higher proportion of BM-MSCs (P = 0.04 and 0.0016, respectively). No correlations were observed for sRANKL, OPG, BM-MSCs, and established risk parameters of PC. The results of the study indicate that localized PC is associated with early specific changes of the RANKL pathway in serum and bone marrow (BM). These changes might be part of the pre-metastatic niche of PC and implicate a potential benefit of RANKL inhibition in patients with localized PC. Copyright © 2012 Wiley Periodicals, Inc.

  12. Treatment of pressure ulcers with autologous bone marrow nuclear cells in patients with spinal cord injury

    PubMed Central

    Sarasúa, J González; López, S Pérez; Viejo, M Álvarez; Basterrechea, M Pérez; Rodríguez, A Fernández; Gutiérrez, A Ferrero; Gala, J García; Menéndez, Y Menéndez; Augusto, D Escudero; Arias, A Pérez; Hernández, J Otero

    2011-01-01

    Context Pressure ulcers are especially difficult to treat in patients with spinal cord injury (SCI) and recurrence rates are high. Prompted by encouraging results obtained using bone marrow stem cells to treat several diseases including chronic wounds, this study examines the use of autologous stem cells from bone marrow to promote the healing of pressure ulcers in patients with SCI. Objective To obtain preliminary data on the use of bone marrow mononuclear cells (BM-MNCs) to treat pressure ulcers in terms of clinical outcome, procedure safety, and treatment time. Participants Twenty-two patients with SCI (19 men, 3 women; mean age 56.41 years) with single type IV pressure ulcers of more than 4 months duration. Interventions By minimally invasive surgery, the ulcers were debrided and treated with BM-MNCs obtained by Ficoll density gradient separation of autologous bone marrow aspirates drawn from the iliac crest. Results In 19 patients (86.36%), the pressure ulcers treated with BM-MNCs had fully healed after a mean time of 21 days. The number of MNCs isolated was patient dependent, although similar clinical outcomes were observed in each case. Compared to conventional surgical treatment, mean intra-hospital stay was reduced from 85.16 to 43.06 days. Following treatment, 5 minutes of daily wound care was required per patient compared to 20 minutes for conventional surgery. During a mean follow-up of 19 months, none of the resolved ulcers recurred. Conclusions Our data indicate that cell therapy using autologous BM-MNCs could be an option to treat type IV pressure ulcers in patients with SCI, avoiding major surgical intervention. PMID:21756569

  13. 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.

  14. Composite vascularized skin/bone transplantation models for bone marrow-based tolerance studies.

    PubMed

    Ozmen, Selahattin; Ulusal, Betul G; Ulusal, Ali E; Izycki, Dariusz; Siemionow, Maria

    2006-03-01

    There is an ongoing need to understand the mechanisms of bone marrow-based allograft tolerance. This is important in clarifying the diverse variables influencing the ultimate outcome of the solid organ and composite tissue transplants. To establish bone marrow transplantation as a routine clinical application, further experimental studies should be conducted to overcome the obstacles related to the bone marrow transplantation. These obstacles include graft versus host disease, immunocompetence, and toxicity of the conditioning regimens. For these purposes, novel experimental models are needed. In an attempt to provide a reliable research tool for bone marrow-based tolerance induction studies, we introduced different experimental models of modified vascularized skin/bone marrow (VSBM) transplantation technique for tolerance induction, monitoring, and maintenance studies. In this skin/bone transplantation model, the technical feasibility of concurrent or consecutive transplantation of the combination of bilateral vascularized skin, vascularized bone marrow, or vascularized skin/bone marrow transplants was investigated. Isograft transplantations were performed between genetically identical Lewis (LEW, RT1) rats. Five different experimental designs in 5 groups of 5 animals each were studied. Group I: Bilateral vascularized skin (VS) transplantation; group II: bilateral vascularized skin/bone transplantation; group III: vascularized skin transplantation on one side and vascularized skin/bone transplantation on the contralateral side; group IV: vascularized bone transplantation on one side and vascularized skin/bone transplantation on the contralateral side; group V: vascularized bone transplantation on one side and vascularized skin transplantation on the contralateral side. Successful transplantations were performed in all groups. The survival of the isograft transplants was evaluated clinically and histologically. All skin flaps remained pink and pliable and grew new

  15. Cell Fate and Differentiation of Bone Marrow Mesenchymal Stem Cells

    PubMed Central

    Jimi, Eijiro

    2016-01-01

    Osteoblasts and bone marrow adipocytes originate from bone marrow mesenchymal stem cells (BMMSCs) and there appears to be a reciprocal relationship between adipogenesis and osteoblastogenesis. Alterations in the balance between adipogenesis and osteoblastogenesis in BMMSCs wherein adipogenesis is increased relative to osteoblastogenesis are associated with decreased bone quality and quantity. Several proteins have been reported to regulate this reciprocal relationship but the exact nature of the signals regulating the balance between osteoblast and adipocyte formation within the bone marrow space remains to be determined. In this review, we focus on the role of Transducin-Like Enhancer of Split 3 (TLE3), which was recently reported to regulate the balance between osteoblast and adipocyte formation from BMMSCs. We also discuss evidence implicating canonical Wnt signalling, which plays important roles in both adipogenesis and osteoblastogenesis, in regulating TLE3 expression. Currently, there is demand for new effective therapies that target the stimulation of osteoblast differentiation to enhance bone formation. We speculate that reducing TLE3 expression or activity in BMMSCs could be a useful approach towards increasing osteoblast numbers and reducing adipogenesis in the bone marrow environment. PMID:27298623

  16. Qualitative Aspects of Bone Marrow Adiposity in Osteoporosis

    PubMed Central

    Pino, Ana María; Miranda, Melissa; Figueroa, Carolina; Rodríguez, Juan Pablo; Rosen, Clifford J.

    2016-01-01

    The function of marrow adipocytes and their origin has not been defined although considerable research has centered on their presence in certain conditions, such as osteoporosis. Less work has focused on the qualitative aspects of marrow fat. Bone marrow serum is composed of multiple nutrients that almost certainly relate to functional aspects of the niche. Previous studies using non-invasive techniques have shown that osteoporotic individuals have more marrow fat and that the ratio of saturated: unsaturated fatty acid is high. We recently reported that bone marrow sera from osteoporotic patients with fracture showed a switch toward decreased content of total saturated versus unsaturated fatty acids, compared to patients without fracture highlighting a dynamic relationship between the composition of fatty acids in the bone microenvironment and the metabolic requirements of cells. The relative distribution of fatty acids differed considerably from that in the serum providing further evidence that energy utilization is high and that marrow adipocytes may contribute to this pool. Whether these lipids can affect osteoblast function in a positive or negative manner is still not certain but will require further investigation. PMID:27826285

  17. Mechanical stimulation of bone marrow in situ induces bone formation in trabecular explants.

    PubMed

    Birmingham, E; Kreipke, T C; Dolan, E B; Coughlin, T R; Owens, P; McNamara, L M; Niebur, G L; McHugh, P E

    2015-04-01

    Low magnitude high frequency (LMHF) loading has been shown to have an anabolic effect on trabecular bone in vivo. However, the precise mechanical signal imposed on the bone marrow cells by LMHF loading, which induces a cellular response, remains unclear. This study investigates the influence of LMHF loading, applied using a custom designed bioreactor, on bone adaptation in an explanted trabecular bone model, which isolated the bone and marrow. Bone adaptation was investigated by performing micro CT scans pre and post experimental LMHF loading, using image registration techniques. Computational fluids dynamic models were generated using the pre-experiment scans to characterise the mechanical stimuli imposed by the loading regime prior to adaptation. Results here demonstrate a significant increase in bone formation in the LMHF loaded group compared to static controls and media flow groups. The calculated shear stress in the marrow was between 0.575 and 0.7 Pa, which is within the range of stimuli known to induce osteogenesis by bone marrow mesenchymal stem cells in vitro. Interestingly, a correlation was found between the bone formation balance (bone formation/resorption), trabecular number, trabecular spacing, mineral resorption rate, bone resorption rate and mean shear stresses. The results of this study suggest that the magnitude of the shear stresses generated due to LMHF loading in the explanted bone cores has a contributory role in the formation of trabecular bone and improvement in bone architecture parameters.

  18. Risk factors in interstitial pneumonitis following allogenic bone marrow transplantation

    SciTech Connect

    Pino Y Torres, J.L.; Bross, D.S.; Lam, W.C.; Wharam, M.D.; Santos, G.W.; Order, S.E.

    1982-08-01

    Total body irradiation is part of the preparatory regimen for allogeneic bone marrow transplantation because of its cytotoxic and immunosuppressive properties. A major toxicity of bone marrow transplantation has been interstitial pneumonitis, which may be, in part, related to the lung irradiation. One hundred and sixty-one consecutive patients receiving allogeneic bone marrow transplantation for leukemia and aplastic anemia at Johns Hopkins Hospital (1968-1979) were retrospectively studied. The present study demonstrated that lung shielding to 600 rad maximum in single dose total body irradiation, fractionation of total body irradiation in comparison to single dose total body irradiation, and absence of graft versus host disease in the leukemia patients, each reduced the risk of interstitial pneumonitis. Total body irradiation significantly reduced the leukemia recurrence rate and/or the failure of remission induction.

  19. Bones of contention: marrow-derived cells in myocardial regeneration.

    PubMed

    Sussman, Mark A; Murry, Charles E

    2008-06-01

    Almost 7 years have passed since the initial publication reporting that bone marrow cells regenerate infarcted myocardium. The subsequent years produced hundreds of investigations that ran the gamut of findings from validation to disproof. Undeterred by the concurrent debate, clinical trials ensued to test the safety and efficacy of bone marrow-derived cell population for autologous therapy in clinical treatment of myocardial disease. In the following conversational exchange, two scientists with distinct perspectives weigh the pros and cons of pursuing bone marrow stem cell therapy and look toward finding a consensus of where the future lies for regenerative medicine and the heart. The conclusion is that the two camps may not be as far apart as it may seem from the rancor in literature and at meetings, and the potential of one day achieving regenerative therapy is indeed a vision that both parties enthusiastically share.

  20. Whole bone marrow irradiation for the treatment of multiple myeloma

    SciTech Connect

    Coleman, M.; Saletan, S.; Wolf, D.; Nisce, L.; Wasser, J.; McIntyre, O.R.; Tulloh, M.

    1982-04-01

    Nine patients with multiple myeloma were treated with whole bone marrow irradiation. Six had heavily pretreated disease refractory to chemotherapy. Three had stable disease lightly pretreated by chemotherapy. A modification of the ''three and two'' total nodal radiation technique was employed. Although varying and often severe treatment related cytopenia occurred, infectious complications, clinical bleeding, and nonhematalogic complications were minimal. Five of nine patients showed a decrease in monoclonal protein components, and one showed an increase during treatment. These preliminary results indicate that a reduction of tumor cell burden may occur in patients following whole bone marrow irradiation and that the technique is feasible. Whole bone marrow irradiation combined with chemotherapy represents a new conceptual therapeutic approach for multiple myeloma.

  1. Suppressive activity of acivicin on murine bone marrow hemopoietic progenitors.

    PubMed

    Castello, G; Mencoboni, M; Lerza, R; Cerruti, A; Bogliolo, G; Pannacciulli, I

    1992-01-01

    Acivicin (AVC), a L-glutamine antagonist, is an intriguing antimetabolite coupling cell growth inhibition activity with differentiating effects. In this in vivo study the influence of acivicin on mice bone marrow hemopoietic progenitors was tested. 10 mg/kg b.w./day of acivicin were i.p. injected in B6D2F1 mice for nine days. Leucocyte and reticulocyte level (in peripheral blood), CFU-S (multipotent stem cells) and GM-CFU (granulocyte-macrophage committed progenitors) content in bone marrow were determined during drug administration and for 14 days thereafter. All tested populations decreased severely during the first days of treatment. The drop was particularly striking for bone marrow CFU-S. The recovery of hemopoietic progenitors, however, began while AVC was still administered. These results suggest that the effects of acivicin on normal mouse hemopoietic system are mainly inhibitory, causing considerable myelosuppression.

  2. The transient appearance of small blastoid cells in the marrow after bone marrow transplantation.

    PubMed

    Kobayashi, S D; Seki, K; Suwa, N; Koama, C; Yamamoto, T; Aiba, K; Maruta, A; Matsuzaki, M; Fukawa, H; Kanamori, H

    1991-08-01

    Of 14 patients who underwent allogeneic or syngeneic bone marrow transplantation, 6 had a transient appearance of small blastoid cells in the bone marrow after transplantation. Most of these patients (11) had leukemia, although 3 had severe aplastic anemia. The cells were 8-18 micron in diameter and had scant cytoplasm and dense nuclei with smooth, homogeneous chromatin. They often had distinct nuclear clefts. These cells constituted 4.0-21.3% of the total number of bone marrow cells. They were not reactive with peroxidase, alpha-naphtyl butylate esterase, naphthol AS-D chloroacetate esterase, or periodic acid-Schiff stains. Immunocytochemical analysis revealed that the small blastoid cells expressed terminal deoxynucleotidyl transferase, Ia-like, CD19, and CD10 antigens and cytoplasmic mu heavy chains, indicating a precursor B-cell phenotype. CD20 antigen was not expressed on these cells. The data suggest that cytoplasmic mu may be expressed earlier than CD20 antigen in the differentiation of B-cell lineage. The morphologic, cytochemical, and immunophenotypic characteristics did not distinguish these nonneoplastic cells distinctly from leukemic lymphoblastic cells. The increase of small blastoid cells was a transient and self-limited phenomenon, in contrast to that of neoplastic blasts. These cells should be recognized as a common component of the bone marrow of marrow transplant recipients. The significance and role of these cells in immune recovery and hematopoiesis remain uncertain.

  3. [Pathological diagnosis of pediatric Burkitt lymphoma involving bone marrow].

    PubMed

    Sun, Qi; Chen, Zhenping; Liu, Enbin; Li, Zhanqi; Yang, Qingying; Sun, Fujun; Ma, Yue; Zhang, Hongju; Zhang, Peihong; Ru, Kun

    2015-02-01

    To investigate pathologic and differential diagnostic features of pediatric Burkitt lymphoma (BL). A total of 20 cases of pediatric BL were retrospectively reviewed for their clinical and pathologic profiles. Bone marrow aspiration specimens were available in all cases and bone marrow biopsies were available for immunohistochemical study in 18 cases. Flow cytometry study was available in 16 cases. MYC translocation by FISH method was performed in 11 cases. Atypical lymphocytes with cytoplasmic vacuoles were found in bone marrow smears in all 20 cases and peripheral blood films in all 19 available cases. The bone marrow biopsies showed infiltration by uniform medium-sized atypical lymphocytes with multiple small nucleoli but without the starry-sky pattern in all 18 cases. Immunohistochemistry showed the following results in all 18 cases: positive for CD20, PAX-5, CD10, CD34 and TdT, but negative for bcl-2 and CD3 with Ki-67 > 95%.Flow cytometry showed CD19+CD20+CD10+FMC7+CD22+TdT-CD3- in 16 cases, including κ+ in 8 cases, λ+ in 7 cases, and κ-λ- in 1 case. MYC gene rearrangement by FISH was observed in 10 of the 11 cases. The histopathology of BL is distinct, including atypical lymphocytes with cytoplasmic vacuoles in bone marrow aspirate, lack of starry-sky patternin bone marrow biopsy. Generally, the diagnosis should be made with a combined immunophenotype and FISH approach. Pediatric BL must be distinguished from DLBCL and B-cell lymphoma, unclassifiable, which has intermediate features between DLBCL and Burkitt lymphoma.

  4. 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.

  5. [Connections between bone marrow and mesenchyme of the middle ear].

    PubMed

    Whyte Orozco, Jaime Rafael; Cisneros Gimeno, Ana Isabel; Pérez Sanz, Raúl; Yus Gotor, Carmen; Gañet Solé, José Francisco; Sarrat Torres, Marco Antonio

    2007-01-01

    To investigate the presence of connections between the bone marrow of the ossicles and the mesenchyme that fills the future tympanic cavity. Ninety temporal bones from embryos and foetuses were examined, selecting 15 aged between 20th to 30th weeks of development, to show connections between ossicle marrow and mesenchyme. The connections are transitory and appear in the malleus and the incus between 20th to 24th weeks of development, while in the stapes appear later, being between 24th to 28th weeks. These connections may have an important role in the phagocytosis of the mesenchymal remains and join in the detritus elimination mechanisms produced during the regression.

