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Sample records for hematopoietic microenvironment origin

  1. Hematopoietic microenvironment. Origin, lineage, and transplantability of the stromal cells in long-term bone marrow cultures from chimeric mice

    SciTech Connect

    Perkins, S.; Fleischman, R.A.

    1988-04-01

    Studies of bone marrow transplant patients have suggested that the stromal cells of the in vitro hematopoietic microenvironment are transplantable into conditioned recipients. Moreover, in patients with myeloproliferative disorders, all of the stromal cells, which include presumptive endothelial cells, appear to be derived from hematopoietic precursors. To confirm these findings, we have constructed two chimeric mouse models: (a) traditional radiation chimeras, and (b) fetal chimeras, produced by placental injection of bone marrow into genetically anemic Wx/Wv fetuses, a technique that essentially precludes engraftment of nonhematopoietic cells. Using two-color indirect immunofluorescence, the stromal cells in long-term bone marrow culture derived from these chimeras were analyzed for donor or host origin by strain-specific H-2 antigens, and for cell lineage by a variety of other specific markers. 75-95% of the stromal cells were shown to be hematopoietic cells of the monocyte-macrophage lineage, based upon donor origin, phagocytosis, and expression of specific hematopoietic surface antigens. The remaining 5-25% of the stromal cells were exclusively host in origin. Apart from occasional fat cells, these cells uniformly expressed collagen type IV, laminin, and a surface antigen associated with endothelial cells. Since these endothelial-like cells are not transplantable into radiation or fetal chimeras, they are not derived from hematopoietic stem cells. The contrast between our findings and human studies suggests either unexpected species differences in the origin of stromal lineages or limitations in the previous methodology used to detect nonhematopoietic stromal cells.

  2. Redefining the Hematopoietic Microenvironment

    DTIC Science & Technology

    2013-04-01

    canine were cloned and tested for the macrophage- specific expression by luciferase reporter assay. However, insertion of CD163 promoter constructs into...fragment of the canine genomic fragment homologous to the human CD163 promoter was synthesized (GenScript) and cloned upstream of the iCasp9fusion...fragment of iCasp9 was annealed and cloned into p140MGMT lentiviral vector. In the original grant application, I proposed to use the CD68 promoter

  3. 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.

  4. Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

    PubMed Central

    Kovtonyuk, Larisa V.; Fritsch, Kristin; Feng, Xiaomin; Manz, Markus G.; Takizawa, Hitoshi

    2016-01-01

    All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of “Inflamm-Aging,” or inflammation-associated aging of hematopoiesis. PMID:27895645

  5. 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

  6. Muscle-derived hematopoietic stem cells are hematopoietic in origin

    PubMed Central

    McKinney-Freeman, Shannon L.; Jackson, Kathyjo A.; Camargo, Fernando D.; Ferrari, Giuliana; Mavilio, Fulvio; Goodell, Margaret A.

    2002-01-01

    It has recently been shown that mononuclear cells from murine skeletal muscle contain the potential to repopulate all major peripheral blood lineages in lethally irradiated mice, but the origin of this activity is unknown. We have fractionated muscle cells on the basis of hematopoietic markers to show that the active population exclusively expresses the hematopoietic stem cell antigens Sca-1 and CD45. Muscle cells obtained from 6- to 8-week-old C57BL/6-CD45.1 mice and enriched for cells expressing Sca-1 and CD45 were able to generate hematopoietic but not myogenic colonies in vitro and repopulated multiple hematopoietic lineages of lethally irradiated C57BL/6-CD45.2 mice. These data show that muscle-derived hematopoietic stem cells are likely derived from the hematopoietic system and are a result not of transdifferentiation of myogenic stem cells but instead of the presence of substantial numbers of hematopoietic stem cells in the muscle. Although CD45-negative cells were highly myogenic in vitro and in vivo, CD45-positive muscle-derived cells displayed only very limited myogenic activity and only in vivo. PMID:11830662

  7. Deficiency of lipid phosphatase SHIP enables long-term reconstitution of hematopoietic inductive bone marrow microenvironment.

    PubMed

    Liang, Olin D; Lu, Jiayun; Nombela-Arrieta, César; Zhong, Jia; Zhao, Li; Pivarnik, Gregory; Mondal, Subhanjan; Chai, Li; Silberstein, Leslie E; Luo, Hongbo R

    2013-05-28

    A dysfunctional bone marrow (BM) microenvironment is thought to contribute to the development of hematologic diseases. However, functional replacement of pathologic BM microenvironment through BM transplantation has not been possible. Furthermore, the study of hematopoietic inductive BM microenvironment is hampered by the lack of a functional nonhematopoietic reconstitution system. Here, we show that a deficiency of SH2-containing inositol-5'-phosphatase-1 (SHIP) in a nonhematopoietic host microenvironment enables its functional reconstitution by wild-type donor cells. This microenvironment reconstitution normalizes hematopoiesis in peripheral blood and BM and alleviates pathology of spleen and lung in the SHIP-deficient recipients. SHIP-deficient BM contains a significantly smaller population of multipotent stromal cells with distinct properties, which may contribute to the reconstitution by wild-type cells. We further demonstrate that it is the nonhematopoietic donor cells that are responsible for the reconstitution. Thus, we have established a nonhematopoietic BM microenvironment reconstitution system to functionally study specific cell types in hematopoietic niches.

  8. Hyaluronan Expressed by the Hematopoietic Microenvironment Is Required for Bone Marrow Hematopoiesis*

    PubMed Central

    Goncharova, Valentina; Serobyan, Naira; Iizuka, Shinji; Schraufstatter, Ingrid; de Ridder, Audrey; Povaliy, Tatiana; Wacker, Valentina; Itano, Naoki; Kimata, Koji; Orlovskaja, Irina A.; Yamaguchi, Yu; Khaldoyanidi, Sophia

    2012-01-01

    The contribution of hyaluronan (HA) to the regulatory network of the hematopoietic microenvironment was studied using knock-out mice of three hyaluronan synthase genes (Has1, Has2, and Has3). The number of hematopoietic progenitors was decreased in bone marrow and increased in extramedullary sites of Prx1-Cre;Has2flox/flox;Has1−/−;Has3−/− triple knock-out (tKO) mice as compared with wild type (WT) and Has1−/−;Has3−/− double knock-out (dKO) mice. In line with this observation, decreased hematopoietic activity was observed in long term bone marrow cultures (LTBMC) from tKO mice, whereas the formation of the adherent layer and generation of hematopoietic cells in WT and dKO cultures was not different. 4-Methylumbelliferone (4MU) was used to pharmacologically inhibit the production of HA in LTBMC. Treatment with 4MU inhibited HA synthesis, decreased expression of HAS2 and HAS3, and eliminated hematopoiesis in LTBMC, and this effect was alleviated by the addition of exogenous HA. Exogenous HA also augmented the cell motility in LTBMC, which correlated with the HA-stimulated production of chemokines and growth factors. Conditioned media from HA-induced LTBMC enhanced the chemotaxis of hematopoietic stem/progenitor cells (HSPC) in response to SDF-1. Exposure of endothelial cells to 4MU decreased their ability to support HSPC rolling and adhesion. In addition, migration of transplanted HSPC into the marrow of 4MU-pretreated mice was lower than in untreated mice. Collectively, the results suggest that HA depletion reduces the ability of the microenvironment to support HSPC, and confirm a role for HA as a necessary regulatory element in the structure of the hematopoietic microenvironment. PMID:22654110

  9. In vivo imaging of hematopoietic stem cells and their microenvironment.

    PubMed

    Lo Celso, Cristina; Wu, Juwell W; Lin, Charles P

    2009-11-01

    In this review we provide a description of the basic concepts and paradigms currently constituting the foundations of adult stem cell biology, and discuss the role that live imaging techniques have in the development of the field. We focus on live imaging of hematopoietic stem cells (HSCs) as the basic biology and clinical applications of HSCs have historically been at the forefront of the stem cell field, and HSC are the first mammalian tissue stem cells to be visualized in vivo using advanced light microscopy techniques. We outline the current technical challenges that remain to be overcome before stem cells and their niche can be more fully characterized using the live imaging technology. (c) 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

  10. Hematopoietic stem cell origin of connective tissues.

    PubMed

    Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

    2010-07-01

    Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications.