  6. 18F-FDG super bone marrow uptake

    PubMed Central

    Alam, Mohammed Shah; Fu, Lilan; Ren, Yun-Yan; Wu, Hu-Bing; Wang, Quan-Shi; Han, Yan-Jiang; Zhou, Wen-Lan; Li, Hong-Sheng; Wang, Zhen

    2016-01-01

    Abstract The present study was performed to investigate whether the markedly 2-deoxy-2-(fluorine-18) fluoro-D-glucose (18F-FDG) uptake in the bone marrow (BM) is a presentation of malignant infiltration (MI). Super bone marrow uptake (super BMU) was used to name the markedly 18F-FDG uptake on BM, which was similar to or higher than that of the brain. From April 2008 to December 2015, 31 patients with such presentation were retrospectively reviewed. The 18F-FDG uptake was semiquantified using SUVmax and BM to cerebellum (BM/C) ratio. The origin of super BMU was diagnosed by pathology. Some blood parameters, as well as fever, were also collected and analyzed. For comparison, 106 patients with mildly and moderately uptake in BM and 20 healthy subjects were selected as the control group. Bone marrow MI was diagnosed in 93.5% (29/31) patients with super BMU, which mostly originated from acute leukemia and highly aggressive lymphoma. The super BMU group had markedly higher 18F-FDG uptake in the BM than those of mildly and moderately uptake, and the control subjects (all P = 0.000) and the BM/C ratio reached a high of 1.24 ± 0.36. The incidence of bone marrow MI in the super BMU group was markedly higher than that of mildly and moderately uptake (93.5% vs 36.8%, P = 0.000). Based on the receiver operating characteristic analysis, when cut-off values of BM/C and SUVmax were set at 0.835 and 6.560, the diagnostic specificity for bone marrow MI reached the high levels of 91.4% and 95.7%, respectively. In 15 patients with bone marrow MI, the extra-BM malignant lesions were simultaneously detected by 18F-FDG PET/CT. The liver and the nasal cavity involvements were only found in the patients with lymphoma, but not in those with leukemia. A decrease of leukocyte, hemoglobin, and platelet counts was noted in 48.4%, 86.2%, and 51.5% of patients with bone marrow MI, respectively. The present study revealed that super BMU was a highly potent indicator for the bone

  7. Systemic bone marrow disorders: Characterization with proton chemical shift imaging

    SciTech Connect

    Gueckel, F.B.; Brix, G.; Semmler, W.; Zuna, I.; Knauf, W.; Ho, A.D.; van Kaick, G. )

    1990-07-01

    In a prospective clinical study, 26 patients (22 with malignant lymphoma and 4 with myelofibrosis) and 9 healthy volunteers were examined by conventional magnetic resonance and proton chemical shift imaging (CSI; modified Dixon method). On the basis of the CSI data, a quantitative evaluation of the relative fat and water signal fractions in regions of interest of the femur, pelvis, and spine was performed. In 16 of 17 patients with biopsy-proven bone marrow disorders, CSI revealed a significant reduction in the fat fraction of the bone marrow relative to that of normal volunteers. The visual assessment could detect only 14 of the 17 pathological cases.

  8. Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

    DTIC Science & Technology

    2016-10-01

    Award Number: W81XWH-14-1-0297 TITLE: Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells PRINCIPAL INVESTIGATOR: Raymond J...Molecule Protection of Bone Marrow Hematopoietic Stem Cells Stem Cells ’ 5a. CONTRACT NUMBER W81XWH-14-1-0297 W81XWH-14-1-0297 W81XWH-14-1-0297 5b...hematopoietic stem cells (HSCs) from damage or killing by endogenous aldehydes. Proof-of-concept for these experiments has been developed using isogenic

  9. Genotoxicity of ibuprofen in mouse bone marrow cells in vivo.

    PubMed

    Tripathi, Rina; Pancholi, Shyam S; Tripathi, Pankaj

    2012-10-01

    Genotoxicity of ibuprofen was evaluated by employing the mouse in vivo chromosomal aberration (CA) test. Ibuprofen administered orally at doses of 10, 20, 40, and 60 mg/kg body weight to mice resulted in mitotic depression and induction of CAs. A dose-related decrease in mitotic index (MI) and an increase in the frequencies of chromosomal aberrations per cell (CAs/cell) were recorded in bone marrow cells. However, a statistically significant reduction in MI and an increase in CAs/cell were found for both the higher doses. The results obtained indicate that ibuprofen is capable of inducing dose-dependent genotoxicity in bone marrow cells of mice.

  10. 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

  11. A rapid method for obtaining mesenchymal stem cells and platelets from bone marrow aspirate.

    PubMed

    Dozza, Barbara; Gobbi, Giuliana; Lucarelli, Enrico; Pierini, Michela; Di Bella, Claudia; Frisoni, Tommaso; Tazzari, Pier Luigi; Ricci, Francesca; Mirandola, Prisco; Carubbi, Cecilia; Giannini, Sandro; Donati, Davide; Vitale, Marco

    2014-06-01

    Mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) are currently used alone or in combination for therapeutic applications especially for bone repair. We tested whether MSCs can be isolated from bone marrow (BM) aspirate using a commercially available kit commonly used to obtain PRP from peripheral blood (PB). Results revealed that mononuclear cells and platelets from both PB and BM could be efficiently isolated by obtaining a mononuclear and platelet rich fraction (PB-MPRF and BM-MPRF, respectively). Starting with comparable volumes, the number of platelets increased 1.5-fold in BM-MPRF compared to PB-MPRF. The number of clonogenic cells in BM-MPRF samples was significantly higher than whole BM samples as revealed by CFU-F assay (54.92 ± 8.55 CFU-F/1.5 x 10(5) nucleated cells and 32.50 ± 12.43 CFU-F/1.5 x 10(5) nucleated cells, respectively). Cells isolated from BM-MPRF after in vitro expansion fulfilled the definition of MSCs by phenotypic criteria, and differentiated along osteogenic, adipogenic and chondrogenic lineages following induction. Results showed that the kit isolated MSCs and platelets from BM aspirate. Isolated MSCs were further expanded in a laboratory and BM-MPRF was used clinically following BM withdrawal for rapid intra-operative cell therapy for the treatment of bone defects.

  12. Tc-99m sestamibi bone marrow scintigraphy in Gaucher disease.

    PubMed

    Aharoni, Dvora; Krausz, Yodphat; Elstein, Deborah; Hadas-Halpern, Irith; Zimran, Ari

    2002-07-01

    No imaging technique has been found to be adequate to assess the severity and extent of bone involvement in patients with Gaucher disease. Marrow involvement, as determined by Tc-99m sulfur colloid, correlated well with the clinical and radiologic changes of the skeleton, but a normal pattern was found in the early stages of the disease. Subsequently, Tc-99m sestamibi (MIBI) has been suggested for direct visualization of glycolipid deposits in the bone marrow. This study was initiated as a pilot using MIBI to detect various forms of bone disease in patients with Gaucher disease of varying severity. Eleven patients (9 men; median age, 39.9; age range, 21 to 61 years) were evaluated. The clinical severity of disease was scored at presentation, and four patients with moderate to severe disease were treated with enzyme replacement therapy. Each patient underwent a radiographic skeletal survey, bone densitometry, and MIBI scintigraphy. The scan included static images of the lower limbs, with a whole-body scan acquired between the early and late acquisition. Tracer uptake in the bone marrow was graded and correlated with clinical and objective variables. All but one patient had increased MIBI uptake in the bone marrow. No correlation was noted between MIBI uptake and severity score, radiographic changes, densitometry z score, or treatment status. MIBI scanning is a sensitive technique for detecting bone marrow deposits in Gaucher disease, but it is inadequate for early identification of patients at high risk for skeletal complications or for the follow-up of patients treated with enzyme replacement.

  13. [DISSEMINATED CARCINOMATOSIS OF THE BONE MARROW WITH UROTHELIAL CARCINOMA].

    PubMed

    Kohno, Mitsuru; Miyama, Ken; Gohbara, Ayako; Onuki, Tatsuaki; Sugiura, Shinpei; Ikeda, Ichiro

    2015-04-01

    Disseminated carcinomatosis of the bone marrow with urothelial carcinoma in a 75-year-old man: A case study. A 75-year-old-man had first medical examination due to gross hematuria. The imaging study and cystoscopy revealed left ureteral and bladder tumor. The patient was referred for a laparoscopic assisted left nephroureterectomy and transurethral resection of a bladder tumor (TUR-Bt). Pathological findings included urothelial carcinoma, high grade, both a pT3 ureteral tumor and a pTa bladder tumor. The patient received 2 courses of gemcitabine and cisplatin and 1 course of methotrexate, epirubicin and nedaplatin as adjuvant chemotherapy. TUR-Bt was performed twice due to recurrence in the bladder and similar pathological findings. The patient received intravesical instillation of pirarubicin (THP 30 mg in 30 mL of saline) to prevent recurrence in the bladder, but discontinued in the 3rd time because of gross hematuria. The patient was then admitted to our hospital due to gross hematuria, general fatigue, and abnormal findings in the blood analysis. On admission, pancytopenia was detected and the serum ALP level had increased to 30,266 IU/L. A biopsy and bone marrow aspiration were performed because a super bone scan image was obtained using a bone scintigram. Diffuse bone marrow metastasis of the urothelial carcinoma was observed in the pathological evaluations. Therefore, our diagnosis was urothelial carcinoma with disseminated carcinomatosis of the bone marrow. Although treatment with zoledronic acid and blood transfusion were performed, the patient died 20 days after the admission. To the best of our knowledge, this is the first case of disseminated carcinomatosis of the bone marrow with urothelial carcinoma.

  14. 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.

  15. Canine Cranial Reconstruction Using Autologous Bone Marrow Stromal Cells

    PubMed Central

    Mankani, Mahesh H.; Kuznetsov, Sergei A.; Shannon, Brian; Nalla, Ravi K.; Ritchie, Robert O.; Qin, Yixian; Robey, Pamela Gehron

    2006-01-01

    Limited-sized transplants of culture-expanded autologous or allogeneic bone marrow stromal cells (BMSCs) form cortico-cancellous bone in rodent models. Initiation of clinical studies using autologous BMSC transplantation requires effective bone formation among sizable transplants in a large animal model as well as noninvasive techniques for evaluating transplant success. Here, we obtained bone marrow from the femurs of six dogs and expanded BMSCs in tissue culture. Autologous BMSC-hydroxyapatite/tricalcium phosphate (HA/TCP) transplants were introduced into critical-sized calvarial defects and contralateral control skull defects received HA/TCP vehicle alone. At intervals ranging from 2 to 20 months, transplants were biopsied or harvested for histological and mechanical analysis. Noninvasive studies, including quantitative computed tomography scans and ultrasound, were simultaneously obtained. In all animals, BMSC-containing transplants formed significantly more bone than their control counterparts. BMSC-associated bone possessed mechanical properties similar to the adjacent normal bone, confirmed by both ultrasound and ex vivo analysis. Evaluation by quantitative computed tomography confirmed that the extent of bone formation demonstrated by histology could be discerned through noninvasive means. These results show that autologous cultured BMSC transplantation is a feasible therapy in clinical-sized bone defects and that such transplants can be assessed noninvasively, suggesting that this technique has potential for use in patients with certain bone defects. PMID:16436668

  16. Hematopoietic Stem Cells in Neural-crest Derived Bone Marrow

    PubMed Central

    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.

    2016-01-01

    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. PMID:28000662

  17. Impaired Function of Bone Marrow Stromal Cells in Systemic Mastocytosis

    PubMed Central

    Nemeth, K.; Wilson, T.M.; Ren, J.J.; Sabatino, M.; Stroncek, D.F.; Krepuska, M.; Bai, Y.; Robey, P.G.; Metcalfe, D.D.; Mezey, E.

    2015-01-01

    Patients with systemic mastocytosis (SM) have a wide variety of problems, including skeletal abnormalities. The disease results from a mutation of the stem cell receptor (c-kit) in mast cells and we wondered if the function of bone marrow stromal cells (BMSCs; also known as MSCs or mesenchymal stem cells) might be affected by the invasion of bone marrow by mutant mast cells. As expected, BMSCs from SM patients do not have a mutation in c-kit, but they proliferate poorly. In addition, while osteogenic differentiation of the BMSCs seems to be deficient, their adipogenic potential appears to be increased. Since the hematopoietic supportive abilities of BMSCs are also important, we also studied the engraftment in NSG mice of human CD34+ hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM could not support hematopoiesis to the extent that healthy BMSCs do. Finally, we performed an expression analysis and found significant differences between healthy and SM derived BMSCs in the expression of genes with a variety of functions, including the WNT signaling, ossification, and bone remodeling. We suggest that some of the symptoms associated with SM might be driven by epigenetic changes in BMSCs caused by dysfunctional mast cells in the bone marrow of the patients. PMID:26001169

  18. Bone marrow chimera experiments to determine the contribution of hematopoietic stem cells to cerebral angiogenesis.

    PubMed

    Machein, Marcia Regina; Plate, Karl H

    2014-01-01

    The generation of bone marrow chimera in mice is a valuable tool to study a variety of cellular processes. Donor bone marrow cells expressing reporter genes have been used to study the process of cell differentiation and the mechanisms involved in bone marrow cell recruitment. Bone marrow cells bearing genetic manipulation have been used in bone marrow chimeras to elucidate the role of molecules in different physiological and pathological settings. Since in the normal adult brain angiogenesis does not occur, models of brain injury like ischemia and tumor growth have been used to study the contribution of bone marrow-derived cells to the cerebral vasculature. This chapter describes the procedures to perform bone marrow transplantation in order to study the contribution of bone marrow-derived cells to vascularization in an orthotopic glioma model.

  19. Gene expression profiling of bone marrow mesenchymal stem cells from Osteogenesis Imperfecta patients during osteoblast differentiation.

    PubMed

    Kaneto, Carla Martins; Pereira Lima, Patrícia S; Prata, Karen Lima; Dos Santos, Jane Lima; de Pina Neto, João Monteiro; Panepucci, Rodrigo Alexandre; Noushmehr, Houtan; Covas, Dimas Tadeu; de Paula, Francisco José Alburquerque; Silva, Wilson Araújo

    2017-06-01

    Mesenchymal stem cells (MSCs) are precursors present in adult bone marrow that are able to differentiate into osteoblasts, adipocytes and chondroblasts that have gained great importance as a source for cell therapy. Recently, a number of studies involving the analysis of gene expression of undifferentiated MSCs and of MSCs in the differentiation into multiple lineage processes were observed but there is no information concerning the gene expression of MSCs from Osteogenesis Imperfecta (OI) patients. Osteogenesis Imperfecta is characterized as a genetic disorder in which a generalized osteopenia leads to excessive bone fragility and severe bone deformities. The aim of this study was to analyze gene expression profile during osteogenic differentiation from BMMSCs (Bone Marrow Mesenchymal Stem Cells) obtained from patients with Osteogenesis Imperfecta and from control subjects. Bone marrow samples were collected from three normal subjects and five patients with OI. Mononuclear cells were isolated for obtaining mesenchymal cells that had been expanded until osteogenic differentiation was induced. RNA was harvested at seven time points during the osteogenic differentiation period (D0, D+1, D+2, D+7, D+12, D+17 and D+21). Gene expression analysis was performed by the microarray technique and identified several differentially expressed genes. Some important genes for osteoblast differentiation had lower expression in OI patients, suggesting a smaller commitment of these patient's MSCs with the osteogenic lineage. Other genes also had their differential expression confirmed by RT-qPCR. An increase in the expression of genes related to adipocytes was observed, suggesting an increase of adipogenic differentiation at the expense osteogenic differentiation. Copyright © 2017. Published by Elsevier Masson SAS.