  11. Hematopoietic Stem Cell–Derived Cancer–Associated Fibroblasts Are Novel Contributors to the Pro-Tumorigenic Microenvironment12

    PubMed Central

    McDonald, Lindsay T.; Russell, Dayvia L.; Kelly, Ryan R.; Xiong, Ying; Motamarry, Anjan; Patel, Risha K.; Jones, Jeffrey A.; Watson, Patricia M.; Turner, David P.; Watson, Dennis K.; Soloff, Adam C.; Findlay, Victoria J.; LaRue, Amanda C.

    2015-01-01

    Targeting the tumor microenvironment is critical toward improving the effectiveness of cancer therapeutics. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types of the tumor microenvironment, playing an important role in tumor progression. Multiple origins for CAFs have been proposed including resident fibroblasts, adipocytes, and bone marrow. Our laboratory previously identified a novel hematopoietic stem cell (HSC) origin for CAFs; however, the functional roles of HSC-derived CAFs (HSC-CAFs) in tumor progression have not yet been examined. To test the hypothesis that HSC-CAFs promote tumor progression through contribution to extracellular matrix (ECM) and paracrine production of pro-angiogenic factors, we developed a method to isolate HSC-CAFs. HSC-CAFs were profiled on the basis of their expression of hematopoietic and fibroblastic markers in two murine tumor models. Profiling revealed production of factors associated with ECM deposition and remodeling. Functional in vivo studies showed that co-injection of HSC-CAFs with tumor cells resulted in increased tumor growth rate and significantly larger tumors than tumor cells alone. Immunohistochemical studies revealed increased blood vessel density with co-injection, demonstrating a role for HSC-CAFs in tumor vascularization. Mechanistic in vitro studies indicated that HSC-CAFs play a role in producing vascular endothelial growth factor A and transforming growth factor–β1 in endothelial tube formation and patterning. In vitro and in vivo findings suggest that HSC-CAFs are a critical component of the tumor microenvironment and suggest that targeting the novel HSC-CAF may be a promising therapeutic strategy. PMID:26025666

  12. In vivo hematopoietic Myc activation directs a transcriptional signature in endothelial cells within the bone marrow microenvironment

    PubMed Central

    Franke, Katharina; Vilne, Baiba; da Costa, Olivia Prazeres; Rudelius, Martina; Peschel, Christian; Oostendorp, Robert A.J.; Keller, Ulrich

    2015-01-01

    Cancer pathogenesis involves tumor-intrinsic genomic aberrations and tumor-cell extrinsic mechanisms such as failure of immunosurveillance and structural and functional changes in the microenvironment. Using Myc as a model oncogene we established a conditional mouse bone marrow transduction/transplantation model where the conditional activation of the oncoprotein Myc expressed in the hematopoietic system could be assessed for influencing the host microenvironment. Constitutive ectopic expression of Myc resulted in rapid onset of a lethal myeloproliferative disorder with a median survival of 21 days. In contrast, brief 4-day Myc activation by means of the estrogen receptor (ER) agonist tamoxifen did not result in gross changes in the percentage/frequency of hematopoietic lineages or hematopoietic stem/progenitor cell (HSPC) subsets, nor did Myc activation significantly change the composition of the non-hematopoietic microenvironment defined by phenotyping for CD31, ALCAM, and Sca-1 expression. Transcriptome analysis of endothelial CD45- Ter119- cells from tamoxifen-treated MycER bone marrow graft recipients revealed a gene expression signature characterized by specific changes in the Rho subfamily pathway members, in the transcription-translation-machinery and in angiogenesis. In conclusion, intra-hematopoietic Myc activation results in significant transcriptome alterations that can be attributed to oncogene-induced signals from hematopoietic cells towards the microenvironment, e. g. endothelial cells, supporting the idea that even pre-leukemic HSPC highjack components of the niche which then could protect and support the cancer-initiating population. PMID:26308666

  13. Bone Marrow Cells in Acute Lymphoblastic Leukemia Create a Proinflammatory Microenvironment Influencing Normal Hematopoietic Differentiation Fates

    PubMed Central

    Vilchis-Ordoñez, Armando; Contreras-Quiroz, Adriana; Dorantes-Acosta, Elisa; Reyes-López, Alfonso; Quintela-Nuñez del Prado, Henry Martin; Venegas-Vázquez, Jorge; Mayani, Hector; Ortiz-Navarrete, Vianney; López-Martínez, Briceida; Pelayo, Rosana

    2015-01-01

    B-cell acute lymphoblastic leukemia (B-ALL) is a serious public health problem in the pediatric population worldwide, contributing to 85% of deaths from childhood cancers. Understanding the biology of the disease is crucial for its clinical management and the development of therapeutic strategies. In line with that observed in other malignancies, chronic inflammation may contribute to a tumor microenvironment resulting in the damage of normal processes, concomitant to development and maintenance of neoplastic cells. We report here that hematopoietic cells from bone marrow B-ALL have the ability to produce proinflammatory and growth factors, including TNFα, IL-1β, IL-12, and GM-CSF that stimulate proliferation and differentiation of normal stem and progenitor cells. Our findings suggest an apparently distinct CD13+CD33+ population of leukemic cells contributing to a proinflammatory microenvironment that may be detrimental to long-term normal hematopoiesis within B-ALL bone marrow. PMID:26090405

  14. [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.

  15. Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow.

    PubMed

    Park, Min Hee; Jin, Hee Kyung; Min, Woo-Kie; Lee, Won Woo; Lee, Jeong Eun; Akiyama, Haruhiko; Herzog, Herbert; Enikolopov, Grigori N; Schuchman, Edward H; Bae, Jae-sung

    2015-06-12

    Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide.

  16. Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow

    PubMed Central

    Park, Min Hee; Jin, Hee Kyung; Min, Woo-Kie; Lee, Won Woo; Lee, Jeong Eun; Akiyama, Haruhiko; Herzog, Herbert; Enikolopov, Grigori N; Schuchman, Edward H; Bae, Jae-sung

    2015-01-01

    Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide. PMID:25916827

  17. Role of neuropeptide Y in the bone marrow hematopoietic stem cell microenvironment.

    PubMed

    Park, Min Hee; Min, Woo-Kie; Jin, Hee Kyung; Bae, Jae-Sung

    2015-12-01

    The sympathetic nervous system (SNS) or neurotransmitters in the bone marrow microenvironment has been known to regulate hematopoietic stem cell (HSC) functions such as self-renewal, proliferation and differentiation. However, the specific role of neuropeptide Y (NPY) in this process remains relatively unexplored. In this study, we demonstrated that NPY deficient mice have significantly reduced HSC numbers and impaired bone marrow regeneration due to apoptotic destruction of SNS fibers and/or endothelial cells. Moreover, NPY treatment prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while conditional knockout mice lacking the Y1 receptor in macrophages did not restore bone marrow dysfunction in spite of NPY injection. Transforming growth factor-beta (TGF-β) secreted by NPY-mediated Y1 receptor stimulation in macrophages plays a key role in neuroprotection and HSC survival in the bone marrow. Therefore, this study reveals a new role of NPY in bone marrow HSC microenvironment, and provides an insight into the therapeutic application of this neuropeptide.

  18. LCN2 overexpression in bone enhances the hematopoietic compartment via modulation of the bone marrow microenvironment.