  20. Growth Hormone Regulates the Balance Between Bone Formation and Bone Marrow Adiposity

    PubMed Central

    Menagh, Philip J; Turner, Russell T; Jump, Donald B; Wong, Carmen P; Lowry, Malcolm B; Yakar, Shoshana; Rosen, Clifford J; Iwaniec, Urszula T

    2010-01-01

    Cancellous bone decreases and bone marrow fat content increases with age. Osteoblasts and adipocytes are derived from a common precursor, and growth hormone (GH), a key hormone in integration of energy metabolism, regulates the differentiation and function of both cell lineages. Since an age-related decline in GH is associated with bone loss, we investigated the relationship between GH and bone marrow adiposity in hypophysectomized (HYPOX) rats and in mice with defects in GH signaling. HYPOX dramatically reduced body weight gain, bone growth and mineralizing perimeter, serum insulin-like growth factor 1 (IGF-1) levels, and mRNA levels for IGF-1 in liver and bone. Despite reduced body mass and adipocyte precursor pool size, HYPOX resulted in a dramatic increase in bone lipid levels, as reflected by increased bone marrow adiposity and bone triglyceride and cholesterol content. GH replacement normalized bone marrow adiposity and precursor pool size, as well as mineralizing perimeter in HYPOX rats. In contrast, 17β -estradiol, IGF-1, thyroxine, and cortisone were ineffective. Parathyroid hormone (PTH) reversed the inhibitory effects of HYPOX on mineralizing perimeter but had no effect on adiposity. Finally, bone marrow adiposity was increased in mice deficient in GH and IGF-1 but not in mice deficient in serum IGF-1. Taken together, our findings indicate that the reciprocal changes in bone and fat mass in GH signaling-deficient rodents are not directly coupled with one another. Rather, GH enhances adipocyte as well as osteoblast precursor pool size. However, GH increases osteoblast differentiation while suppressing bone marrow lipid accumulation. © 2010 American Society for Bone and Mineral Research PMID:19821771

  1. A murine model of experimental metastasis to bone and bone marrow.

    PubMed

    Arguello, F; Baggs, R B; Frantz, C N

    1988-12-01

    Bone is a common site of metastasis in human cancer. A major impediment to understanding the pathogenesis of bone metastasis has been the lack of an appropriate animal model. In this paper, we describe an animal model in which B16 melanoma cells injected in the left cardiac ventricle reproducibly colonize specific sites of the skeletal system of mice. Injection of 10(5) cells resulted in melanotic tumor colonies in most organs, including the skeletal system. Injection of 10(4) or fewer cells resulted in experimental metastasis almost entirely restricted to the skeletal system and ovary. In contrast, i.v. injection of 10(5) cells resulted in tumor colonies in the lung only. Left cardiac injection of 10(2) cells caused bone colonization, but the same number of cells injected i.v. did not colonize the lung. The number of bones with tumor colonies increased with increasing number of cells injected. Melanotic tumor colonies in the bone were characteristically distributed in the metaphysis of long bones and in the periphery of flat bones. Most animals developed paraplegia due to spinal cord compression by bony metastasis to the spine. Tumor colonization of bone occurred only in regions of bone containing hematopoietic bone marrow. This suggests that the injected tumor cells lodge, survive in the hematopoietic bone marrow environment, and grow to destroy adjacent bone. This experimental model of metastasis to bone will facilitate future studies of the pathophysiology and treatment of bone and bone marrow metastasis.

  2. IMMUNOLOGIC MEMORY CELLS OF BONE MARROW ORIGIN

    PubMed Central

    Miller, Harold C.; Cudkowicz, Gustavo

    1972-01-01

    Individual immunocompetent precursor cells of (C57BL/10 x C3H)F1 mouse marrow generate, on transplantation, three to five times more antibody-forming cells localized in recipient spleens during secondary than during primary immune responses. The increased burst size is immunologically specific since antigens of horse and chicken erythrocytes and of Salmonella typhimurium do not cause this effect in marrow cells responsive to sheep red blood cells. Both sensitized and nonsensitized precursors require the helper function of thymus-derived cells and antigen for the final steps of differentiation and maturation. The burst size of primed precursor cells is the same after cooperative interactions with virgin or educated helper cells of thymic origin. The greater potential of these marrow precursors may be attributable to self-replication and migration before differentiation into antibody-forming descendants. In fact, the progeny cells of primed precursor units are distributed among a multiplicity of foci, whereas those of nonimmune precursors are clustered into one focus. The described properties of specifically primed marrow precursors are those underlying immunologic memory. It remains to be established whether memory cells are induced or selected by antigens and whether the thymus plays a role in this process. PMID:4553850

  3. HLA Typing for Bone Marrow Transplantation

    DTIC Science & Technology

    2007-10-31

    storage of the first product at the apheresis center. It is also common, particularly if products arrive late in the business day, for either PBSC or marrow...over time with products stored at 20°C whereas no notable change was observed with products stored at 4’C (p ɘ.0003). However for BM, platelet

  4. Regulation of vitamin C transporter in the type 1 diabetic mouse bone and bone marrow.

    PubMed

    Sangani, Rajnikumar; Naime, Mohammad; Zakhary, Ibrahim; Ahmad, Saif; Chutkan, Norman; Zhu, Andy; Ha, Yonju; Hamrick, Mark; Isales, Carlos; Elsalanty, Mohammed; Smith, Sylvia; Liou, Gregory I; Fulzele, Sadanand

    2013-12-01

    A number of studies have revealed that Type I diabetes (T1D) is associated with bone loss and an increased risk of fractures. T1D induces oxidative stress in various tissues and organs. Vitamin C plays an important role in the attenuation of oxidative stress; however, little is known about the effect of T1D induced oxidative stress on the regulation of vitamin C transporter in bone and bone marrow cells. To investigate this, T1D was induced in mice by multiple low dose injections of streptozotocin. We have demonstrated that endogenous antioxidants, glutathione peroxidase (GPx) and superoxide dismutase (SOD) are down-regulated in the bone and bone marrow of T1D. The vitamin C transporter isoform SVCT2, the only known transporter expressed in bone and bone marrow stromal cells (BMSCs), is negatively regulated in the bone and bone marrow of T1D. The μCT imaging of the bone showed significantly lower bone quality in the 8 week T1D mouse. The in-vitro study in BMSCS showed that the knockdown of SVCT2 transporter decreases ascorbic acid (AA) uptake, and increases oxidative stress. The significant reversing effect of antioxidant vitamin C is only possible in control cells, not in knockdown cells. This study suggested that T1D induces oxidative stress and decreases SVCT2 expression in the bone and bone marrow environment. Furthermore, this study confirms that T1D increases bone resorption, decreases bone formation and changes the microstructure of bones. This study has provided evidence that the regulation of the SVCT2 transporter plays an important role not only in T1D osteoporosis but also in other oxidative stress-related musculoskeletal complications.

  5. Reversal of Methanol-Induced Blindness in Adults by Autologous Bone Marrow-Derived Stem Cells: A Case Series.

    PubMed

    Bansal, Himanshu; Chaparia, Yogesh; Agrawal, Anupama; Koka, Prasad S

    2015-01-01

    Methanol ingestion leads to severe damage to visual pathways and permanent loss of vision. Current treatment is aimed at removal of methanol from system and prevention of generation of toxic metabolites along with symptomatic management of patient. Autologous bone marrow mononuclear stem cells (MNC) can be used to rejuvenate the damaged retinal cells and restoration of vision. Five patients suffering from methanol induced complete blindness within three months of insult and no known comorbidities during the past 6 months were enrolled to receive autologous bone marrow derived mononuclear cell fraction on compassionate grounds. The visual acuity and visual evoked responses (VER) were done at the time of enrollment and during follow-up visits. Visual acuity of these patients at the time of enrollment: no perception of light. Improvement in visual acuity was recorded by 7 days which reached maximum at 3 weeks after treatment in three patients and three months in two patients. The patients had acuity of 6/9, finger counting and reading with magnifying glasses with no subsequent improvement till 2 years of follow-up. Visual Evoked Responses demonstrated improvements following treatment. No adverse reactions were noticed during follow-up. Treatment with Autologous Bone marrow derived MNC offers a new line of management in patients with loss of vision following methanol ingestion. The efficacy and safety of this line of management needs to be evaluated in controlled clinical trials.

  6. Autologous bone marrow stem cell transplantation for the treatment of ulcerative colitis complicated with herpes zoster: a case report.

    PubMed

    Xiang, Hang; Zhang, Xiaomei; Yang, Chao; Xu, Wenhuan; Ge, Xin; Zhang, Rong; Qiu, Ya; Sun, Wanjun; Li, Fan; Xiang, Tianyuan; Chen, Haixu; Wang, Zheng; Zeng, Qiang

    2016-12-01

    Ulcerative colitis (UC) is a chronic inflammatory bowel disease with continuous or recurrent symptoms. A 42-year-old male patient with intermittent diarrhea accompanied by bloody mucopurulent stools was admitted to our hospital. The diagnosis of UC was confirmed by a combination of laboratory examination, colonoscopy, and histological assay. The patient developed herpes zoster in the hospital, which challenged traditional treatments. Therefore, we performed an autologous bone marrow cells to modulate the immune system with his permission. Autologous bone marrow mononuclear cells were collected and injected locally into the bowel mucosa, and subsequently injected systemically through a peripheral vein. After the patient underwent auto bone marrow mononuclear cells transplantations twice, the patient's symptoms were alleviated. Furthermore, he recovered from hematochezia, and his hypersensitive C reactive protein decreased. Colonoscopy results showed reduced lesions and decreased areas with bleeding and edema in the sigmoid colon and rectum. No recurrence occurred in the subsequent two years, but long-time monitoring is still necessary for the prophylaxis of colorectal cancer.

  7. Total body irradiation in bone marrow transplantation: the influence of fractionation and delay of marrow infusion

    SciTech Connect

    Lichter, A.S.; Tracy, D.; Lam, W.C.; Order, S.E.

    1980-03-01

    Bone marrow transplantation (BMT) after total body irradiation (TBI) and cyclophosphamide is being employed increasingly in the therapy of end stage leukemia. Interstitial pneumonitis (IP) represents a major acute toxicity after allogeneic transplantation. A more rapid reconstitution of lymphoid organs and bone marrow post transplant may result in increased immune competence and hence fewer opportunistic pulmonary infections and IP. By delaying the infusion of marrow to 72 hr after TBI (1250 rad at 7.5 rad/min) instead of the customary 24 hr, we can demonstrate an increase in initial repopulation of thymus, spleen and bone marrow, with syngeneic transplants in Lewis rats. Interstitial pneumonitis may also be caused, in part, by the pulmonary toxicity of large single exposures of TBI. Clinical and laboratory data suggest that fractionated TBI may be less toxic to the lung. When fractionated TBI (625 rad x 2, 7.5 rad/min) is compared to single dose TBI (1250 rad, 7.5 rad/min), and increased initial repopulation of lymphoid organs is observed when fractionated therapy is employed. Delay in marrow infusion and fractionation of TBI exposure may have clinical advantages in patients who receive BMT.

  8. Mechanisms of bone marrow-derived cell therapy in ischemic cardiomyopathy with left ventricular assist device bridge to transplant.

    PubMed

    Stempien-Otero, April; Helterline, Deri; Plummer, Tabitha; Farris, Stephen; Prouse, Andrew; Polissar, Nayak; Stanford, Derek; Mokadam, Nahush A

    2015-04-14

    Clinical trials report improvements in function and perfusion with direct injection of bone marrow cells into the hearts of patients with ischemic cardiomyopathy. Preclinical data suggest these cells improve vascular density, which would be expected to decrease fibrosis and inflammation. The goal of this study was to test the hypothesis that bone marrow stem cells (CD34+) will improve histological measurements of vascularity, fibrosis, and inflammation in human subjects undergoing left ventricular assist device (LVAD) placement as a bridge to cardiac transplantation. Subjects with ischemic cardiomyopathy who were scheduled for placement of an LVAD as a bridge to transplantation underwent bone marrow aspiration the day before surgery; the bone marrow was processed into cell fractions (bone marrow mononuclear cells, CD34+, and CD34-). At LVAD implantation, all fractions and a saline control were injected epicardially into predetermined areas and each injection site marked. At the time of transplantation, injected areas were collected. Data were analyzed by paired Student t test comparing the effect of cell fractions injected within each subject. Six subjects completed the study. There were no statistically significant differences in complications with the procedure versus control subjects. Histological analysis indicated that myocardium injected with CD34+ cells had decreased density of endothelial cells compared to saline-injected myocardium. There were no significant differences in fibrosis or inflammation between groups; however, density of activated fibroblasts was decreased in both CD34+ and CD34- injected areas. Tissue analysis does not support the hypothesis that bone marrow-derived CD34+ cells promote increased vascular tissue in humans with ischemic cardiomyopathy via direct injection. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  9. Comparison of Uncultured Marrow Mononuclear Cells and Culture-Expanded Mesenchymal Stem Cells in 3D Collagen-Chitosan Microbeads for Orthopedic Tissue Engineering

    PubMed Central

    Wise, Joel K.; Alford, Andrea I.; Goldstein, Steven A.

    2014-01-01

    Stem cell-based therapies have shown promise in enhancing repair of bone and cartilage. Marrow-derived mesenchymal stem cells (MSC) are typically expanded in vitro to increase cell number, but this process is lengthy, costly, and there is a risk of contamination and altered cellular properties. Potential advantages of using fresh uncultured bone marrow mononuclear cells (BMMC) include heterotypic cell and paracrine interactions between MSC and other marrow-derived cells including hematopoietic, endothelial, and other progenitor cells. In the present study, we compared the osteogenic and chondrogenic potential of freshly isolated BMMC to that of cultured-expanded MSC, when encapsulated in three-dimensional (3D) collagen-chitosan microbeads. The effect of low and high oxygen tension on cell function and differentiation into orthopedic lineages was also examined. Freshly isolated rat BMMC (25×106 cells/mL, containing an estimated 5×104 MSC/mL) or purified and culture-expanded rat bone marrow-derived MSC (2×105 cells/mL) were added to a 65–35 wt% collagen-chitosan hydrogel mixture and fabricated into 3D microbeads by emulsification and thermal gelation. Microbeads were cultured in control MSC growth media in either 20% O2 (normoxia) or 5% O2 (hypoxia) for an initial 3 days, and then in control, osteogenic, or chondrogenic media for an additional 21 days. Microbead preparations were evaluated for viability, total DNA content, calcium deposition, and osteocalcin and sulfated glycosaminoglycan expression, and they were examined histologically. Hypoxia enhanced initial progenitor cell survival in fresh BMMC-microbeads, but it did not enhance osteogenic potential. Fresh uncultured BMMC-microbeads showed a similar degree of osteogenesis as culture-expanded MSC-microbeads, even though they initially contained only 1/10th the number of MSC. Chondrogenic differentiation was not strongly supported in any of the microbead formulations. This study demonstrates the microbead

  10. Role of bone marrow transplantation for correcting hemophilia A in mice

    PubMed Central

    Follenzi, Antonia; Raut, Sanj; Merlin, Simone; Sarkar, Rita

    2012-01-01

    To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)–derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. By contrast, donor BM-derived mononuclear and mesenchymal stromal cells were more abundant and expressed FVIII mRNA as well as FVIII protein. Moreover, injection of healthy mouse Kupffer cells (liver macrophage/mononuclear cells), which predominantly originate from BM, or of healthy BM-derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearance of FVIII in blood. Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and mesenchymal stromal cells. These insights into FVIII synthesis and production in alternative cell types will advance studies of pathophysiological mechanisms and therapeutic development in hemophilia A. PMID:22368271

  11. Exercise promotes bone marrow cell survival and recipient reconstitution post-bone marrow transplantation, which is associated with increased survival.

    PubMed

    De Lisio, Michael; Baker, Jeff M; Parise, Gianni

    2013-02-01

    Bone marrow transplantation (BMT) is associated with a high risk of mortality, partially because of the harmful effects of the preconditioning myeloablative regimens. We have recently demonstrated increased bone marrow cell survival and proliferation in response to exercise training, which may be attributable to increased quality of the niche. The purpose of the present study was to determine the extent to which exercise preconditioning of recipients could increase the success of BMT. Recipient mice remained sedentary (SED) or were exercise-trained (EX) on a treadmill (3 d/wk for 8 weeks) before reconstitution with green fluorescent protein (GFP)-labeled donor marrow. Recipient survival, both donor-derived and total (donor- and recipient-derived) blood reconstitution were measured by flow cytometry. The first and fourth day after BMT apoptosis, cellularity and donor cell homing were determined in the recipients' bone marrow cavity by flow cytometry. Whereas only 25% of SED mice survived, 82% of EX recipients survived the BMT. Homing of donor-derived marrow cells to the recipients' marrow cavity acutely after BMT was not altered in EX, but EX mice displayed decreased levels (10%; p < 0.05) of activated caspase-3/-7 one day after BMT, leading to a maintenance of marrow cellularity in mice preconditioned with exercise. The acute inhibition of marrow cell apoptosis in EX mice resulted in increased total blood cell reconstitution at 1 and 3.5 months after BMT in EX mice (42% and 43%, respectively; both p < 0.05). Short- and long-term donor-derived engraftment was not different between EX and SED recipients. Exercise training increases recipient survival after BMT with increased total blood cell reconstitution. Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  12. Cellular survival of human marrow during placement of marrow-cancellous bone grafts.

    PubMed

    Marx, R E; Snyder, R M; Kline, S N

    1979-10-01

    The survival of human marrow cells during the placement of marrow-cancellous bone grafts was studied by three independent viability assays. Marrow cells are resistant cells able to survive the surgical harvest from the ilium. Salt solutions such as normal saline solution and 5% dextrose in water (D5W) were superior to tissue culture medium, the serum of the patients, and several other solutions in supporting the survival of the graft cells. High survival rates of marrow cells stored in normal saline solution and D5W for four hours or less established that 95% to 100% live cells can be transplanted even with long delays between harvest and placement of the graft.

  13. 40 CFR 798.5395 - In vivo mammalian bone marrow cytogenetics tests: Micronucleus assay.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 33 2012-07-01 2012-07-01 false In vivo mammalian bone marrow... Genetic Toxicity § 798.5395 In vivo mammalian bone marrow cytogenetics tests: Micronucleus assay. (a... mitotic apparatus by chemicals. Polychromatic erythrocytes in the bone marrow of rodents are used in...

  14. 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...

  15. Development of hybrid type artificial bone marrow using sintered hydroxyapatite.

    PubMed

    Nishihara, K; Tange, T; Hirota, K; Kawase, K

    1994-01-01

    In vivo inducement of hybrid-type artificial bone marrow with hemopoietic inductive microenvironment (HIM) in sintered hydroxyapatite (HA) chamber was carried out. This research is important to disclose the mechanisms of hemopoiesis and is useful for clinical application. In the evolution of vertebrates, cartilage of the inner skeleton changed into bone, having biomechanical properties to form bone marrow cavities. The hemopoietic nests immigrated into the cavities from the spleen. We should be able to induce hemopoietic nests in a hydroxyapatite chamber in place of bone, if we can find optimal structural conditions. Therefore, we tried to artificially induce a hematopoietic field in muscles using sintered porous tubular hydroxyapatite and new type hydroxyapatite plate made by high-pressure gas technique. As a result, not only in the pore sites of tubular hydroxyapatite artificial bone, but at the surface of the new type hydroxyapatite plate implanted in the dorsal muscles, marked differentiation of bone marrow cell clusters of the hematopoietic field could be observed.

  16. Effect of Rosiglitazone on Radiation Damage in Bone Marrow Hemopoiesis

    NASA Astrophysics Data System (ADS)

    Benkő, Klára; Pintye, Éva; Szabó, Boglárka; Géresi, Krisztina; Megyeri, Attila; Benkő, Ilona

    2008-12-01

    To study radiobiological effects and drugs, which can modify radiation injury, has an importance if we would like to avoid harmful effects of radiation due to emergency situations or treat patients with malignant diseases by radiotherapy. During the long treatment schedules patients may be treated by not only anticancer but many other drugs because of accompanying diseases. These drugs may also modify radiobiological effects. Rosiglitazone pre-treatment proved to be myeloprotective and accelerated recovery of 5-fluorouracil-damaged bone marrow in our previous experiments. Our new studies are designed to evaluate whether rosiglitazone has similar beneficial effects in radiation-damaged hemopoiesis. Bone marrow damage was precipitated by total body irradiation (TBI) using single increasing doses (2-10 Gy) of γ—irradiation in groups of mice. Lethality was well correlated with damage in hemopoiesis measured by cellularity of bone marrow (LD50 values were 4.8 and 5.3 gray respectively). Rosiglitazone, an insulin-sensitizing drug, had no significant effect on bone marrow cellularity. Insulin resistance associated with obesity or diabetes mellitus type 2 is intensively growing among cancer patients requiring some kind of radiotherapy. Therefore it is important to know whether drugs used for their therapy can modify radiation effects.

  17. Treating Families of Bone Marrow Recipients and Donors

    ERIC Educational Resources Information Center

    Cohen, Marie; And Others

    1977-01-01

    Luekemia and aplastic anemia are beginning to be treated by bone marrow transplants, involving donors and recipients from the same family. Such intimate involvement in the patient's life and death struggles typically produces a family crisis and frequent maladaptive responses by various family members. (Author)

  18. Effect of Rosiglitazone on Radiation Damage in Bone Marrow Hemopoiesis

    SciTech Connect

    Benko', Klara; Pintye, Eva; Szabo, Boglarka; Geresi, Krisztina; Megyeri, Attila; Benko, Ilona

    2008-12-08

    To study radiobiological effects and drugs, which can modify radiation injury, has an importance if we would like to avoid harmful effects of radiation due to emergency situations or treat patients with malignant diseases by radiotherapy. During the long treatment schedules patients may be treated by not only anticancer but many other drugs because of accompanying diseases. These drugs may also modify radiobiological effects. Rosiglitazone pre-treatment proved to be myeloprotective and accelerated recovery of 5-fluorouracil-damaged bone marrow in our previous experiments. Our new studies are designed to evaluate whether rosiglitazone has similar beneficial effects in radiation-damaged hemopoiesis. Bone marrow damage was precipitated by total body irradiation (TBI) using single increasing doses (2-10 Gy) of {gamma}--irradiation in groups of mice. Lethality was well correlated with damage in hemopoiesis measured by cellularity of bone marrow (LD{sub 50} values were 4.8 and 5.3 gray respectively). Rosiglitazone, an insulin-sensitizing drug, had no significant effect on bone marrow cellularity. Insulin resistance associated with obesity or diabetes mellitus type 2 is intensively growing among cancer patients requiring some kind of radiotherapy. Therefore it is important to know whether drugs used for their therapy can modify radiation effects.

  19. Body/bone-marrow differential-temperature sensor

    NASA Technical Reports Server (NTRS)

    Anselmo, V. J.; Berdahl, C. M.

    1978-01-01

    Differential-temperature sensor developed to compare bone-marrow and body temperature in leukemia patients uses single stable amplifier to monitor temperature difference recorded by thermocouples. Errors are reduced by referencing temperatures to each other, not to separate calibration points.

  20. Usefulness of bone marrow transplantation in the Hurler syndrome.

    PubMed

    Braunlin, Elizabeth A; Stauffer, Nanci R; Peters, Charles H; Bass, John L; Berry, James M; Hopwood, John J; Krivit, William

    2003-10-01

    The Hurler syndrome, an autosomal recessive storage disease of childhood, leads to death within the first decade of life from progressive deposition of glycosaminoglycans within the myointima of the coronary arteries and airways. Cardiac ultrasound findings of patients with this syndrome >10 years after successful bone marrow transplantation are described.

  1. Can yoga therapy stimulate stem cell trafficking from bone marrow?

    PubMed

    Shree, Nitya; Bhonde, Ramesh R

    It has been established that mesenchymal stromal cells (MSCs) from bone marrow enter the peripheral circulation intermittently for possible tissue regeneration, repair and to take care of daily wear and tear. This is evident from the detection of MSCs from peripheral blood. The factors governing this migration remain elusive. These MSCs carry out the work of policing and are supposed to repair the injured tissues. Thus, these cells help in maintaining the tissue and organ homeostasis. Yoga and pranayama originated in India and is now being practiced all over the world for positive health. So far, the chemical stimulation of bone marrow has been widely used employing injection of colony stimulating factor. However, the role of physical factors such as mechanical stimulation and stretching has not been substantiated. It is claimed that practicing yoga delays senescence, improves the physiological functions of heart and lung and yoga postures make the body elastic. It remains to be seen whether the yoga therapy promotes trafficking of the stem cells from bone marrow for possible repair and regeneration of worn out and degenerating tissues. We cover in this short review, mainly the role of physical factors especially the yoga therapy on stem cells trafficking from bone marrow. Copyright © 2016 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

  2. Histochemistry of blood and bone marrow cells in pangolins.

    PubMed

    Caxton-Martins, A E

    1977-04-01

    Blood and bone marrow cells of pangolins have been examined histochemically. Sudanophilia, PAS positivity and acid phosphatase and alkaline phosphatase reactivity were confined to cells of the granulocytic and monocytic series, while peroxidase reactivity was confined to cells of the erythroid series. In this latter respect the pangolin is unique among mammals so far studied.

  3. Atypical diabetes mellitus associated with bone marrow transplantation.

    PubMed

    Tor, Ozlem; Garg, Rajesh K

    2010-01-01

    To describe 3 cases of atypical diabetes mellitus following bone marrow transplantation. We describe the clinical presentation and relevant laboratory findings of 3 patients who presented with new-onset diabetes mellitus after bone marrow transplantation and discuss the possible mechanisms. A 52-year-old white man with chronic myelogenous leukemia, a 51-year-old white woman with acute myelogenous leukemia, and a 38-year-old Hispanic woman with acute myelogenous leukemia presented with acute onset of diabetes mellitus after bone marrow transplantation. Although blood glucose levels were initially very high, the patients required only small insulin dosages for glycemic control. Both the acute onset and requirement of relatively small insulin dosages were characteristic of type 1 diabetes mellitus. Onset of diabetes appeared to be unrelated to immunosuppressive drug therapy because it happened several months after starting these drugs. C-peptide was detectable, and glutamic acid decarboxylase antibodies were absent. Diabetes mellitus remitted spontaneously after a few months while the immunosuppressive drugs were continued. Although the underlying mechanisms are unknown, cytokine changes after bone marrow transplantation may have led to temporary beta-cell dysfunction in these patients.

  4. Oestrogen-induced bone marrow aplasia in a dog.

    PubMed

    Bland-van den Berg, P; Bomzon, L; Lurie, A

    1978-12-01

    A case of oestrogen toxicity in the dog is described. The bone marrow was primarily affected with resultant non-regenerative anaemia, leukocytosis followed by leukopaenia, and thrombocytopaenia. Endometritis, toxaemia and disseminate intravascular coagulation were complicating factors. The case terminated fatally intensive therapy.

  5. A Role For Photodynamic Therapy In Autologous Bone Marrow Transplantation

    NASA Astrophysics Data System (ADS)

    Sieber, Fritz

    1988-02-01

    Simultaneous exposure to the amphipathic fluorescent dye merocyanine 540 (MC 540) and light of a suitable wavelength rapidly kills leukemia, lymphoma, and neuroblastoma cells but spares normal pluripotent hematopoietic stem cells. Tests in several preclinical models and early results of a phase I clinical trial suggest that MC 540-mediated photosensitization may be useful for the extracorporeal purging of autologous remission bone marrow grafts.

  6. Development of insulin allergy after bone marrow transplantation.

    PubMed

    Yoshida, N; Okubo, M; Ishiguro, K; Mori, Y

    2012-10-01

    Insulin allergy is a not uncommon condition even though human insulin and insulin analogues are widely used. However, the development of insulin allergy after bone marrow transplantation has not been reported. A 44-year-old Japanese woman had aplastic anaemia and secondary haemochromatosis. She was diagnosed with having diabetes at age 32 years and had been treated with human insulin. At age 34 years, bone marrow transplantation was performed. One year later, a rash and urticaria appeared immediately after insulin injections. Intracutaneous tests were positive for both human insulins and analogues, whereas the test for protamine was negative. Furthermore, an IgE-radioallergosorbent test against insulin was positive. Thus, we diagnosed the patient with having an IgE-mediated type I allergy against insulin. Insulin therapy with insulin aspart, which showed the least skin reaction, was continued and the insulin allergy disappeared in 7 years. This is the first description of insulin allergy after bone marrow transplantation. Our case underscores the effects of bone marrow cells on IgE-mediated type I allergy for insulin. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  7. Bone marrow transplantation in Schimke immuno-osseous dysplasia.

    PubMed

    Baradaran-Heravi, Alireza; Lange, Jonas; Asakura, Yumi; Cochat, Pierre; Massella, Laura; Boerkoel, Cornelius F

    2013-10-01

    Schimke immuno-osseous dysplasia (SIOD, OMIM 242900) is a rare autosomal recessive multisystem childhood disorder characterized by short stature, renal failure, T-cell immunodeficiency, and hypersensitivity to genotoxic agents. SIOD is associated with biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response enzyme with annealing helicase activity. Two features of SIOD causing much morbidity and mortality are bone marrow failure and T-cell deficiency with the consequent opportunistic infections. To address the safety and efficacy of bone marrow transplantation (BMT) in SIOD, we reviewed the outcomes of the only five SIOD patients known to us in whom bone marrow or hematopoietic stem cell transplantation has been attempted. We find that only one patient survived the transplantation procedure and that the existing indicators of a good prognosis for bone marrow transplantation were not predictive in this small cohort. Given these observations, we also discuss some considerations for the poor outcomes. Copyright © 2013 Wiley Periodicals, Inc.

  8. Generation of eosinophils from cryopreserved murine bone marrow cells.

    PubMed

    Schollaert, Kaila L; Stephens, Michael R; Gray, Jerilyn K; Fulkerson, Patricia C

    2014-01-01

    Eosinophils are produced in the bone marrow from CD34+ eosinophil lineage-committed progenitors, whose levels in the bone marrow are elevated in a variety of human diseases. These findings suggest that increased eosinophil lineage-committed progenitor production is an important process in disease-associated eosinophilia. The pathways central to the biology of the eosinophil lineage-committed progenitor remain largely unknown. Thus, developing new methods to investigate the regulators of eosinophil lineage-committed progenitor differentiation is needed to identify potential therapeutic targets to specifically inhibit eosinophil production. We tested cytokine regimens to optimize liquid cultures for the study of eosinophil lineage-committed progenitor and eosinophil precursor differentiation into mature eosinophils. Stem cell factor (but not fms-related tyrosine kinase 3 ligand) was required for optimal yield of eosinophils. Furthermore, we evaluated the effects of cell preservation and scale on the culture, successfully culturing functional eosinophils from fresh and frozen murine bone marrow cells and in a standard-sized and 96-well culture format. In summary, we have developed an adaptable culture system that yields functionally competent eosinophils from murine low-density bone marrow cells and whose cytokine regime includes expansion of progenitors with stem cell factor alone with subsequent differentiation with interleukin 5.

  9. Treating Families of Bone Marrow Recipients and Donors

    ERIC Educational Resources Information Center

    Cohen, Marie; And Others

    1977-01-01

    Luekemia and aplastic anemia are beginning to be treated by bone marrow transplants, involving donors and recipients from the same family. Such intimate involvement in the patient's life and death struggles typically produces a family crisis and frequent maladaptive responses by various family members. (Author)

  10. Engineering a mimicry of bone marrow tissue ex vivo.

    PubMed

    Panoskaltsis, Nicki; Mantalaris, Athanasios; Wu, J H David

    2005-07-01

    Hematopoietic stem cells reside in specific niches in the bone marrow and give rise to either more stem cells or maturing hematopoietic progeny depending on the signals provided in the bone marrow microenvironment. This microenvironment is comprised of cellular components as well as soluble constituents called cytokines. The use of cytokines alone for the ex vivo expansion of stem cells in flat, two-dimensional culture flasks, dishes or bags is inadequate and, given the three-dimensionality of the in vivo bone marrow microenvironment, inappropriate. Three-dimensional culture conditions can therefore provide an ex vivo mimicry of bone marrow, recapitulate the desired niche, and provide a suitable environment for stem cell expansion and differentiation. Choice of scaffold, manipulation and reproducibility of the scaffold properties and directed structuring of the niche, by choosing pore size and porosity may inform the resident stem cells of their fate in a directed fashion. The use of bioreactors for cultivation of hematopoietic cells will allow for culture control, optimization, standardization, scale-up, and a "hands-off" operation making the end-product dependable, predictable and free of contaminants, and therefore suitable for human use and therapeutic applications.