    PubMed

    Costa, Delfina; Principi, Elisa; Lazzarini, Edoardo; Descalzi, Fiorella; Cancedda, Ranieri; Castagnola, Patrizio; Tavella, Sara

    2017-11-01

    Lipocalin-2 (LCN2) is a member of the lipocalin family whose expression is modulated in several conditions, including cell differentiation, innate immunity, stress, and cancer. Although it is known that it is expressed in bone, its function in this tissue remains poorly studied. To this end, we took advantage of transgenic mice lines that expressed LCN2 driven by a bone specific type I collagen (LCN2-Tg). In the bone marrow (BM) of LCN2-Tg mice we observed an increased number of phenotypically long-term hematopoietic stem cells (LT-HSC) that also displayed a higher proliferation rate compared to wild-type controls (Wt). Furthermore, hematopoietic progenitor cells, obtained from LCN2-Tg BM showed an increased clonogenic capacity compared to those obtained from LCN2-Tg spleen, a higher concentration of serum erythropoietin and a higher number of mature erythrocytes in the peripheral blood of old LCN2-Tg animals compared to aged-matched wt. The findings of a combined increase in the BM of the LCN2-Tg mice of SDF-1, SCF, and TIMP-1 levels along with the reduction of both MMP-9 activity and cathepsin K concentration may explain the observed effects on the HSC compartment. This study shows that LCN2 overexpression in bones modifies the BM microenvironment via modulation of the expression of key secreted factors and cytokines, which in turn regulate the HSC niche behavior enhancing both HSC homing in young mice and erythrocytes production in older mice. © 2016 Wiley Periodicals, Inc.

  19. Modeling the Pro-inflammatory Tumor Microenvironment in Acute Lymphoblastic Leukemia Predicts a Breakdown of Hematopoietic-Mesenchymal Communication Networks

    PubMed Central

    Enciso, Jennifer; Mayani, Hector; Mendoza, Luis; Pelayo, Rosana

    2016-01-01

    Lineage fate decisions of hematopoietic cells depend on intrinsic factors and extrinsic signals provided by the bone marrow microenvironment, where they reside. Abnormalities in composition and function of hematopoietic niches have been proposed as key contributors of acute lymphoblastic leukemia (ALL) progression. Our previous experimental findings strongly suggest that pro-inflammatory cues contribute to mesenchymal niche abnormalities that result in maintenance of ALL precursor cells at the expense of normal hematopoiesis. Here, we propose a molecular regulatory network interconnecting the major communication pathways between hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs) within the BM. Dynamical analysis of the network as a Boolean model reveals two stationary states that can be interpreted as the intercellular contact status. Furthermore, simulations describe the molecular patterns observed during experimental proliferation and activation. Importantly, our model predicts instability in the CXCR4/CXCL12 and VLA4/VCAM1 interactions following microenvironmental perturbation due by temporal signaling from Toll like receptors (TLRs) ligation. Therefore, aberrant expression of NF-κB induced by intrinsic or extrinsic factors may contribute to create a tumor microenvironment where a negative feedback loop inhibiting CXCR4/CXCL12 and VLA4/VCAM1 cellular communication axes allows for the maintenance of malignant cells. PMID:27594840

  20. On the origin of hematopoietic stem cells: progress and controversy.

    PubMed

    Boisset, Jean-Charles; Robin, Catherine

    2012-01-01

    Hematopoietic Stem Cells (HSCs) are responsible for the production and replenishment of all blood cell types during the entire life of an organism. Generated during embryonic development, HSCs transit through different anatomical niches where they will expand before colonizing in the bone marrow, where they will reside during adult life. Although the existence of HSCs has been known for more than fifty years and despite extensive research performed in different animal models, there is still uncertainty with respect to the precise origins of HSCs. We review the current knowledge on embryonic hematopoiesis and highlight the remaining questions regarding the anatomical and cellular identities of HSC precursors.

  1. The embryonic origins of hematopoietic stem cells: a tale of hemangioblast and hemogenic endothelium.

    PubMed

    Bollerot, Karine; Pouget, Claire; Jaffredo, Thierry

    2005-01-01

    The developmental origin of hematopoietic stem cells has been for decades the subject of great interest. Once thought to emerge from the yolk sac, hematopoietic stem cells have now been shown to originate from the embryonic aorta. Increasing evidence suggests that hematopoietic stem cells are produced from an endothelial intermediate designated by the authors as hemangioblast or hemogenic endothelium. Recently, the allantois in the avian embryo and the placenta in the mouse embryo were shown to be a site of hematopoietic cell production/expansion and thus appear to play a critical role in the formation of the hematopoietic system. In this review we shall give an overview of the data obtained from human, mouse and avian models on the cellular origins of the hematopoietic system and discuss some aspects of the molecular mechanisms controlling hematopoietic cell production.

  2. Metabolic origins of spatial organization in the tumor microenvironment

    PubMed Central

    Carmona-Fontaine, Carlos; Akkari, Leila; Thompson, Craig B.; Joyce, Johanna A.; Xavier, Joao B.

    2017-01-01

    The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity. PMID:28246332

  3. Origin of the hematopoietic system in the human embryo.

    PubMed

    Julien, Emmanuelle; El Omar, Reine; Tavian, Manuela

    2016-11-01

    The continuous generation of blood cells throughout life relies on the existence of hematopoietic stem cells (HSC) generated during embryogenesis. Given the importance of HSC transplantation in cell-based therapeutic approaches, considerable efforts have been made toward understanding the developmental origins of embryonic HSC. Adult-type HSC are first generated in the aorta-gonad-mesonephros (AGM) region between days 27 and 40 of human embryonic development, but an elusive blood-forming potential is present earlier in the underlying splanchnopleura. It is relatively well accepted that the HSC emerge in the AGM through a hemogenic endothelium, but the direct precursor of this cell type remains to be clearly identified. This review is intended to summarize the recent advances made to understand the origins of hematopoietic stem cells in the early human embryo. In addition, we discuss in detail the discovery of the angiotensin-converting enzyme (ACE) as a novel marker of human HSC and of prehematopoietic precursors inside the embryo. © 2016 Federation of European Biochemical Societies.

  4. Expression of human bone-related proteins in the hematopoietic microenvironment.

    PubMed Central

    Long, M W; Williams, J L; Mann, K G

    1990-01-01

    Given the intimate relationship between bone and bone marrow, we hypothesized that the human bone marrow may function as a source (or reservoir) of bone-forming progenitor cells. We observed a population of cells within the bone marrow which produce bone-specific or bone-related proteins. The production of these proteins was developmentally regulated in human long-term bone marrow cell cultures; the bone protein-producing cells (BPPC) are observed under serum-free, short-term culture conditions, respond to bone-related and not hematopoietic growth factors, and are derived from a population of low-density, nonadherent, My10-negative (or low My10 density), marrow cells (My10 is an antigen found on most hematopoietic progenitor cells). Cultivation of marrow-derived BPPC in secondary, serum-containing cultures results in their differentiation into osteoblastlike cells. At this stage of development, BPPC produce an extracellular matrix which incorporates both bone-related proteins and radiolabeled calcium. Human bone marrow BPPC thus represent a newly described cell phenotype important to both bone and hematopoietic cell biology. Images PMID:2243119

  5. Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment

    PubMed Central

    Vernot, Jean-Paul; Bonilla, Ximena; Rodriguez-Pardo, Viviana; Vanegas, Natalia-Del Pilar

    2017-01-01

    An understanding of the cell interactions occurring in the leukemic microenvironment and their functional consequences for the different cell players has therapeutic relevance. By co-culturing mesenchymal stem cells (MSC) with the REH acute lymphocytic leukemia (ALL) cell line, we have established an in vitro leukemic niche for the functional evaluation of hematopoietic stem/progenitor cells (HSPC, CD34+ cells). We showed that the normal homeostatic control exerted by the MSC over the HSPC is considerably lost in this leukemic microenvironment: HSPC increased their proliferation rate and adhesion to MSC. The adhesion molecules CD54 and CD44 were consequently upregulated in HSPC from the leukemic niche. Consequently, with this adhesive phenotype, HSPC showed less Stromal derived factor-1 (SDF-1)-directed migration. Interestingly, multipotency was severely affected with an important reduction in the absolute count and the percentage of primitive progenitor colonies. It was possible to simulate most of these HSPC alterations by incubation of MSC with a REH-conditioned medium, suggesting that REH soluble factors and their effect on MSC are important for the observed changes. Of note, these HSPC alterations were reproduced when primary leukemic cells from an ALL type B (ALL-B) patient were used to set up the leukemic niche. These results suggest that a general response is induced in the leukemic niche to the detriment of HSPC function and in favor of leukemic cell support. This in vitro leukemic niche could be a valuable tool for the understanding of the molecular events responsible for HSPC functional failure and a useful scenario for therapeutic evaluation. PMID:28216566