  11. Agent-Based Deterministic Modeling of the Bone Marrow Homeostasis

    PubMed Central

    2016-01-01

    Modeling of stem cells not only describes but also predicts how a stem cell's environment can control its fate. The first stem cell populations discovered were hematopoietic stem cells (HSCs). In this paper, we present a deterministic model of bone marrow (that hosts HSCs) that is consistent with several of the qualitative biological observations. This model incorporates stem cell death (apoptosis) after a certain number of cell divisions and also demonstrates that a single HSC can potentially populate the entire bone marrow. It also demonstrates that there is a production of sufficient number of differentiated cells (RBCs, WBCs, etc.). We prove that our model of bone marrow is biologically consistent and it overcomes the biological feasibility limitations of previously reported models. The major contribution of our model is the flexibility it allows in choosing model parameters which permits several different simulations to be carried out in silico without affecting the homeostatic properties of the model. We have also performed agent-based simulation of the model of bone marrow system proposed in this paper. We have also included parameter details and the results obtained from the simulation. The program of the agent-based simulation of the proposed model is made available on a publicly accessible website. PMID:27340402

  12. Agent-Based Deterministic Modeling of the Bone Marrow Homeostasis.

    PubMed

    Kurhekar, Manish; Deshpande, Umesh

    2016-01-01

    Modeling of stem cells not only describes but also predicts how a stem cell's environment can control its fate. The first stem cell populations discovered were hematopoietic stem cells (HSCs). In this paper, we present a deterministic model of bone marrow (that hosts HSCs) that is consistent with several of the qualitative biological observations. This model incorporates stem cell death (apoptosis) after a certain number of cell divisions and also demonstrates that a single HSC can potentially populate the entire bone marrow. It also demonstrates that there is a production of sufficient number of differentiated cells (RBCs, WBCs, etc.). We prove that our model of bone marrow is biologically consistent and it overcomes the biological feasibility limitations of previously reported models. The major contribution of our model is the flexibility it allows in choosing model parameters which permits several different simulations to be carried out in silico without affecting the homeostatic properties of the model. We have also performed agent-based simulation of the model of bone marrow system proposed in this paper. We have also included parameter details and the results obtained from the simulation. The program of the agent-based simulation of the proposed model is made available on a publicly accessible website.

  13. Anaplasma platys in Bone Marrow Megakaryocytes of Young Dogs

    PubMed Central

    De Tommasi, A. Sara; Baneth, Gad; Breitschwerdt, Edward B.; Stanneck, Dorothee; Dantas-Torres, Filipe; Otranto, Domenico

    2014-01-01

    Anaplasma platys is an obligate intracellular rickettsial pathogen that infects platelets of dogs, forming basophilic intracellular morulae. In the present report, cellular inclusions were documented in bone marrow thrombocyte precursors of two young naturally infected dogs, indicating that A. platys can infect megakaryocytes and promegakaryocytes. PMID:24622106

  14. Identification of Bone Marrow-Derived Soluble Factors Regulating Human Mesenchymal Stem Cells for Bone Regeneration.

    PubMed

    Tsai, Tsung-Lin; Li, Wan-Ju

    2017-02-14

    Maintaining properties of human bone marrow-derived mesenchymal stem cells (BMSCs) in culture for regenerative applications remains a great challenge. An emerging approach of constructing a culture environment mimicking the bone marrow niche to regulate BMSC activities has been developed. In this study, we have demonstrated a systematic approach to identify soluble factors of interest extracted from human bone marrow and used them in BMSC culture for tissue regeneration. We have found that lipocalin-2 and prolactin are key factors in bone marrow, involved in regulating BMSC activities. Treating the cell with lipocalin-2 and prolactin delays cellular senescence of BMSCs and primes the cell for osteogenesis and chondrogenesis. We have also demonstrated that BMSCs pretreated with lipocalin-2 and prolactin can enhance the repair of calvarial defects in mice. Together, our study provides research evidence of using a viable approach to prime BMSC properties in vitro for improving cell-based tissue regeneration in vivo.

  15. Biological dosimetry of bone marrow for incorporated yttrium-90.

    PubMed

    Goddu, S M; Howell, R W; Giuliani, D C; Rao, D V

    1998-03-01

    The biological response of bone marrow to incorporated radionuclides depends on several factors such as absorbed dose, dose rate, proliferation and marrow reserve. The determination of the dose rate and absorbed dose to bone marrow from incorporated radionuclides is complex. This research used survival of granulocyte-macrophage colony-forming cells (GM-CFCs) as a biological dosimeter to determine experimentally the dose rate and dose to bone marrow after administration of 90Y-citrate. The radiochemical 90Y-citrate was administered intravenously to Swiss Webster mice. Biokinetics studies indicated that the injected 90Y quickly localized in the femurs (0.8% ID/femur) and cleared with an effective half-time of 62 hr. Subsequently, GM-CFC survival was determined as a function of femur uptake and injected activity. Finally, to calibrate GM-CFC survival as a biological dosimeter, mice were irradiated with external 137Cs gamma rays at dose rates that decreased exponentially with a half-time of 62 hr. Femur uptake was linearly proportional to injected activity. The survival of GM-CFCs was exponentially dependent on both the initial 90Y femur activity and the initial dose rate from external 137Cs gamma rays with 5.1 kBq/femur and 1.9 cGy/hr, respectively, required to achieve 37% survival. Thus, 90Y-citrate delivers a dose rate of 0.37 cGy/hr to the femoral marrow per kBq of femur activity and the dose rate decreased with an effective half-time of 62 hr. Survival of GM-CFCs can serve as a biological dosimeter to experimentally determine the dose rate kinetics in bone marrow.

  16. A Dosimetric Study of Radionuclide Therapy for Bone Marrow Ablation.

    NASA Astrophysics Data System (ADS)

    Bayouth, John Ellis

    In a phase I clinical trial, six multiple myeloma patients, who were non-responsive to conventional therapy and were scheduled for bone marrow transplantation, received Holmium-166 (166Ho) labeled to a bone seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane -1,4,7,10-tetramethylene-phosphonic acid), for the purpose of bone marrow ablation. The specific aims of my research within this protocol were to evaluate the toxicity and efficacy of 166Ho DOTMP by quantifying the in vivo pharmacokinetics and radiation dosimetry, and by correlating these results to the biologic response observed. The reproducibility of pharmacokinetics from multiple injections of 166 Ho DOTMP administered to these myeloma patients was demonstrated from both blood and whole body retention. The skeletal concentration of 166 Ho DOTMP was heterogenous in all six patients: high in the ribs, pelvis, and lumbar vertebrae regions, and relatively low in the femurs, arms, and head. A novel technique was developed to calculate the radiation dose to the bone marrow in each skeletal ROI, and was applied to all six 166 Ho DOTMP patients. Radiation dose estimates for the bone marrow calculated using the standard MIRD "S" factors were compared with the average values derived from the heterogenous distribution of activity in the skeleton (i.e., the regional technique). The results from the two techniques were significantly different; the average of the dose estimates from the regional technique were typically 30% greater. Furthermore, the regional technique provided a range of radiation doses for the entire marrow volume, while the MIRD "S" factors only provided a single value. Dose volume histogram analysis of data from the regional technique indicated a range of dose estimates that varied by a factor of 10 between the high dose and low dose regions. Finally, the observed clinical response of cells and abnormal proteins measured in bone marrow aspirates and peripheral blood samples were compared with

  17. Histological characterization of bone marrow in ectopic bone, induced by devitalized Saos-2 human osteosarcoma cells.

    PubMed

    Nahar, Niru N; Tague, Sarah E; Wang, Jinxi; Danley, Marsha; Garimella, Rama; Anderson, H Clarke

    2013-01-01

    Devitalized Saos-2, cultured human osteosarcoma cells, or guanidinium-hydrochloride (GuHCl) extracts of these cells, induce ectopic bone and marrow formation when implanted subcutaneously in Nu/Nu mice. The aim of the present study was to characterize the bone marrow induced by Saos-2 cell extracts, specifically to determine which of the four major hematopoietic cell lineages: erythropoietic, granulopoietic, lymphopoietic and megakaryocytic, are induced by Saos-2 cell derivatives. Immunohistochemical localization of specific antigens was used to determine the presence of each major cell type (glycophorin A for erythropoietic, neutrophil elastase for granulopoietic, factor-VIII related antigen for megakaryocytes, and CD79a for B lymphocytes). Standard H & E stains confirmed the presence of normally organized apparently complete bone marrow within all newly induced bone at 3 weeks post-implantation of devitalized Saos-2 cells. Immunohistochemistry confirmed the presence of erythropoietic cells, granulopoietic cells, megakaryocytes and B lymphocytes in the ectopic marrow. Saos-2 cells (freeze-dried) or their extracts, implanted subcutaneously into Nu/Nu mice, can induce normal marrow that is host-derived, and contains all major hematopoietic cell lineages. Saos-2 induced marrow could potentially restore deficient marrow and promote bone repair.

  18. Histological characterization of bone marrow in ectopic bone, induced by devitalized Saos-2 human osteosarcoma cells

    PubMed Central

    Nahar, Niru N; Tague, Sarah E; Wang, Jinxi; Danley, Marsha; Garimella, Rama; Anderson, H Clarke

    2013-01-01

    Devitalized Saos-2, cultured human osteosarcoma cells, or guanidinium-hydrochloride (GuHCl) extracts of these cells, induce ectopic bone and marrow formation when implanted subcutaneously in Nu/Nu mice. The aim of the present study was to characterize the bone marrow induced by Saos-2 cell extracts, specifically to determine which of the four major hematopoietic cell lineages: erythropoietic, granulopoietic, lymphopoietic and megakaryocytic, are induced by Saos-2 cell derivatives. Methods: Immunohistochemical localization of specific antigens was used to determine the presence of each major cell type (glycophorin A for erythropoietic, neutrophil elastase for granulopoietic, factor-VIII related antigen for megakaryocytes, and CD79a for B lymphocytes). Results: Standard H & E stains confirmed the presence of normally organized apparently complete bone marrow within all newly induced bone at 3 weeks post-implantation of devitalized Saos-2 cells. Immunohistochemistry confirmed the presence of erythropoietic cells, granulopoietic cells, megakaryocytes and B lymphocytes in the ectopic marrow. Conclusion: Saos-2 cells (freeze-dried) or their extracts, implanted subcutaneously into Nu/Nu mice, can induce normal marrow that is host-derived, and contains all major hematopoietic cell lineages. Clinical Significance: Saos-2 induced marrow could potentially restore deficient marrow and promote bone repair. PMID:23386915

  19. Status and prospects of liver cirrhosis treatment by using bone marrow-derived cells and mesenchymal cells.

    PubMed

    Terai, Shuji; Takami, Taro; Yamamoto, Naoki; Fujisawa, Koichi; Ishikawa, Tsuyoshi; Urata, Yohei; Tanimoto, Haruko; Iwamoto, Takuya; Mizunaga, Yuko; Matsuda, Takashi; Oono, Takashi; Marumoto, Miho; Burganova, Guzel; Fernando Quintanilha, Luiz; Hidaka, Isao; Marumoto, Yoshio; Saeki, Issei; Uchida, Koichi; Yamasaki, Takahiro; Tani, Kenji; Taura, Yasuho; Fujii, Yasuhiko; Nishina, Hiroshi; Okita, Kiwamu; Sakaida, Isao

    2014-06-01

    In 2003, we started autologous bone marrow cell infusion (ABMi) therapy for treating liver cirrhosis. ABMi therapy uses 400 mL of autologous bone marrow obtained under general anesthesia and infused mononuclear cells from the peripheral vein. The clinical study expanded and we treated liver cirrhosis induced by HCV and HBV infection and alcohol consumption. We found that the ABMi therapy was effective for cirrhosis patients and now we are treating patients with combined HIV and HCV infection and with metabolic syndrome-induced liver cirrhosis. Currently, to substantiate our findings that liver cirrhosis can be successfully treated by the ABMi therapy, we are conducting randomized multicenter clinical studies designated "Advanced medical technology B" for HCV-related liver cirrhosis in Japan. On the basis of our clinical study, we developed a proof-of-concept showing that infusion of bone marrow cells (BMCs) improved liver fibrosis and sequentially activated proliferation of hepatic progenitor cells and hepatocytes, further promoting restoration of liver functions. To treat patients with severe forms of liver cirrhosis, we continued translational research to develop less invasive therapies by using mesenchymal stem cells derived from bone marrow. We obtained a small quantity of BMCs under local anesthesia and expanded them into mesenchymal stem cells that will then be used for treating cirrhosis. In this review, we present our strategy to apply the results of our laboratory research to clinical studies.

  20. Ischemic stroke activates hematopoietic bone marrow stem cells.

    PubMed

    Courties, Gabriel; Herisson, Fanny; Sager, Hendrik B; Heidt, Timo; Ye, Yuxiang; Wei, Ying; Sun, Yuan; Severe, Nicolas; Dutta, Partha; Scharff, Jennifer; Scadden, David T; Weissleder, Ralph; Swirski, Filip K; Moskowitz, Michael A; Nahrendorf, Matthias

    2015-01-30

    The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood. To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells. Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (P<0.05 versus pre tMCAO). Flow cytometry and cell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19% to 7.32%±0.52% after tMCAO (P<0.05). In vivo microscopy corroborated proliferation of adoptively transferred hematopoietic progenitors in the bone marrow of mice with stroke. The hematopoietic system's myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 (P<0.05), and by a decline in lymphocyte precursors. In mice after tMCAO, tyrosine hydroxylase levels in sympathetic fibers and bone marrow noradrenaline levels rose (P<0.05, respectively), associated with a decrease of hematopoietic niche factors that promote stem cell quiescence. In mice with genetic deficiency of the β3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, P=0.51). Ischemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6C(high) monocytes and neutrophils. © 2014 American Heart Association, Inc.

  1. 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.

  2. Low-frequency vibration treatment of bone marrow stromal cells induces bone repair in vivo

    PubMed Central

    He, Shengwei; Zhao, Wenzhi; Zhang, Lu; Mi, Lidong; Du, Guangyu; Sun, Chuanxiu; Sun, Xuegang

    2017-01-01

    Objective(s): To study the effect of low-frequency vibration on bone marrow stromal cell differentiation and potential bone repair in vivo. Materials and Methods: Forty New Zealand rabbits were randomly divided into five groups with eight rabbits in each group. For each group, bone defects were generated in the left humerus of four rabbits, and in the right humerus of the other four rabbits. To test differentiation, bones were isolated and demineralized, supplemented with bone marrow stromal cells, and implanted into humerus bone defects. Varying frequencies of vibration (0, 12.5, 25, 50, and 100 Hz) were applied to each group for 30 min each day for four weeks. When the bone defects integrated, they were then removed for histological examination. mRNA transcript levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligan, and pre-collagen type 1 α were measured. Results: Humeri implanted with bone marrow stromal cells displayed elevated callus levels and wider, more prevalent, and denser trabeculae following treatment at 25 and 50 Hz. The mRNA levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligand, and pre-collagen type 1 α were also markedly higher following 25 and 50 Hz treatment. Conclusion: Low frequency (25–50 Hz) vibration in vivo can promote bone marrow stromal cell differentiation and repair bone injury. PMID:28133520

  3. Low-frequency vibration treatment of bone marrow stromal cells induces bone repair in vivo.

    PubMed

    He, Shengwei; Zhao, Wenzhi; Zhang, Lu; Mi, Lidong; Du, Guangyu; Sun, Chuanxiu; Sun, Xuegang

    2017-01-01

    To study the effect of low-frequency vibration on bone marrow stromal cell differentiation and potential bone repair in vivo. Forty New Zealand rabbits were randomly divided into five groups with eight rabbits in each group. For each group, bone defects were generated in the left humerus of four rabbits, and in the right humerus of the other four rabbits. To test differentiation, bones were isolated and demineralized, supplemented with bone marrow stromal cells, and implanted into humerus bone defects. Varying frequencies of vibration (0, 12.5, 25, 50, and 100 Hz) were applied to each group for 30 min each day for four weeks. When the bone defects integrated, they were then removed for histological examination. mRNA transcript levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligan, and pre-collagen type 1 α were measured. Humeri implanted with bone marrow stromal cells displayed elevated callus levels and wider, more prevalent, and denser trabeculae following treatment at 25 and 50 Hz. The mRNA levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligand, and pre-collagen type 1 α were also markedly higher following 25 and 50 Hz treatment. Low frequency (25-50 Hz) vibration in vivo can promote bone marrow stromal cell differentiation and repair bone injury.

  4. Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats.