  6. Involvement of urokinase receptor in the cross-talk between human hematopoietic stem cells and bone marrow microenvironment

    PubMed Central

    Salvati, Annamaria; Serio, Bianca; Pesapane, Ada; Ricci, Patrizia; Gorrasi, Anna; Santi, Anna Li; Hoyer-Hansen, Gunilla; Ragno, Pia

    2016-01-01

    Hematopoietic stem cells (HSCs) reside in bone marrow (BM) and can be induced to mobilize into the circulation for transplantation. Homing and lodgement into BM of transplanted HSCs are the first critical steps in their engraftment and involve multiple interactions between HSCs and the BM microenvironment. uPAR is a three domain receptor (DIDIIDIII) which binds urokinase, vitronectin, integrins. uPAR can be cleaved and shed from the cell surface generating full-length and cleaved soluble forms (suPAR and DIIDIII-suPAR). DIIDIII-suPAR can bind fMLF receptors through the SRSRY sequence (residues 88-92). We previously reported the involvement of soluble uPAR in HSC mobilization. We now investigate its possible role in HSC homing and engraftment. We show similar levels of circulating full-length suPAR in healthy donors and in acute myeloid leukemia (AML) patients before and after the pre-transplant conditioning regimen. By contrast, levels of circulating DIIDIII-suPAR in AML patients are higher as compared to controls and significantly decrease after the conditioning. We found that suPAR and uPAR84-95, a uPAR-derived peptide which mimics active DIIDIII-suPAR, induce a significant increase in Long Term Culture (LTC)-Initiating Cells (ICs) and in the release of clonogenic progenitors from LTCs of CD34+ HSCs. Further, suPAR increases adhesion and survival of CD34+ KG1 AML cells, whereas uPAR84-95 increases their proliferation. Thus, circulating DIIDIII-suPAR, strongly increased in HSC mobilization, is indeed down-regulated by pre-transplant conditioning, probably to favour HSC homing. BM full-length suPAR and DIIDIII-suPAR may be involved in HSC lodgement within the BM by contributing to a suitable microenvironment. PMID:27517491

  7. [Submicroscopic features of cells in the microenvironment of hematopoietic development of virus-induced Rauscher leukemia].

    PubMed

    Butenko, Z A; Naumenko, O I

    1993-06-01

    The study was made of submicroscopic changes in the cells of bone marrow and splenic microenvironment in mice developing virus-induced Rauscher leukemia. As shown by electron microscopy, ultrastructural cytochemistry and immunocytochemistry, ultrastructure of the complexes from the stromal and hemopoietic cells underwent noticeable alterations as early as the first days after the virus introduction. This suggests that bone marrow is the primary target of the virus in Rauscher leukemia. Affections of the macrophages, dendrite, interdigital and lymphoid cells of the spleen reflect their participation in the body defenses against the virus. Progressive shift of erythropoiesis from the bone marrow into the spleen is related to morphofunctional changes in the microenvironmental cells. The findings may be useful in consideration of cellular pathogenetic aspects of acute leukemia.

  8. Studies on the organization and regeneration of bone marrow: origin, growth, and differentiation of endocloned hematopoietic colonies

    SciTech Connect

    Lambertsen, R.H.; Weiss, L.

    1983-04-01

    Hematopoietic colonies were studied by light microscopy in the marrow of alternate fraction x-irradiated mice (C576J/B1) to investigate the microenvironmental organization of marrow and identify early hematopoietic cell-stromal cell interactions. Undifferentiated colonies (UC) were detected at 3 days postirradiation, showed a marked predilection for bone surfaces, and disappeared as differentiated colonies developed. Some UC occurred along marrow arteries. Neutrophilic granulocyte colonies (GC) occurred in all areas at 3 days but grew rapidly only subosteally. Few eosinophilic colonies (GCe) occurred. Erythrocytic colonies (EC) appeared at 4 days as dispersed populations of motile cells within a localized area of marrow; these tended to proliferate initially in intermediate and central marrow zones. Macrophage colonies (M phi C) of two ''subtypes'' were detected, peaking in relative frequency at 4 days. These appeared active in stromal repair and monocytopoiesis. Megakaryocyte colonies (MC) originated along bone and differentiated away from bone. These results were interpreted as evidence that in x-irradiated marrow: (1) hematopoietic microenvironments (HMs) for stem-cell proliferation and commitment to differentiation, with the possible exception of HMs determining erythroid differentiation, occur in endosteal and periarterial regions; (2) a proliferative and/or chemotactic stimulus to erythroid progenitors exists in intermediate and central marrow regions; and (3) some subosteal regions may exclude erythropoiesis, or preferentially support nonerythroid differentiation. Elaborate associations occurred between macrophages and early UC, GC, and EC, but not MC hematopoietic cells. UC and GC often associated with osteoclasts. Reticular and other fibroblastic cells associated with the cells of all colony types.

  9. [Origin of Hematopoietic Stem Cells in Bone Marrow--Endothelial to Hematopoietic Transition (EHT)?].

    PubMed

    Wang, Fen; Yuan, Yan; Chen, Tong

    2015-06-01

    In contrast to primitive hematopoiesis, during embryonic definitive hematopoiesis, it has been demonstrated that multilineage hematopoietic stem/progenitor cells (HSPCs) arise from hemogenic endothelium, and the endothelial to hematopoietic transition (EHT) exists within the yolk sac, placenta, AGM, mouse head vascular and extraembryonic vessels. However, whether hemogenic endothelial cells contribute to blood cell development at other sites of definitive hematopoiesis, including fetal liver and bone marrow, remains largely unknown. Recently, more and more researches showed that hematopoiesis within bone marrow had a close relationship with vascular endothelium development, too. This review summarizes the mechanism of EHT during embryo development, and discuss whether EHT exists in adult hematopoiesis.

  10. Redefining the Hematopoietic Microenvironment

    DTIC Science & Technology

    2012-10-01

    clones into a reverse orientation in the lentiviral vector to avoid splicing during retroviral packaging. While I attempted to clone this promoter...sequence in the reverse orientation using different conditions, the cloning was not successful, likely due to the toxicity of the DNA in the bacteria. I...sequences inhuman and dog were cloned , tested for the macrophage-specific expression by Luciferase assay. I am currently constructing multiple lentiviral

  11. p19INK4d Controls Hematopoietic Stem Cells in a Cell-Autonomous Manner during Genotoxic Stress and through the Microenvironment during Aging

    PubMed Central

    Hilpert, Morgane; Legrand, Céline; Bluteau, Dominique; Balayn, Natalie; Betems, Aline; Bluteau, Olivier; Villeval, Jean-Luc; Louache, Fawzia; Gonin, Patrick; Debili, Najet; Plo, Isabelle; Vainchenker, William; Gilles, Laure; Raslova, Hana

    2014-01-01

    Summary Hematopoietic stem cells (HSCs) are characterized by the capacity for self-renewal and the ability to reconstitute the entire hematopoietic compartment. Thrombopoietin maintains adult HSCs in a quiescent state through the induction of cell cycle inhibitors p57Kip2 and p19INK4d. Using the p19INK4d−/− mouse model, we investigated the role of p19INK4d in basal and stress-induced hematopoiesis. We demonstrate that p19INK4d is involved in the regulation of HSC quiescence by inhibition of the G0/G1 cell cycle transition. Under genotoxic stress conditions, the absence of p19INK4d in HSCs leads to accelerated cell cycle exit, accumulation of DNA double-strand breaks, and apoptosis when cells progress to the S/G2-M stages of the cell cycle. Moreover, p19INK4d controls the HSC microenvironment through negative regulation of megakaryopoiesis. Deletion of p19INK4d results in megakaryocyte hyperproliferation and increased transforming growth factor β1 secretion. This leads to fibrosis in the bone marrow and spleen, followed by loss of HSCs during aging. PMID:25458892

  12. Characterization of an atypical γ-secretase complex from hematopoietic origin

    PubMed Central

    Placanica, Lisa; Chien, Jennifer W.; Li, Yue-Ming

    2010-01-01

    γ-Secretase is a widely expressed multi-subunit enzyme complex which is involved in the pathogenesis of Alzheimer disease and hematopoietic malignancies through its aberrant processing of the amyloid precursor protein (APP) and Notch1, respectively. While γ-secretase has been extensively studied, there is a dearth of information surrounding the activity, composition, and function of γ-secretase expressed in distinct cellular populations. Here we show that endogenous γ-secretase complexes of hematopoietic origin are distinct from epithelial derived γ-secretase complexes. Hematopoietic γ-secretase has reduced activity for APP and Notch1 processing compared to epithelial γ-secretase. Characterization of the active complexes with small molecule affinity probes reveals that hematopoietic γ-secretase has an atypical subunit composition with significantly altered subunit stoichiometry. Furthermore, we demonstrate that these discrete complexes exhibit cell-line specific substrate selectivity suggesting a possible mechanism of substrate regulation. These data underscore the need for studying endogenous γ-secretase to fully understand of the biology of γ-secretase and its complexity as a molecular target for the development of disease therapeutics. PMID:20178366

  13. Hematopoiesis on cellulose ester membranes. XI. Induction of new bone and a hematopoietic microenvironment by matrix factors secreted by marrow stromal cells.

    PubMed

    Knospe, W H; Husseini, S G; Fried, W

    1989-07-01

    Cellulose ester membranes (CEM) were coated with stromal cells from bone marrow (BM) or bone and implanted intraperitoneally (IP) in CAF1 mice for intervals of 1 to 6 months. Previous studies indicated that matrix factors [glycoproteins (GPs), proteoglycans (PGs), and glycosaminoglycans (GAGs)] were secreted by the regenerating stromal cells and adsorbed by the CEM. After 1 to 6 months, the CEMs were removed, scraped free of adherent cells, and irradiated in vitro with 40 Gy. The scraped and irradiated CEMs were then reimplanted IP or subcutaneously (SC) for periods of 1 to 6 months in secondary syngeneic murine hosts. They were then removed for histologic study. CEMs reimplanted in SC sites developed bone and hematopoiesis as early as 1 month after implantation. Maximum hematopoiesis and bone formation was observed after 3 months. CEMs coated during the initial implantation with bone-derived stromal cells contained more bone and hematopoietic cells than did CEMs coated with marrow-derived stromal cells after SC implementation. Neither the CEMs coated with bone stromal cells nor those coated with marrow stromal cells developed new bone or trilineal hematopoiesis after being implanted IP. A few CEMs contained small foci of granulopoiesis only. We conclude that noncellular matrix substances deposited on CEMs by bone, and to a lesser degree by marrow cells, can induce prestromal cells in the SC tissues to produce a microenvironment suitable for trilineal hematopoiesis.

  14. Hematopoietic Stem Cell Origin of BRAFV600E Mutations in Hairy Cell Leukemia

    PubMed Central

    Chung, Young Rock; Lito, Piro; Teruya-Feldstein, Julie; Hu, Wenhuo; Beguelin, Wendy; Monette, Sebastien; Duy, Cihangir; Rampal, Raajit; Telis, Leon; Patel, Minal; Kim, Min Kyung; Huberman, Kety; Bouvier, Nancy; Berger, Michael F.; Melnick, Ari M.; Rosen, Neal; Tallman, Martin S.

    2014-01-01

    Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder characterized by somatic BRAFV600E mutations. The malignant cell in HCL has immunophenotypic features of a mature B cell, but no normal counterpart along the continuum of developing B lymphocytes has been delineated as the cell of origin. We find that the BRAFV600E mutation is present in hematopoietic stem cells (HSCs) in HCL patients, and that these patients exhibit marked alterations in hematopoietic stem/progenitor cell (HSPC) frequencies. Quantitative sequencing analysis revealed a mean BRAFV600E-mutant allele frequency of 4.97% in HSCs from HCL patients. Moreover, transplantation of BRAFV600E-mutant HSCs from an HCL patient into immunodeficient mice resulted in stable engraftment of BRAFV600E-mutant human hematopoietic cells, revealing the functional self-renewal capacity of HCL HSCs. Consistent with the human genetic data, expression of BRafV600E in murine HSPCs resulted in a lethal hematopoietic disorder characterized by splenomegaly, anemia, thrombocytopenia, increased circulating soluble CD25, and increased clonogenic capacity of B lineage cells—all classic features of human HCL. In contrast, restricting expression of BRafV600E to the mature B cell compartment did not result in disease. Treatment of HCL patients with vemurafenib, an inhibitor of mutated BRAF, resulted in normalization of HSPC frequencies and increased myeloid and erythroid output from HSPCs. These findings link the pathogenesis of HCL to somatic mutations that arise in HSPCs and further suggest that chronic lymphoid malignancies may be initiated by aberrant HSCs. PMID:24871132

  15. Reactive Oxygen Species Regulate Hematopoietic Stem Cell Self-Renewal, Migration and Development, As Well As Their Bone Marrow Microenvironment

    PubMed Central

    Ludin, Aya; Gur-Cohen, Shiri; Golan, Karin; Kaufmann, Kerstin B.; Itkin, Tomer; Medaglia, Chiara; Lu, Xin-Jiang; Ledergor, Guy; Kollet, Orit

    2014-01-01

    Abstract Significance: Blood forming, hematopoietic stem cells (HSCs) mostly reside in the bone marrow in a quiescent, nonmotile state via adhesion interactions with stromal cells and macrophages. Quiescent, proliferating, and differentiating stem cells have different metabolism, and accordingly different amounts of intracellular reactive oxygen species (ROS). Importantly, ROS is not just a byproduct of metabolism, but also plays a role in stem cell state and function. Recent Advances: ROS levels are dynamic and reversibly dictate enhanced cycling and myeloid bias in ROShigh short-term repopulating stem cells, and ROSlow quiescent long-term repopulating stem cells. Low levels of ROS, regulated by intrinsic factors such as cell respiration or nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity, or extrinsic factors such as stem cell factor or prostaglandin E2 are required for maintaining stem cell self-renewal. High ROS levels, due to stress and inflammation, induce stem cell differentiation and enhanced motility. Critical Issues: Stem cells need to be protected from high ROS levels to avoid stem cell exhaustion, insufficient host immunity, and leukemic transformation that may occur during chronic inflammation. However, continuous low ROS production will lead to lack of stem cell function and opportunistic infections. Ultimately, balanced ROS levels are crucial for maintaining the small stem cell pool and host immunity, both in homeostasis and during stress situations. Future Directions: Deciphering the signaling pathway of ROS in HSC will provide a better understanding of ROS roles in switching HSC from quiescence to activation and vice versa, and will also shed light on the possible roles of ROS in leukemia initiation and development. Antioxid. Redox Signal. 21, 1605–1619. PMID:24762207

  16. Restricted intra-embryonic origin of bona fide hematopoietic stem cells in the chicken.

    PubMed

    Yvernogeau, Laurent; Robin, Catherine

    2017-07-01

    Hematopoietic stem cells (HSCs), which are responsible for blood cell production, are generated during embryonic development. Human and chicken embryos share features that position the chicken as a reliable and accessible alternative model to study developmental hematopoiesis. However, the existence of HSCs has never been formally proven in chicken embryos. Here, we have established a complete cartography and quantification of hematopoietic cells in the aorta during development. We demonstrate the existence of bona fide HSCs, originating from the chicken embryo aorta (and not the yolk sac, allantois or head), through an in vivo transplantation assay. Embryos transplanted in ovo with GFP embryonic tissues on the chorio-allantoic membrane provided multilineage reconstitution in adulthood. Historically, most breakthrough discoveries in the field of developmental hematopoiesis were first made in birds and later extended to mammals. Our study sheds new light on the avian model as a valuable system to study HSC production and regulation in vivo. © 2017. Published by The Company of Biologists Ltd.