    PubMed

    Fan, Chiaming; Georgiou, Kristen R; McKinnon, Ross A; Keefe, Dorothy M K; Howe, Peter R C; Xian, Cory J

    2016-05-01

    The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation.

  5. Stem cell niche failure concerns bone marrow failure--a diagnostic and therapeutic consideration.

    PubMed

    Law, Sujata; Chaudhuri, Samaresh

    2011-01-01

    Diseases of the bone marrow often referred to as "Bone marrow failure" have complicated pathophysiological picture with respect to hematopoietic systemic function. The reason for such bone marrow disorder is not well understood till date, although some sporadic etiological sources have been described earlier. With the advent of current investigations, hematopoietic stem cell involvement together with the failure of signaling interaction within the bone marrow niche has been found to reveal interesting correlations with the disease onset. The present review furnishes justification for bone marrow failure as a concern of stem cell niche failure and hints at providing important clues for disease diagnosis and therapeutic maneuver.

  6. Bone marrow necrosis in a cat infected with feline leukemia virus.

    PubMed

    Shimoda, T; Shiranaga, N; Mashita, T; Hasegawa, A

    2000-01-01

    A one-year old castrated male cat was admitted to the hospital with vomiting and diarrhea. Laboratory examination revealed pancytopenia and positive for FeLV antigen. A bone marrow examination indicated necrosis of the nucleated cells. Based on these findings, the cat was diagnosed as bone marrow necrosis. Pancytopenia was effectively treated with corticosteroids. Re-examination of the bone marrow confirmed a recovery of normal hematopoietic cells with a infiltration of many macrophages. It is strongly suspected that the bone marrow necrosis in this case could be associated with a bone marrow suppression due to FeLV infection.

  7. Antibody formation by bone marrow cells in irradiated mice

    PubMed Central

    Playfair, J. H. L.; Purves, Elizabeth C.

    1971-01-01

    Bone marrow-thymus cooperation experiments were carried out in lethally irradiated mice with sheep red blood cells (SRBC) as the antigen and direct plaque-forming cells (PFC) as the end point. Various parameters were altered, with the following results: (1) Above 800 rad, the response by marrow cells alone, as well as the increase due to added thymus cells, was independent of irradiation dose. (2) The response of marrow cells was greatest at high SRBC concentrations, but the co-operative effect of thymus cells was most evident at lower SRBC levels, and completely absent at high levels. (3) Increasing the number of marrow cells, without thymus, gave increasing numbers of PFC, but the dose-response curve did not suggest cell synergism. (4) Thymectomy and antithymocyte serum treatment of host or donor did not prevent the response by marrow cells alone. It was concluded that this was a true IgM response by antibody-forming precursors from the marrow, unaided by thymus-derived cells. PMID:4934135

  8. Bone marrow to liver: the blood of Prometheus.

    PubMed

    Theise, Neil D; Krause, Diane S

    2002-12-01

    The existence of hepatic stem or progenitor cells has been controversial for decades, though it was presumed that if such cells existed, they would lie within the liver. There is now consensus, however, that not only do facultative hepatic stem cells exist within the liver, but also that cells from extra-hepatic sites, in particular the bone marrow, can contribute to hepatocyte and cholangiocyte regeneration. Despite confidence that engraftment of marrow cells in the liver occurs, the mechanistic details of this process remain poorly understood. Moreover, the physiological importance and therapeutic utility of this phenomenon remains controversial.

  9. Expression and characterization of erythropoietin receptors on normal human bone marrow cells

    SciTech Connect

    Hoshino, S.; Teramura, M.; Takahashi, M.; Motoji, T.; Oshimi, K.; Ueda, M.; Mizoguchi, H.

    1989-05-01

    We studied the specific binding of /sup 125/I-labeled bioactive recombinant human erythropoietin (Epo) to human bone marrow mononuclear cells (BMNC) obtained from normal subjects. The /sup 125/I-labeled Epo bound specifically to the BMNC. Scatchard analysis of the data showed two classes of binding sites; one high affinity (Kd 0.07 nM) and the other low affinity (Kd 0.38 nM). The number of Epo binding sites per BMNC was 46 +/- 16 high-affinity receptors and 91 +/- 51 low-affinity receptors. The specific binding was displaced by unlabeled Epo, but not by other growth factors. Receptor internalization was observed significantly at 37 degrees C, but was prevented by the presence of 0.2% sodium azide. These findings indicate that human BMNC possess two classes of specific Epo receptors with characteristics of a hormone-receptor association.

  10. Autologous Bone Marrow Derived Stem Cells for the Treatment of Multiple Sclerosis.

    PubMed

    Abi Chahine, Nassim; Wehbe, Tarek; Rashed, Johny; Hilal, Ramzi; Elias, Nada

    2016-11-30

    Stem cell therapy, an evolving, progressive field of therapeutics has shown several successes in areas where classic treatments failed to prevent or stop disability. Starting in 2009, twenty two sequential patients with progressive Multiple Sclerosis (MS) courses were treated with Autologous Bone Marrow Mononuclear stem cells (BM-MNSCs). The cells were given both intravenously and intrathecally. Using the Expanded Disability Status Scale (EDSS) score for evaluation, our data indicates that the majority of the patients benefited on the average one point on the scale. This paper adds to the body of evidence suggesting the safety and efficacy of autologous BM-MNSCs in the treatment of MS and awaits validation through larger, randomized studies.

  11. Autologous Bone Marrow Derived Stem Cells for the Treatment of Multiple Sclerosis

    PubMed Central

    Chahine, Nassim Abi; Wehbe, Tarek; Rashed, Johny; Hilal, Ramzi; Elias, Nada

    2016-01-01

    Stem cell therapy, an evolving, progressive field of therapeutics has shown several successes in areas where classic treatments failed to prevent or stop disability. Starting in 2009, twenty two sequential patients with progressive Multiple Sclerosis (MS) courses were treated with Autologous Bone Marrow Mononuclear stem cells (BM-MNSCs). The cells were given both intravenously and intrathecally. Using the Expanded Disability Status Scale (EDSS) score for evaluation, our data indicates that the majority of the patients benefited on the average one point on the scale. This paper adds to the body of evidence suggesting the safety and efficacy of autologous BM-MNSCs in the treatment of MS and awaits validation through larger, randomized studies. PMID:27788571

  12. Bone marrow derived stem cell therapy for type 2 diabetes mellitus

    PubMed Central

    Chahine, Nassim Abi; Sissi, Salam; Abou-Joaude, Isabelle; Chalhoub, Louis

    2016-01-01

    In this study, 6 patients with type 2 diabetes (T2D) underwent autologous bone marrow mononuclear stem cell (BM-MNSC) infusion into the celiac and superior mesenteric arteries without pretreatment with any myeloablative or immune-suppressive therapy. Five of 6 (83%) showed normalization of their fasting glucose and the glycosylated hemoglobin (HbA1C) with significant reduction of their medication requirements. The HbA1C dropped on average 2.2 points. The three patients with diabetic complications showed improvement or stabilization and most patients reported improved energy and stamina. The durations of response varied between 6 months and 2 years. No patients had any significant adverse effects. PMID:28066789

  13. Clinical and experimental observations of peripheral blood leukocytes and nucleated bone marrow cells after local irradiation.

    PubMed

    Zhang, X G; Du, A N; Geng, C; Guo, F; He, M; Gu, F; Wang, J; Song, W B; Xu, H; Sheng, W; Liu, Y; Ye, T

    2014-02-01

    Aim of the study was to observe the impact of bone marrow damage induced by local irradiation on leukopenia. For the human study, five cancer patients received local radiation therapy. Bone marrow aspiration was conducted to measure nucleated cell count and 99mTc-Sc sulfur colloid ECT imaging was carried out to examine bone marrow function. For the animal study, fifty New Zealand white rabbits were divided into 3 groups: non-irradiated control group (N.=10), abdomen irradiation group (irradiation area did not cover bone marrow) (N.=20), chest irradiation group (irradiation area covered bone marrow) (N.=20). Nucleated cell counts were taken after confirming onset of leukopenia. Bone marrow of five patients proliferated normally. ECT imaging showed no abnormality in the pattern of red bone marrow distribution. Hematopoietic function was mildly active. Suppressed myeloproliferative function does not fully account for irradiation-induced leukopenia.

  14. 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.

  15. Bone marrow regeneration following fractionated radiation therapy. [/sup 60/Co or HMV linear accelerator

    SciTech Connect

    Hill, D.R.; Benak, S.B.; Phillips, T.L.; Price, D.C.

    1980-09-01

    Eight patients were studied with /sup 99m/Tc-S colloid bone marrow scans prior to or at various intervals following megavoltage irradiation. None had marrow tumor involvement and none had chemotherapy during the study period. If reticuloendothelial marrow activity reflects hematopoietic activity, there appears to be maximal depression of marrow activity 6 months post irradiation. Total nodal irradiated patients regenerated marrow as well as local field patients despite the larger marrow volume irradiated.

  16. Cancer stemness in bone marrow micrometastases of human breast cancer.

    PubMed

    Kuo, Marissa C; Kothari, Anai N; Kuo, Paul C; Mi, Zhiyong

    2017-10-05

    Cancer cells metastasize to the bone marrow to create the premetastatic niche. Cancer stemness (expression of stem cell characteristics) is regulated by the tumor microenvironment and associated with self-renewal and poor clinical outcomes. Osteopontin induces mesenchymal stem cells in the tumor microenvironment to adopt a cancer-associated fibroblast phenotype to potentiate cancer growth and metastasis. The mechanisms by which cancer cells and tumor microenvironment regulate stemness in the bone marrow premetastatic niche is unknown. Human breast cancer cell lines, MDA-MB-231 and MCF-7 were used in an orthotopic murine xenograft model. NOD-scid mice were implanted with 2 × 10(6) tumor cells in the presence and absence of human mesenchymal stem cells-green fluorescent protein cells and/or osteopontin aptamer, which blocks and inactivates extracellular osteopontin, or mutant aptamer (osteopontin mutant aptamer). In select instances, MCF-7 cells transfected to express osteopontin were coimplanted instead of MCF-7. Stemness markers (Nanog, Oct4, Sox2) in the tumor cells and cancer-associated fibroblast (α-smooth muscle actin, Vimentin) markers in the mesenchymal stem cells were measured in femoral bone marrow via real-time polymerase chain reaction. Cell number was determined by titrating cell number to Ct value in vitro. Tumor cells and mesenchymal stem cells migrate from the primary tumor site to the bone marrow. Migration of mesenchymal stem cells is osteopontin dependent. In both MDA-MB-231 and MCF-7 cell lines, levels of both cancer-associated fibroblast and stemness markers were 3 to 4 times greater under conditions wherein mesenchymal stem cells were present with osteopontin. Inactivation of extracellular osteopontin with an aptamer decreased migration of mesenchymal stem cells and expression of both cancer-associated fibroblast and stemness markers. Cancer cells exhibited a significantly increased stem cell profile in the presence of cancer

  17. [Primary study on origination of bone marrow abnormal clones in patients with myelodysplastic syndrome].

    PubMed

    Zhang, Qing-Xia; Li, Xiao; He, Qi; Wu, Ling-Yun; Xu, Feng; Zhang, Zheng

    2011-08-01

    The study was aimed to investigate the origination of abnormal clones in hematopoietic cells of MDS patients. That is to say if there are abnormal clones in CD34(+)CD38(-) and CD34(+)CD38(+) cells and their proportions in MDS patients. Immuno-magnetic bead technique was used to sort CD34(+)CD38(-) and CD34(+)CD38(+) in bone marrow mononuclear cells of 9 MDS patients with chromosome abnormalities (four cases with trisomy 8, 1 case with trisomy 8 complex karyotype, 2 cases with 5q(-), 1 case with 5q(-)complex karyotype, 1 case with 5q(-) accompanying trisomy 8) and smears were made respectively. Then the percentage of abnormal clones in CD34(+)CD38(-) and CD34(+)CD38(+) cells were compared by using FISH. The results indicated that abnormal clones were involved in the two population cells in 9 patients. The percentage of abnormal clones in CD34(+)CD38(-) cells (41.8 ± 8.4%)was obviously lower than that in CD34(+)CD38(+) cells(72.4 ± 7.7%) (p < 0.001), and the percentage of abnormal clones in karyocytes was 70.8 ± 9.2%. It is concluded the abnormal clones of bone marrow hematopoietic cells may originate from stem cell stage in MDS patients with 5q(-) and +8, and the abnormal clones are predominant at stage of progenitors.

  18. Intracoronary infusion of a combination of bone marrow-derived stem cells in dogs

    PubMed Central

    Minguell, José J; Florenzano, Fernando M; Ramírez, Manuel R; Martínez, Ramón F; Lasala, Gabriel P

    2010-01-01

    BACKGROUND: Infusion of diverse types of bone marrow cells, as a source of endothelial progenitor cells (EPCs), into the ischemic myocardium is emerging as a promising therapy for coronary ischemia, probably mediated by the formation of new blood vessels. Studies have shown that while the procedure is safe and feasible, efficacy results are contentious. The investigators in the present preclinical translation study hypothesized that the infusion of a combination cell product consisting of EPCs and other cell types, such as mesenchymal stem cells, promotes the formation of more stable and mature blood vessels resulting in improved clinical outcomes. The safety and feasibility of the intracoronary infusion of such a cell combination was assessed in a canine model. METHODS: A mixture of canine autologous mononuclear cells (as the source of EPCs) and ex vivo-expanded bone marrow-derived mesenchymal stem cells or a placebo solution were intracoronarily infused into healthy dogs. Follow-up after cell/placebo infusion included an electrocardiogram, serum cardiac enzyme testing, a transthoracic echocardiography and a histopathological heart examination. RESULTS: On follow-up at all time points after infusion, no significant changes or abnormalities in vital signs, electrocardiogram, transthoracic echocardiography and heart histology were detected. CONCLUSIONS: From a clinical perspective, the safety and feasibility of the protocol used in the present animal study demonstrated clinical relevance and provided direct evidence supporting the intracoronary infusion of combination stem/progenitor cell products. PMID:20631864

  19. Standardization of the Immunocytochemical Detection of Neuroblastoma Cells in Bone Marrow

    PubMed Central

    Swerts, Katrien; Ambros, Peter F.; Brouzes, Chantal; Navarro, José M. Fernandez; Gross, Nicole; Rampling, Dyanne; Schumacher-Kuckelkorn, Roswitha; Sementa, Angela R.; Ladenstein, Ruth; Beiske, Klaus

    2005-01-01

    Standard cytomorphological examination of bone marrow (BM) aspirates does not appear to be sensitive enough to detect single neuroblastoma cells. The SIOPEN Neuroblastoma Bone Marrow Committee developed a sensitive and reproducible anti-GD2 immunocytochemical assay and introduced morphological and immunocytological criteria for the interpretation of results. Fixed cytospins were incubated with a commercially available anti-GD2 monoclonal antibody and an APAAP kit. Cells fulfilling all morphological and immunocytological criteria were called criteria-positive cells (CPCs). Not convincingly interpretable cells fulfilled some, but not all, criteria, and negative cells displayed only exclusion criteria. The genetic profile of doubtful cells was checked by fluorescence in situ hybridization. Ideally, 3 × 106 cells were analyzed to reach a 95% probability of detecting one tumor cell in 1 × 106 mononuclear cells. Four quality control rounds were organized to validate the method. A total of 111 quality control samples were analyzed. Two main improvements were achieved: in discordant cases, the range between the lowest and highest reported result was reduced by half, and discordant results were only found in samples with less than 10 CPCs per 1 × 106. This article describes the first internationally standardized protocol to detect and quantify rare neuroblastoma cells by immunocytochemistry. This method is an indispensable tool for multicenter studies evaluating the clinical significance of minimal residual disease in neuroblastoma. PMID:15956022

  20. Intracoronary infusion of a combination of bone marrow-derived stem cells in dogs.

    PubMed

    Minguell, José J; Florenzano, Fernando M; Ramírez, Manuel R; Martínez, Ramón F; Lasala, Gabriel P

    2010-01-01

    Infusion of diverse types of bone marrow cells, as a source of endothelial progenitor cells (EPCs), into the ischemic myocardium is emerging as a promising therapy for coronary ischemia, probably mediated by the formation of new blood vessels. Studies have shown that while the procedure is safe and feasible, efficacy results are contentious. The investigators in the present preclinical translation study hypothesized that the infusion of a combination cell product consisting of EPCs and other cell types, such as mesenchymal stem cells, promotes the formation of more stable and mature blood vessels resulting in improved clinical outcomes. The safety and feasibility of the intracoronary infusion of such a cell combination was assessed in a canine model. A mixture of canine autologous mononuclear cells (as the source of EPCs) and ex vivo-expanded bone marrow-derived mesenchymal stem cells or a placebo solution were intracoronarily infused into healthy dogs. Follow-up after cell/placebo infusion included an electrocardiogram, serum cardiac enzyme testing, a transthoracic echocardiography and a histopathological heart examination. On follow-up at all time points after infusion, no significant changes or abnormalities in vital signs, electrocardiogram, transthoracic echocardiography and heart histology were detected. From a clinical perspective, the safety and feasibility of the protocol used in the present animal study demonstrated clinical relevance and provided direct evidence supporting the intracoronary infusion of combination stem/progenitor cell products.