  17. Hair follicle: a reliable source of recipient origin after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Hong, Y C; Liu, H M; Chen, P S; Chen, Y J; Lyou, J Y; Hu, H Y; Yi, M F; Lin, J S; Tzeng, C-H

    2007-11-01

    Blood, buccal swab and hair follicles are among the most commonly used sources for forensic science, parentage testing and personal identification. A total of 29 patients who have had a sustained engraftment from 15 months to 21.5 years after allogeneic hematopoietic stem cell transplantation (HSCT) without rejection, relapse or chronic GVHD involving oral mucosa were enrolled for a chimerism study. PCR-amplified short tandem repeat analyses were conducted per patient every 3 months for at least three consecutive times. The results for blood were all donor type except one who had a mixed chimerism, 14.5 years after receiving a transplant for lymphoma. As for buccal swab, mixed chimerism ranging from 10 to 96% donor origin was noted for 28 recipients except the one who had mixed chimerism of blood and retained total recipient type. In contrast, hair follicles were 100% recipient type for the entire group. It is concluded that the hair follicle is devoid of adult stem cell plasticity and may serve as a reliable source of recipient's origin when pre-transplant DNA fingerprinting or reference DNA is not available for people who have successfully received allogeneic HSCT while in need of a personal identification.

  18. Endothelial cells mediate the regeneration of hematopoietic stem cells

    PubMed Central

    Li, Bei; Bailey, Alexis S.; Jiang, Shuguang; Liu, Bin; Goldman, Devorah C.; Fleming, William H.

    2010-01-01

    Recent studies suggest that endothelial cells are a critical component of the normal hematopoietic microenvironment. Therefore, we sought to determine whether primary endothelial cells have the capacity to repair damaged hematopoietic stem cells. Highly purified populations of primary CD31+ microvascular endothelial cells isolated from the brain or lung did not express the pan hematopoietic marker CD45, hematopoietic lineage markers, or the progenitor marker c-kit and did not give rise hematopoietic cells in vitro or in vivo. Remarkably, the transplantation of small numbers of these microvascular endothelial cells consistently restored hematopoiesis following bone marrow lethal doses of irradiation. Analysis of the peripheral blood of rescued recipients demonstrated that both short term and long term multilineage hematopoietic reconstitution was exclusively of host origin. Secondary transplantation studies revealed that microvascular endothelial cell-mediated hematopoietic regeneration also occurs at the level of the hematopoietic stem cell. These findings suggest a potential therapeutic role for microvascular endothelial cells in the self-renewal and repair of adult hematopoietic stem cells. PMID:19720572

  19. The role of population origin and microenvironment in seedling emergence and early survival in Mediterranean maritime pine (Pinus pinaster Aiton).

    PubMed

    Vizcaíno-Palomar, Natalia; Revuelta-Eugercios, Bárbara; Zavala, Miguel A; Alía, Ricardo; González-Martínez, Santiago C

    2014-01-01

    Understanding tree recruitment is needed to forecast future forest distribution. Many studies have reported the relevant ecological factors that affect recruitment success in trees, but the potential for genetic-based differences in recruitment has often been neglected. In this study, we established a semi-natural reciprocal sowing experiment to test for local adaptation and microenvironment effects (evaluated here by canopy cover) in the emergence and early survival of maritime pine (Pinus pinaster Aiton), an emblematic Mediterranean forest tree. A novel application of molecular markers was also developed to test for family selection and, thus, for potential genetic change over generations. Overall, we did not find evidence to support local adaptation at the recruitment stage in our semi-natural experiment. Moreover, only weak family selection (if any) was found, suggesting that in stressful environments with low survival, stochastic processes and among-year climate variability may drive recruitment. Nevertheless, our study revealed that, at early stages of recruitment, microenvironments may favor the population with the best adapted life strategy, irrespectively of its (local or non-local) origin. We also found that emergence time is a key factor for seedling survival in stressful Mediterranean environments. Our study highlights the complexity of the factors influencing the early stages of establishment of maritime pine and provides insights into possible management actions aimed at environmental change impact mitigation. In particular, we found that the high stochasticity of the recruitment process in stressful environments and the differences in population-specific adaptive strategies may difficult assisted migration schemes.

  20. Infectious hematopoietic necrosis virus: monophyletic origin of European isolates from North American genogroup M.

    PubMed

    Enzmann, P J; Kurath, G; Fichtner, D; Bergmann, S M

    2005-09-23

    Infectious hematopoietic necrosis virus (IHNV) was first detected in Europe in 1987 in France and Italy, and later, in 1992, in Germany. The source of the virus and the route of introduction are unknown. The present study investigates the molecular epidemiology of IHNV outbreaks in Germany since its first introduction. The complete nucleotide sequences of the glycoprotein (G) and non-virion (NV) genes from 9 IHNV isolates from Germany have been determined, and this has allowed the identification of characteristic differences between these isolates. Phylogenetic analysis of partial G gene sequences (mid-G, 303 nucleotides) from North American IHNV isolates (Kurath et al. 2003) has revealed 3 major genogroups, designated U, M and L. Using this gene region with 2 different North American IHNV data sets, it was possible to group the European IHNV strains within the M genogroup, but not in any previously defined subgroup. Analysis of the full length G gene sequences indicated that an independent evolution of IHN viruses had occurred in Europe. IHN viruses in Europe seem to be of a monophyletic origin, again most closely related to North American isolates in the M genogroup. Analysis of the NV gene sequences also showed the European isolates to be monophyletic, but resolution of the 3 genogroups was poor with this gene region. As a result of comparative sequence analyses, several different genotypes have been identified circulating in Europe.

  1. Infectious hematopoietic necrosis virus: Monophyletic origin of European isolates from North American Genogroup M

    USGS Publications Warehouse

    Enzmann, P.-J.; Kurath, G.; Fichtner, D.; Bergmann, S.M.

    2005-01-01

    Infectious hematopoietic necrosis virus (IHNV) was first detected in Europe in 1987 in France and Italy, and later, in 1992, in Germany. The source of the virus and the route of introduction are unknown. The present study investigates the molecular epidemiology of IHNV outbreaks in Germany since its first introduction. The complete nucleotide sequences of the glycoprotein (G) and non-virion (NV) genes from 9 IHNV isolates from Germany have been determined, and this has allowed the identification of characteristic differences between these isolates. Phylogenetic analysis of partial G gene sequences (mid-G, 303 nucleotides) from North American IHNV isolates (Kurath et al. 2003) has revealed 3 major genogroups, designated U, M and L. Using this gene region with 2 different North American IHNV data sets, it was possible to group the European IHNV strains within the M genogroup, but not in any previously defined subgroup. Analysis of the full length G gene sequences indicated that an independent evolution of IHN viruses had occurred in Europe. IHN viruses in Europe seem to be of a monophyletic origin, again most closely related to North American isolates in the M genogroup. Analysis of the NV gene sequences also showed the European isolates to be monophyletic, but resolution of the 3 genogroups was poor with this gene region. As a result of comparative sequence analyses, several different genotypes have been identified circulating in Europe. ?? Inter-Research 2005.

  2. The Role of Population Origin and Microenvironment in Seedling Emergence and Early Survival in Mediterranean Maritime Pine (Pinus pinaster Aiton)

    PubMed Central

    Vizcaíno-Palomar, Natalia; Revuelta-Eugercios, Bárbara; Zavala, Miguel A.; Alía, Ricardo; González-Martínez, Santiago C.

    2014-01-01

    Understanding tree recruitment is needed to forecast future forest distribution. Many studies have reported the relevant ecological factors that affect recruitment success in trees, but the potential for genetic-based differences in recruitment has often been neglected. In this study, we established a semi-natural reciprocal sowing experiment to test for local adaptation and microenvironment effects (evaluated here by canopy cover) in the emergence and early survival of maritime pine (Pinus pinaster Aiton), an emblematic Mediterranean forest tree. A novel application of molecular markers was also developed to test for family selection and, thus, for potential genetic change over generations. Overall, we did not find evidence to support local adaptation at the recruitment stage in our semi-natural experiment. Moreover, only weak family selection (if any) was found, suggesting that in stressful environments with low survival, stochastic processes and among-year climate variability may drive recruitment. Nevertheless, our study revealed that, at early stages of recruitment, microenvironments may favor the population with the best adapted life strategy, irrespectively of its (local or non-local) origin. We also found that emergence time is a key factor for seedling survival in stressful Mediterranean environments. Our study highlights the complexity of the factors influencing the early stages of establishment of maritime pine and provides insights into possible management actions aimed at environmental change impact mitigation. In particular, we found that the high stochasticity of the recruitment process in stressful environments and the differences in population-specific adaptive strategies may difficult assisted migration schemes. PMID:25286410

  3. Successfully-treated advanced bile duct cancer of donor origin after hematopoietic stem cell transplantation by pancreaticoduodenectomy: a case report.

    PubMed

    Haruki, Koichiro; Shiba, Hiroaki; Futagawa, Yasuro; Wakiyama, Shigeki; Misawa, Takeyuki; Yanaga, Katsuhiko

    2014-07-01

    Secondary malignancies are one of the late complications observed in long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT). However, reports on secondary non-hematopoietic solid tumors derived from donor cells is extremely rare. We herein report a successfully-treated case of advanced bile duct cancer of donor-origin after allogeneic HSCT. A 44-year-old man was diagnosed with acute myeloid leukemia. When he achieved the third complete response, allogeneic hematopoietic stem cells of one-mismatch female donor were transplanted at the age of 50 years. Post-transplant acute and chronic graft-versus-host disease was treated by increased immunosuppression. At the age of 59, the patient was diagnosed with lower bile duct cancer and underwent pancreaticoduodenectomy with lymph node dissection. Pathological findings revealed a well-differentiated adenocarcinoma of the bile duct. Additional fluorescence in situ hybridization analysis revealed female patterns of the tumor cells, which suggested that the tumor cells originated from the donor. The patient had a satisfactory recovery, and received adjuvant chemotherapy with S-1. He remains well with no evidence of tumor recurrence as of one year after resection.

  4. The bone marrow microenvironment is similarly impaired in allogeneic hematopoietic stem cell transplantation patients with early and late poor graft function.

    PubMed

    Kong, Y; Wang, Y-T; Hu, Y; Han, W; Chang, Y-J; Zhang, X-H; Jiang, Z-F; Huang, X-J

    2016-02-01

    Poor graft function (PGF), including early and late PGF, is a serious complication following allotransplant. We recently reported that bone marrow microenvironment abnormalities may occur in cases of late PGF. Whether these abnormalities occur in early PGF remains unknown. To answer this question, we performed a nested case-control study comparing cellular elements of the bone marrow microenvironment in 10 subjects with early PGF, 30 subjects with late PGF and 40 subjects without PGF. Bone marrow endosteal cells, perivascular cells and endothelial cells were analyzed by flow cytometry and by hematoxylin-eosin and immunohistochemical staining in situ. Subjects with early and late PGF had similar abnormalities in these cell types compared with transplant recipients without PGF. However, none of the aforementioned elements of the bone marrow microenvironment were significantly different between early and late PGF patients. Our data suggest that similar abnormalities in the bone marrow microenvironment may occur in early and late PGF post allotransplant. Cellular approaches, such as the administration of mesenchymal stem cells, promise to be beneficial therapeutic strategies in patients with early or late PGF.

  5. Stromal Fibroblasts in Colorectal Liver Metastases Originate From Resident Fibroblasts and Generate an Inflammatory Microenvironment

    PubMed Central

    Mueller, Lars; Goumas, Freya A.; Affeldt, Marianne; Sandtner, Susanne; Gehling, Ursula M.; Brilloff, Silke; Walter, Jessica; Karnatz, Nadia; Lamszus, Katrin; Rogiers, Xavier; Broering, Dieter C.

    2007-01-01

    Cancer-associated stromal fibroblasts (CAFs) are the main cellular constituents of reactive stroma in primary and metastatic cancer. We analyzed phenotypical characteristics of CAFs from human colorectal liver metastases (CLMs) and their role in inflammation and cancer progression. CAFs displayed a vimentin+, α-smooth-muscle actin+, and Thy-1+ phenotype similar to resident portal-located liver fibroblasts (LFs). We demonstrated that CLMs are inflammatory sites showing stromal expression of interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis. In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-α (TNF-α). The effect of TNF-α on CAFs is inhibited by the nuclear factor-κB inhibitor parthenolide. Conditioned medium of CAFs and LFs similarly stimulated the migration of DLD-1, Colo-678, HuH7 carcinoma cells, and human umbilical vein endothelial cells in vitro. Pretreatment of CAFs with TNF-α increased the chemotaxis of Colo-678 colon carcinoma cells by conditioned medium of CAFs; however, blockage of IL-8 activity showed no inhibitory effect. In conclusion, these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-α-induced up-regulation of IL-8 via nuclear factor-κB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target. PMID:17916596

  6. Epithelial Tumors Originate in Tumor Hotspots, a Tissue-Intrinsic Microenvironment

    PubMed Central

    Tamori, Yoichiro; Suzuki, Emiko; Deng, Wu-Min

    2016-01-01

    Malignant tumors are caused by uncontrolled proliferation of transformed mutant cells that have lost the ability to maintain tissue integrity. Although a number of causative genetic backgrounds for tumor development have been discovered, the initial steps mutant cells take to escape tissue integrity and trigger tumorigenesis remain elusive. Here, we show through analysis of conserved neoplastic tumor-suppressor genes (nTSGs) in Drosophila wing imaginal disc epithelia that tumor initiation depends on tissue-intrinsic local cytoarchitectures, causing tumors to consistently originate in a specific region of the tissue. In this “tumor hotspot” where cells constitute a network of robust structures on their basal side, nTSG-deficient cells delaminate from the apical side of the epithelium and begin tumorigenic overgrowth by exploiting endogenous Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling activity. Conversely, in other regions, the “tumor coldspot” nTSG-deficient cells are extruded toward the basal side and undergo apoptosis. When the direction of delamination is reversed through suppression of RhoGEF2, an activator of the Rho family small GTPases, and JAK/STAT is activated ectopically in these coldspot nTSG-deficient cells, tumorigenesis is induced. These data indicate that two independent processes, apical delamination and JAK/STAT activation, are concurrently required for the initiation of nTSG-deficient-induced tumorigenesis. Given the conservation of the epithelial cytoarchitecture, tumorigenesis may be generally initiated from tumor hotspots by a similar mechanism. PMID:27584724

  7. A Common Origin for B-1a and B-2 Lymphocytes in Clonal Pre- Hematopoietic Stem Cells.

    PubMed

    Hadland, Brandon K; Varnum-Finney, Barbara; Mandal, Pankaj K; Rossi, Derrick J; Poulos, Michael G; Butler, Jason M; Rafii, Shahin; Yoder, Mervin C; Yoshimoto, Momoko; Bernstein, Irwin D

    2017-06-06

    Recent evidence points to the embryonic emergence of some tissue-resident innate immune cells, such as B-1a lymphocytes, prior to and independently of hematopoietic stem cells (HSCs). However, whether the full hematopoietic repertoire of embryonic HSCs initially includes these unique lineages of innate immune cells has been difficult to assess due to lack of clonal assays that identify and assess HSC precursor (pre-HSC) potential. Here, by combining index sorting of single embryonic hemogenic precursors with in vitro HSC maturation and transplantation assays, we analyze emerging pre-HSCs at the single-cell level, revealing their unique stage-specific properties and clonal lineage potential. Remarkably, clonal pre-HSCs detected between E9.5 and E11.5 contribute to the complete B cell repertoire, including B-1a lymphocytes, revealing a previously unappreciated common precursor for all B cell lineages at the pre-HSC stage and a second embryonic origin for B-1a lymphocytes. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. The inflammatory microenvironment in MDS.