  1. Hyaluronan enhances bone marrow cell therapy for myocardial repair after infarction.

    PubMed

    Chen, Chien-Hsi; Wang, Shoei-Shen; Wei, Erika Ih; Chu, Ting-Yu; Hsieh, Patrick C H

    2013-03-01

    Hyaluronan (HA) has been shown to play an important role during early heart development and promote angiogenesis under various physiological and pathological conditions. In recent years, stem cell therapy, which may reduce cardiomyocyte apoptosis, increase neovascularization, and prevent cardiac fibrosis, has emerged as a promising approach to treat myocardial infarction (MI). However, effective delivery of stem cells for cardiac therapy remains a major challenge. In this study, we tested whether transplanting a combination of HA and allogeneic bone marrow mononuclear cells (MNCs) promotes cell therapy efficacy and thus improves cardiac performance after MI in rats. We showed that HA provided a favorable microenvironment for cell adhesion, proliferation, and vascular differentiation in MNC culture. Following MI in rats, compared with the injection of HA alone or MNC alone, injection of both HA and MNCs significantly reduced inflammatory cell infiltration, cardiomyocyte apoptosis, and infarct size and also improved cell retention, angiogenesis, and arteriogenesis, and thus the overall cardiac performance. Ultimately, HA/MNC treatment improved vasculature engraftment of transplanted cells in the infarcted region. Together, our results indicate that combining the biocompatible material HA with bone marrow stem cells exerts a therapeutic effect on heart repair and may further provide potential treatment for ischemic diseases.

  2. In Vivo Functional and Transcriptional Profiling of Bone Marrow Stem Cells after Transplantation into Ischemic Myocardium

    PubMed Central

    Sheikh, Ahmad Y.; Huber, Bruno C.; Narsinh, Kazim H.; Spin, Joshua M.; van der Bogt, Koen; de Almeida, Patricia E.; Ransohoff, Katherine J.; Kraft, Daniel L.; Fajardo, Giovanni; Ardigo, Diego; Ransohoff, Julia; Bernstein, Daniel; Fischbein, Michael P.; Robbins, Robert C.; Wu, Joseph C.

    2011-01-01

    Objective Clinical trials of bone marrow-derived stem cell therapy for the heart have yielded variable results. The basic mechanism(s) that underlie their potential efficacy remains unknown. In the present study, we evaluate the survival kinetics, transcriptional response, and functional outcome of intramyocardial bone marrow mononuclear cell (BMMC) transplantation for cardiac repair in murine myocardial infarction model. Methods and Results We utilized molecular-genetic bioluminescence imaging and high throughput transcriptional profiling to evaluate the in vivo survival kinetics and gene expression changes of transplanted BMMCs after their engraftment into ischemic myocardium. Our results demonstrate short-lived survival of cells following transplant, with less than 1% of cells surviving by 6 weeks post-transplantation. Moreover, transcriptomic analysis of BMMCs revealed non-specific upregulation of various cell regulatory genes with a marked downregulation of cell differentiation and maturation pathways. BMMC therapy caused limited improvement of heart function as assessed by echocardiography, invasive hemodynamics, and positron emission tomography (PET). Histological evaluation of cell fate further confirmed findings of the in vivo cell tracking and transcriptomic analysis. Conclusions Collectively, these data suggest that BMMC therapy, in its present iteration, may be less efficacious than once thought. Additional refinement of existing cell delivery protocols should be considered to induce better therapeutic efficacy. PMID:22034515

  3. Bone Marrow Derivation of Interstitial Cells of Cajal in Small Intestine Following Intestinal Injury

    PubMed Central

    Liu, Dengqun; Wang, Fengchao; Zou, Zhongmin; Dong, Shiwu; Wang, Junping; Ran, Xinze; Li, Chunxue; Shi, Chunmeng; Su, Yongping

    2010-01-01

    Interstitial cells of Cajal (ICCs) in gastrointestinal tract are specialized cells serving as pacemaker cells. The origin of ICCs is currently not fully characterized. In this work, we aimed to study whether bone marrow-derived cells (BMDCs) could contribute to the origin of ICCs in the muscular plexus of small intestine using GFP-C57BL/6 chimeric mice.Engraftment of BMDCs in the intestine was investigated for GFP expression. GFP positive bone marrow mononuclear cells reached a proportion of 95.65% ± 3.72% at different times in chimerism. Donor-derived cells distributed widely in all the layers of the gastrointestinal tract. There were GFP positive BMDCs in the myenteric plexus, which resembled characteristics of ICCs, including myenteric location, c-Kit positive staining, and ramified morphology. Donor-derived ICCs in the myenteric plexus contributed to a percentage ranging 9.25% ± 4.9% of all the ICCs in the myenteric plexus. In conclusion, here we described that donor-derived BMDCs might differentiate into gastrointestinal ICCs after radiation injury, which provided an alternative source for the origin of the ICCs in the muscular plexus of adult intestine. These results further identified the plasticity of BMDCs and indicated therapeutic implications of BMDCs for the gastrointestinal dysmotility caused by ICCs disorders. PMID:20396598

  4. Administration of Autologous Bone Marrow-Derived Stem Cells for Treatment of Cerebral Palsy Patients: A Proof of Concept.

    PubMed

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

    Stem cell therapy is a promising treatment for cerebral palsy, which refers to a category of brain diseases that are associated with chronic motor disability in children. Autologous bone marrow stem cells may be a better cell source and have been studied for the treatment of cerebral palsy because of their functions in tissue repair and the regulation of immunological processes. To assess autologous marrow stem cells as a novel treatment for patients with moderate-to-severe cerebral palsy, a total of 10 cerebral palsy patients were enrolled in this clinical study with 24 months follow-up. A total of 10 cerebral palsy patients received autologous bone marrow cells transplantation (4.5 × 10(8) mononuclear cells; 90% viability) into the subarachnoid cavity and rehabilitation. We recorded the gross motor function measurement scores, manual ability function measurement score, and adverse events up to 24 months post-treatment. The gross motor function measurement scores were significantly higher at month 6 post-treatment compared with the baseline scores and were stable up to 24 months follow-up. The increase in manual ability and communication function measurement scores at 6 months were not significant when compared to the baseline score. All the 10 patients survived and none of the patients experienced any serious adverse events or complications. Our results indicated that bone marrow derived MNCs are safe and effective for the treatment of motor deficits related to cerebral palsy. Further randomized clinical trials are necessary to establish the efficacy of this procedure.

  5. 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

  6. 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

  7. Use of gene marking in bone marrow transplantation.

    PubMed

    Heslop, H E; Rooney, C M; Rill, D R; Krance, R A; Brenner, M K

    1996-01-01

    We have used gene marking to investigate the mechanism of relapse and biology of reconstitution following bone marrow transplantation (BMT). The rationale for our initial protocols was to learn if residual malignant cells in autologous marrow contribute to subsequent relapse. Marked malignant cells were found at the time of relapse in 6/8 patients relapsing after autologous BMT for AML or neuroblastoma showing the infused marrow contributed to disease recurrence. Modifications of this marker approach with two distinguishable vectors are now being used to compare the efficacy of purging techniques. We were also able to evaluate gene transfer to normal progenitors and demonstrated that the marker gene was expressed for up to 36 months. Gene marking is also being used to trace the fate of EBV-specific CTLs that we are administering to recipients of allogeneic BMT and has provided evidence of persistence of adoptively transferred CTL for up to 10 months.

  8. [Bone and Stem Cells. Immune cell regulation by the bone marrow niche].

    PubMed

    Terashima, Asuka; Takayanagi, Hiroshi

    2014-04-01

    Adult hematopoietic stem cells (HSCs) are maintained in the bone marrow and give rise to all blood cell types. The maintenance and the differentiation of blood cells including immune cells are essential for host defense and oxygen delivery. HSCs are maintained in microenvironments called stem cell niches, which consists of various cell types in bone marrow. Recently, new visualization technologies and assay systems brought advances in studies on the stem cell niche. In addition, several reports demonstrated that osteoblasts and osteocytes regulate not only HSC homeostasis but also immune cell differentiation, suggesting a close relationship between bone cells and HSCs.

  9. Discoidin Receptor 2 Controls Bone Formation and Marrow Adipogenesis.

    PubMed

    Ge, Chunxi; Wang, Zhengyan; Zhao, Guisheng; Li, Binbin; Liao, Jinhui; Sun, Hanshi; Franceschi, Renny T

    2016-12-01

    Cell-extracellular matrix (ECM) interactions play major roles in controlling progenitor cell fate and differentiation. The receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), is an important mediator of interactions between cells and fibrillar collagens. DDR2 signals through both ERK1/2 and p38 MAP kinase, which stimulate osteoblast differentiation and bone formation. Here we show that DDR2 is critical for skeletal development and differentiation of marrow progenitor cells to osteoblasts while suppressing marrow adipogenesis. Smallie mice (Ddr2(slie/slie) ), which contain a nonfunctional Ddr2 allele, have multiple skeletal defects. A progressive decrease in tibial trabecular bone volume/total volume (BV/TV) was observed when wild-type (WT), Ddr2(wt/slie) , and Ddr2(slie/slie) mice were compared. These changes were associated with reduced trabecular number (Tb.N) and trabecular thickness (Tb.Th) and increased trabecular spacing (Tb.Sp) in both males and females, but reduced cortical thickness only in Ddr2(slie/slie) females. Bone changes were attributed to decreased bone formation rather than increased osteoclast activity. Significantly, marrow fat and adipocyte-specific mRNA expression were significantly elevated in Ddr2(slie/slie) animals. Additional skeletal defects include widened calvarial sutures and reduced vertebral trabecular bone. To examine the role of DDR2 signaling in cell differentiation, bone marrow stromal cells (BMSCs) were grown under osteogenic and adipogenic conditions. Ddr2(slie/slie) cells exhibited defective osteoblast differentiation and accelerated adipogenesis. Changes in differentiation were related to activity of runt-related transcription factor 2 (RUNX2) and PPARγ, transcription factors that are both controlled by MAPK-dependent phosphorylation. Specifically, the defective osteoblast differentiation in calvarial cells from Ddr2(slie/slie) mice was associated with reduced ERK/MAP kinase and RUNX2-S319 phosphorylation and could

  10. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow

    PubMed Central

    Yu, Vionnie W.C.; Saez, Borja; Cook, Colleen; Lotinun, Sutada; Pardo-Saganta, Ana; Wang, Ying-Hua; Lymperi, Stefania; Ferraro, Francesca; Raaijmakers, Marc H.G.P.; Wu, Joy Y.; Zhou, Lan; Rajagopal, Jayaraj; Kronenberg, Henry M.; Baron, Roland

    2015-01-01

    Production of the cells that ultimately populate the thymus to generate α/β T cells has been controversial, and their molecular drivers remain undefined. Here, we report that specific deletion of bone-producing osteocalcin (Ocn)-expressing cells in vivo markedly reduces T-competent progenitors and thymus-homing receptor expression among bone marrow hematopoietic cells. Decreased intrathymic T cell precursors and decreased generation of mature T cells occurred despite normal thymic function. The Notch ligand DLL4 is abundantly expressed on bone marrow Ocn+ cells, and selective depletion of DLL4 from these cells recapitulated the thymopoietic abnormality. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell–based adaptive immunity. PMID:25918341

  11. [Bone and Stem Cells. Bone marrow microenvironment niches for hematopoietic stem and progenitor cells].

    PubMed

    Nagasawa, Takashi

    2014-04-01

    In bone marrow, the special microenvironments known as niches control proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs) . However, the identity and functions of the niches has been a subject of longstanding debate. Although it has been reported previously that osteoblasts lining the bone surface act as HSC niches, their precise role in HSC maintenance remains unclear. On the other hand, the adipo-osteogenic progenitors with long processes, termed CXCL12-abundant reticular (CAR) cells, which preferentially express the chemokine CXCL12, stem cell factor (SCF) , leptin receptor and PDGF receptor-β were identified in the bone marrow. Recent studies revealed that endothelial cells of bone marrow vascular sinuses and CAR cells provided niches for HSCs. The identity and functions of various other candidate HSC niche cells, including nestin-expressing cells and Schwann cells would also be discussed in this review.

  12. Bone marrow macrophages support prostate cancer growth in bone

    PubMed Central

    Soki, Fabiana N.; Cho, Sun Wook; Kim, Yeo Won; Jones, Jacqueline D.; Park, Serk In; Koh, Amy J.; Entezami, Payam; Daignault-Newton, Stephanie; Pienta, Kenneth J.; Roca, Hernan; McCauley, Laurie K.

    2015-01-01

    Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone. PMID:26459393

  13. Bone marrow macrophages support prostate cancer growth in bone.

    PubMed

    Soki, Fabiana N; Cho, Sun Wook; Kim, Yeo Won; Jones, Jacqueline D; Park, Serk In; Koh, Amy J; Entezami, Payam; Daignault-Newton, Stephanie; Pienta, Kenneth J; Roca, Hernan; McCauley, Laurie K

    2015-11-03

    Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone.

  14. Bone marrow and splenic histology in hairy cell leukaemia.

    PubMed

    Wotherspoon, Andrew; Attygalle, Ayoma; Mendes, Larissa Sena Teixeira

    2015-12-01

    Hairy cell leukaemia is a rare chronic neoplastic B-cell lymphoproliferation that characteristically involves blood, bone marrow and spleen with liver, lymph node and skin less commonly involved. Histologically, the cells have a characteristic appearance with pale/clear cytoplasm and round or reniform nuclei. In the spleen, the infiltrate involves the red pulp and is frequently associated with areas of haemorrhage (blood lakes). The cells stain for B-cell related antigens as well as with antibodies against tartrate-resistant acid phosphatase, DBA44 (CD72), CD11c, CD25, CD103, CD123, cyclin D1 and annexin A1. Mutation of BRAF -V600E is present and antibody to the mutant protein can be used as a specific marker. Bone marrow biopsy is essential in the initial assessment of disease as the bone marrow may be inaspirable or unrepresentative of degree of marrow infiltration as a result of the tumour associated fibrosis preventing aspiration of the tumour cell component. Bone marrow biopsy is important in the assessment of therapy response but in this context staining for CD11c and Annexin A1 is not helpful as they are also markers of myeloid lineage and identification of low level infiltration may be obscured. In this context staining for CD20 may be used in conjunction with morphological assessment and staining of serial sections for cyclin D1 and DBA44 to identify subtle residual infiltration. Staining for CD79a and CD19 is not recommended as these antibodies will identify plasma cells and can lead to over-estimation of disease. Staining for CD20 should not be used in patients following with anti-CD20 based treatments. Down regulation of cyclin D1 and CD25 has been reported in patients following BRAF inhibitor therapy and assessment of these antigens should not be used in this context. Histologically, hairy cell leukaemia needs to be distinguished from other B-cell lymphoproliferations associated with splenomegaly including splenic marginal zone lymphoma, splenic

  15. Late renal dysfunction in adult survivors of bone marrow transplantation

    SciTech Connect

    Lawton, C.A.; Cohen, E.P.; Barber-Derus, S.W.; Murray, K.J.; Ash, R.C.; Casper, J.T.; Moulder, J.E. )

    1991-06-01

    Until recently long-term renal toxicity has not been considered a major late complication of bone marrow transplantation (BMT). Late renal dysfunction has been described in a pediatric population status post-BMT which was attributable to the radiation in the preparatory regimen. A thorough review of adults with this type of late renal dysfunction has not previously been described. Fourteen of 103 evaluable adult patients undergoing allogeneic (96) or autologous (7) bone marrow transplantation, predominantly for leukemia and lymphomas, at the Medical College of Wisconsin (Milwaukee, WI) have had a syndrome of renal insufficiency characterized by increased serum creatinine, decreased glomerular filtration rate, anemia, and hypertension. This syndrome developed at a median of 9 months (range, 4.5 to 26 months) posttransplantation in the absence of specific identifiable causes. The cumulative probability of having this renal dysfunction is 20% at 1 year. Renal biopsies performed on seven of these cases showed the endothelium widely separated from the basement membrane, extreme thickening of the glomerular basement membrane, and microthrombi. Previous chemotherapy, antibiotics, and antifungals as well as cyclosporin may add to and possibly potentiate a primary chemoradiation marrow transplant renal injury, but this clinical syndrome is most analogous to clinical and experimental models of radiation nephritis. This late marrow transplant-associated nephritis should be recognized as a potentially limiting factor in the use of some intensive chemoradiation conditioning regimens used for BMT. Some selective attenuation of the radiation to the kidneys may decrease the incidence of this renal dysfunction.

  16. 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.

  17. A stochastic model of radiation-induced bone marrow damage

    SciTech Connect

    Cotlet, G.; Blue, T.E.

    2000-03-01

    A stochastic model, based on consensus principles from radiation biology, is used to estimate bone-marrow stem cell pool survival (CFU-S and stroma cells) after irradiation. The dose response model consists of three coupled first order linear differential equations which quantitatively describe time dependent cellular damage, repair, and killing of red bone marrow cells. This system of differential equations is solved analytically through the use of a matrix approach for continuous and fractionated irradiations. The analytic solutions are confirmed through the dynamical solution of the model equations using SIMULINK. Rate coefficients describing the cellular processes of radiation damage and repair, extrapolated to humans from animal data sets and adjusted for neutron-gamma mixed fields, are employed in a SIMULINK analysis of criticality accidents. The results show that, for the time structures which may occur in criticality accidents, cell survival is established mainly by the average dose and dose rate.

  18. Juvenile xanthogranuloma with clonal proliferation in the bone marrow.

    PubMed

    Mały, Ewa; Przyborska, Marta; Rybczyńska, Aleksandra; Konatkowska, Benigna; Nowak, Jerzy; Januszkiewicz, Danuta

    2012-04-01

    The triple association between juvenile xanthogranuloma (JXG), juvenile myelomonocytic leukemia and neurofibromatosis was described in literature in about 20 cases. In this paper, the case of an 11-month-old infant boy with a disseminated JXG with unusual cytogenetic representation in the bone marrow was reported. Neurofibromatosis and juvenile myelomonocytic leukemia were excluded, just the same as other leukemias. Bone marrow and peripheral blood cytogenetic analysis revealed a karyotype with many rearrangements 46,XY,-6,der(12)t(6;12)(p21;p13),del(7)(p13p22),+9 once described in the literature as a B-acute lymphoblastic leukemia case. On the contrary, in our patient immunologic testing demonstrated a high activity of T lymphocytes, however, inflammation was excluded. To the best of our knowledge this is the first described case of systemic JXG with determined karyotype representing unusual chromosomal aberrations.

  19. Neuromyelitis optica in an adolescent after bone marrow transplantation.

    PubMed

    Baumer, Fiona M; Kamihara, Junne; Gorman, Mark P

    2015-01-01

    Central nervous system complications of bone marrow transplant are a common occurrence and the differential diagnosis is quite broad, including opportunistic infections, medications toxicities, graft versus host disease, and other autoimmune processes. We summarize previously reported cases of autoimmune myelitis in post-transplant patients and discuss a 17-year-old boy who presented with seronegative neuromyelitis optica after a bone marrow transplant for acute myeloid leukemia. Our patient had a marked improvement in symptoms after plasmapheresis. Including our patient, there have been at least eight cases of post-transplant autoimmune myelitis presented in the literature, and at least three of these are suspicious for neuromyelitis optica. Several of these patients had poor outcomes with persistent symptoms after the myelitis. Autoimmune processes such as neuromyelitis optica should be carefully considered in patients after transplant as aggressive treatment like early plasmapheresis may improve outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Isolation, characterization, and biologic features of bone marrow endothelial cells.

    PubMed

    Almeida-Porada, G; Ascensão, J L

    1996-10-01

    Bone marrow endothelial cells (BMECs) are an integral part of the bone marrow microenvironment and are likely to play an important role in the regulation of hematopoiesis, either by producing growth factors or inhibitory cytokines or by displaying adhesion molecules that can interact with hematopoietic progenitors. In the present study we demonstrate the isolation, propagation, and characterization of BMECs with regard to morphology, growth characteristics, phenotype, and production of cytokines. Furthermore, we report the creation of a cell line with "BMEC-like" characteristics and compare the characteristics of primary BMEC cultures to those of the immortalized cell line. In addition, we demonstrate that BMECs are susceptible to infection by a laboratory strain of human cytomegalovirus (CMV), suggesting that CMV infection of endothelial cells in vivo could potentially play a role in the hematologic abnormalities observed during CMV infection.

  1. Bone marrow-derived stem cells initiate pancreatic regeneration.

    PubMed

    Hess, David; Li, Li; Martin, Matthew; Sakano, Seiji; Hill, David; Strutt, Brenda; Thyssen, Sandra; Gray, Douglas A; Bhatia, Mickie

    2003-07-01

    We show that transplantation of adult bone marrow-derived cells expressing c-kit reduces hyperglycemia in mice with streptozotocin-induced pancreatic damage. Although quantitative analysis of the pancreas revealed a low frequency of donor insulin-positive cells, these cells were not present at the onset of blood glucose reduction. Instead, the majority of transplanted cells were localized to ductal and islet structures, and their presence was accompanied by a proliferation of recipient pancreatic cells that resulted in insulin production. The capacity of transplanted bone marrow-derived stem cells to initiate endogenous pancreatic tissue regeneration represents a previously unrecognized means by which these cells can contribute to the restoration of organ function.

  2. Total lymphatic irradiation and bone marrow in human heart transplantation

    SciTech Connect

    Kahn, D.R.; Hong, R.; Greenberg, A.J.; Gilbert, E.F.; Dacumos, G.C.; Dufek, J.H.

    1984-08-01

    Six patients, aged 36 to 59 years, had heart transplants for terminal myocardial disease using total lymphatic irradiation (TLI) and donor bone marrow in addition to conventional therapy. All patients were poor candidates for transplantation because of marked pulmonary hypertension, unacceptable tissue matching, or age. Two patients are living and well more than four years after the transplants. Two patients died of infection at six and seven weeks with normal hearts. One patient, whose preoperative pulmonary hypertension was too great for an orthotopic heart transplant, died at 10 days after such a procedure. The other patient died of chronic rejection seven months postoperatively. Donor-specific tolerance developed in 2 patients. TLI and donor bone marrow can produce specific tolerance to donor antigens and allow easy control of rejection, but infection is still a major problem. We describe a new technique of administering TLI with early reduction of prednisone that may help this problem.

  3. Bone Marrow Blood Vessels: Normal and Neoplastic Niche

    PubMed Central

    Shahrabi, Saeid; Rezaeeyan, Hadi; Ahmadzadeh, Ahmad; Shahjahani, Mohammad; Saki, Najmaldin

    2016-01-01

    Blood vessels are among the most important factors in the transport of materials such as nutrients and oxygen. This study will review the role of blood vessels in normal bone marrow hematopoiesis as well as pathological conditions like leukemia and metastasis. Relevant literature was identified by a Pubmed search (1992-2016) of English-language papers using the terms bone marrow, leukemia, metastasis, and vessel. Given that blood vessels are conduits for the transfer of nutrients, they create a favorable situation for cancer cells and cause their growth and development. On the other hand, blood vessels protect leukemia cells against chemotherapy drugs. Finally, it may be concluded that the vessels are an important factor in the development of malignant diseases. PMID:27994770

  4. Bone marrow hypoplasia associated with fenbendazole administration in a dog.

    PubMed

    Gary, Anthony T; Kerl, Marie E; Wiedmeyer, Charles E; Turnquist, Susan E; Cohn, Leah A

    2004-01-01

    A 1.5-year-old Doberman pinscher was presented with sudden-onset of fever and malaise. Twelve days prior to presentation, fenbendazole therapy was initiated for a suspected lungworm infection. Results of a complete blood count on presentation showed pancytopenia, while histopathological evaluation of a bone marrow core sample revealed bone marrow hypoplasia of undetermined etiology. Bactericidal antibiotics and fluid therapy, as well as discontinuation of fenbendazole administration, led to a complete resolution of clinical and hematological abnormalities within 15 days. An idiosyncratic reaction to fenbendazole was suspected based on the absence of infectious, neoplastic, autoimmune, and toxic etiologies, as well as resolution of clinical signs and pancytopenia upon drug withdrawal.

  5. [Analysis of neoplasm metastases to the bone marrow in patients with lung cancer].

    PubMed

    Dziecioł, J; Kemona, A; Sulik, M; Sobaniec-Lotowska, M; Sulkowski, S; Ostapiuk, H; Pasztaleniec, L; Deregowski, K

    1989-04-01

    The authors analysed bone marrow metastases in lung cancer in 104 deceased patients. Trepano-biopsy was taken from the sternum, hip bone and spine. Bone marrow metastases were found in 33 cases (31.73%). Most often they were seen in small cell lung cancer (16 cases--35.56%). In 12 cases the bone marrow was the only site of lung cancer metastases.

  6. Osteogenic activity of bone marrow-derived mesenchymal stem cells (BMSCs) seeded on irradiated allogenic bone.

    PubMed

    Tohma, Yasuaki; Dohi, Yoshiko; Ohgushi, Hajime; Tadokoro, Mika; Akahane, Manabu; Tanaka, Yasuhito

    2012-02-01

    Allogenic bone grafting, a technique used in orthopaedic surgery, has several problems, including low osteogenic activity. To overcome the problem, this study aimed to determine whether in vivo osteogenesis could be enhanced using allogenic irradiated bone grafts after seeding with autologous bone marrow-derived mesenchymal stem cells (BMSCs). The allogenic bone cylinders were extracted from ACI rats and sterilized by irradiation. Donor BMSCs were obtained from fresh Fischer 344 (F344) rat bone marrow by cell culture. The allogenic bone with or without BMSCs were transplanted subcutaneously into syngeneic F344 rats. At 4 weeks after transplantation, high alkaline phosphatase (ALP) activity, bone-specific osteocalcin mRNA expression and newly formed bone were detected in the allogenic bone with BMSCs. The origin of the newly formed bone was derived from cultured donor BMSCs. However, none of these identifiers of osteogenesis were detected in either the fresh or the irradiated allogenic bone without BMSCs. These results indicate the availability of autologous BMSCs to heighten the osteogenic response of allogenic bone. Our present tissue-engineering method might contribute to a wide variety of allogenic bone grafting techniques in clinical settings.

  7. [Functional activity of bone marrow-derived peptides (myelopeptides)].

    PubMed

    Mikhaĭlova, A A; Petrov, R V

    2009-12-01

    The review describes structure and functions of bone marrow-derived peptides (myelopeptides). The final biological effects of these endogenous bioregulators (antitumor, antiviral, anti-infectious, antileukemia etc.) are due to their immunocorrecting and differentiating activity. Myelopeptides are the integral parts of the immune homeostasis maintenance system. Nowadays, medical preparations with no side effects and natural mechanisms of action are being developed on the basis of synthesized myelopeptides.

  8. Histochemistry of blood and bone marrow cells in pangolins.

    PubMed Central

    Caxton-Martins, A E

    1977-01-01

    Blood and bone marrow cells of pangolins have been examined histochemically. Sudanophilia, PAS positivity and acid phosphatase and alkaline phosphatase reactivity were confined to cells of the granulocytic and monocytic series, while peroxidase reactivity was confined to cells of the erythroid series. In this latter respect the pangolin is unique among mammals so far studied. Images Figs. 1, 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Figs. 7, 8 Fig. 9 Fig. 10 PMID:858692

  9. Bone marrow myeloid cells in regulation of multiple myeloma progression.

    PubMed

    Herlihy, Sarah E; Lin, Cindy; Nefedova, Yulia

    2017-08-01

    Survival, growth, and response to chemotherapy of cancer cells depends strongly on the interaction of cancer cells with the tumor microenvironment. In multiple myeloma, a cancer of plasma cells that localizes preferentially in the bone marrow, the microenvironment is highly enriched with myeloid cells. The majority of myeloid cells are represented by mature and immature neutrophils. The contribution of the different myeloid cell populations to tumor progression and chemoresistance in multiple myeloma is discussed.

  10. Molecular and functional characterization of human bone marrow adipocytes.

    PubMed

    Poloni, Antonella; Maurizi, Giulia; Serrani, Federica; Mancini, Stefania; Zingaretti, Maria Cristina; Frontini, Andrea; Cinti, Saverio; Olivieri, Attilio; Leoni, Pietro

    2013-06-01

    Adipocytes are a cell population largely located in the human bone marrow cavity. In this specific microenvironment where adipocytes can interact with a variety of different cells, the role of fat is mainly unknown. To our knowledge, this report is the first to characterize mature adipocytes isolated from human bone marrow (BM-A) molecularly and functionally to better understand their roles into the hematopoietic microenvironment. Healthy BM-A were isolated after collagenase digestion and filtration. We studied the morphology of BM-A, their gene expression and immunophenotypic profile and their functional ability in the hematopoietic microenvironment, comparing them with adipocytes derived from adipose tissue (AT-A). BM-A showed a unilocular lipid morphology similar to AT-A and did not lose their morphology in culture; they showed a comparable pattern of stem cell-surface antigens to AT-A. In line with these observations, molecular data showed that BM-A expressed some embryonic stem cells genes, such as Oct4, KLf4, c-myc, Gata4, Tbx1, and Sox17, whereas they did not express the stem cell markers Sox2 and Nanog. Moreover, BM-A had long telomeres that were similar to bone marrow mesenchymal stem cells. Notably, BM-A supported the survival and differentiation of hematopoietic stem cells in long-term cultures. These results showed that BM-A are stromal cells with a gene expression pattern that distinguished them from AT-A. BM-A showed stem cell properties through their hematopoietic supporting function, which was certainly linked to their role in the maintenance of the bone marrow microenvironment. Depending on specific demands, BM-A may acquire different functions based on their local environment. Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  11. Thymopoietic and Bone Marrow Response to Murine Pneumocystis Pneumonia▿

    PubMed Central

    Shi, Xin; Zhang, Ping; Sempowski, Gregory D.; Shellito, Judd E.

    2011-01-01

    CD4+ T cells play a key role in host defense against Pneumocystis infection. To define the role of naïve CD4+ T cell production through the thymopoietic response in host defense against Pneumocystis infection, Pneumocystis murina infection in the lung was induced in adult male C57BL/6 mice with and without prior thymectomy. Pneumocystis infection caused a significant increase in the number of CCR9+ multipotent progenitor (MPP) cells in the bone marrow and peripheral circulation, an increase in populations of earliest thymic progenitors (ETPs) and double negative (DN) thymocytes in the thymus, and recruitment of naïve and total CD4+ T cells into the alveolar space. The level of murine signal joint T cell receptor excision circles (msjTRECs) in spleen CD4+ cells was increased at 5 weeks post-Pneumocystis infection. In thymectomized mice, the numbers of naïve, central memory, and total CD4+ T cells in all tissues examined were markedly reduced following Pneumocystis infection. This deficiency of naïve and central memory CD4+ T cells was associated with delayed pulmonary clearance of Pneumocystis. Extracts of Pneumocystis resulted in an increase in the number of CCR9+ MPPs in the cultured bone marrow cells. Stimulation of cultured bone marrow cells with ligands to Toll-like receptor 2 ([TLR-2] zymosan) and TLR-9 (ODN M362) each caused a similar increase in CCR9+ MPP cells via activation of the Jun N-terminal protein kinase (JNK) pathway. These results demonstrate that enhanced production of naïve CD4+ T lymphocytes through the thymopoietic response and enhanced delivery of lymphopoietic precursors from the bone marrow play an important role in host defense against Pneumocystis infection. PMID:21343353

  12. Primary cutaneous aspergillosis and idiopathic bone marrow aplasia*