    PubMed

    Yang, Lili; Qian, Yaqin; Eksioglu, Erika; Epling-Burnette, Pearlie K; Wei, Sheng

    2015-05-01

    Myelodysplastic syndromes (MDS) are a collection of pre-malignancies characterized by impaired proliferation and differentiation of hematopoietic stem cells and a tendency to evolve into leukemia. Among MDS's pathogenic mechanisms are genetic, epigenetic, apoptotic, differentiation, and cytokine milieu abnormalities. Inflammatory changes are a prominent morphologic feature in some cases, with increased populations of plasma cells, mast cells, and lymphocytes in bone marrow aspirates. Accumulating evidence suggests that the bone marrow microenvironment contributes to MDS disease pathology, with microenvironment alterations and abnormality preceding, and facilitating clonal evolution in MDS patients. In this review, we focus on the inflammatory changes involved in the pathology of MDS, with an emphasis on immune dysfunction, stromal microenvironment, and cytokine imbalance in the microenvironment as well as activation of innate immune signaling in MDS patients. A better understanding of the mechanism of MDS pathophysiology will be beneficial to the development of molecular-targeted therapies in the future.

  9. Acute Myeloid Leukaemia of Donor Cell Origin Developing 17 Years after Allogenic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukaemia

    PubMed Central

    Jiménez, Pilar; Alvarez, J. Carlos; Garrido, Pilar; Lorente, J. Antonio; Palacios, Jorge; Ruiz-Cabello, Francisco

    2012-01-01

    Donor cell leukaemia (DCL) is a rare complication of allogenic hematopoietic cell transplantation (HCT). We report the case of a female patient with acute promyelocytic leukaemia (APL), FAB type M3, who developed acute myeloid leukaemia (AML) type M5 of donor origin 17 years after allogenic bone marrow transplantation (BMT) from her HLA-matched sister. Morphology and immunophenotyping showed differences with the initial leukaemia, and short tandem repeat (STR) analysis confirmed donor-type haematopoiesis. Interphase fluorescence in situ hybridisation (FISH) showed an 11q23 deletion. Given that the latency period between transplant and development of leukaemia was the longest reported to date, we discuss the mechanisms underlying delayed leukaemia onset. PMID:23675279

  10. On hematopoietic stem cell fate.

    PubMed

    Metcalf, Donald

    2007-06-01

    Multipotential hematopoietic stem cells (HSCs) maintain blood-cell formation throughout life. Here, Metcalf considers the origin and heterogeneity of HSCs, their ability to self-generate, and their commitment to the various hematopoietic lineages.

  11. [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.

  12. Targeting c-Mpl for Revival of Human Immunodeficiency Virus Type 1-Induced Hematopoietic Inhibition When CD34+ Progenitor Cells Are Re-Engrafted into a Fresh Stromal Microenvironment In Vivo

    PubMed Central

    Koka, Prasad S.; Kitchen, Christina M. R.; Reddy, Srinivasa T.

    2004-01-01

    The inhibition of multilineage hematopoiesis which occurs in the severe combined immunodeficiency mouse with transplanted human fetal thymus and liver tissues (SCID-hu Thy/Liv) due to human immunodeficiency virus type 1 (HIV-1) infection is also accompanied by a severe loss of c-Mpl expression on these progenitor cells. Inhibition of colony-forming activity (CFA) of the CD34+ progenitor cells is partially revived to about 40% of mock-infected Thy/Liv implants, following reconstitution of the CD34+ cells that were exposed to HIV-1 infection, in a new Thy/Liv stromal microenvironment of irradiated secondary SCID-hu recipients at 3 weeks post-re-engraftment. In addition, in these reconstituted animals, the proportion of c-Mpl+ CD34+ cells relative to c-Mpl− CD34+ cells increased by about 25%, to 35% of mock-infected implants, suggesting a reacquirement of c-Mpl phenotype by the c-Mpl− CD34+ cells. These results suggest a correlation between c-Mpl expression and multilineage CFA of the human CD34+ progenitor cells that have experienced the effects of HIV-1 infection. Treatment of the secondary-recipient animals with the c-Mpl ligand, thrombopoietin (Tpo), further increased c-Mpl expression and CFA of re-engrafted CD34+ cells previously exposed to virus in the primary implants to about 50 to 70% over that of those re-engrafted CD34+ cells derived from implants of untreated animals. Blocking of c-Mpl with anti-c-Mpl monoclonal antibody in vivo by injecting the SCID-hu animals resulted in the reduction or loss of CFA. Thus, inhibition, absence, or loss of c-Mpl expression as in the c-Mpl− CD34+ subset of cells is the likely cause of CFA inhibition. Further, CFA of the CD34+ cells segregates with their c-Mpl expression. Therefore, c-Mpl may play a role in hematopoietic inhibition during HIV-1 infection, and control of its expression levels may aid in hematopoietic recovery and thereby reduce the incidence of cytopenias occurring in infected individuals. PMID:15452260

  13. Targeting hypoxia in the leukemia microenvironment

    PubMed Central

    Benito, Juliana; Zeng, Zhihong; Konopleva, Marina; Wilson, William R

    2013-01-01

    SUMMARY The bone marrow (BM) microenvironment regulates survival and maintenance of normal hematopoietic stem cells. Within the endosteal niche, hypoxia has an essential role in maintenance of the primitive quiescent hematopoietic stem cell. We and others have demonstrated that in the context of hematologic malignancies the BM is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic HIF-1α. This review will provide an overview of the normal and leukemic BM microenvironment with a special emphasis on pathological hypoxia including the development of hypoxia-activated prodrugs and their applicability in hematological malignancies. PMID:24490034

  14. Formation of gullies on Mars: Link to recent climate history and insolation microenvironments implicate surface water flow origin

    PubMed Central

    Head, James W.; Marchant, David R.; Kreslavsky, Mikhail A.

    2008-01-01

    Features seen in portions of a typical midlatitude Martian impact crater show that gully formation follows a geologically recent period of midlatitude glaciation. Geological evidence indicates that, in the relatively recent past, sufficient snow and ice accumulated on the pole-facing crater wall to cause glacial flow and filling of the crater floor with debris-covered glaciers. As glaciation waned, debris-covered glaciers ceased flowing, accumulation zones lost ice, and newly exposed wall alcoves continued as the location for limited snow/frost deposition, entrapment, and preservation. Analysis of the insolation geometry of this pole-facing crater wall, and similar occurrences in other craters at these latitudes on Mars, shows that they are uniquely favored for accumulation of snow and ice, and a relatively more rapid exposure to warmer summer temperatures. We show that, after the last glaciation, melting of residual snow and ice in alcoves could have formed the fluvial channels and sedimentary fans of the gullies. Recent modeling shows that top-down melting can occur in these microenvironments under conditions similar to those currently observed on Mars, if small amounts of snow or frost accumulate in alcoves and channels. Accumulation and melting is even more favored in the somewhat wetter, relatively recent geological past of Mars, after the period of active glaciation. PMID:18725636

  15. Formation of gullies on Mars: link to recent climate history and insolation microenvironments implicate surface water flow origin.

    PubMed

    Head, James W; Marchant, David R; Kreslavsky, Mikhail A

    2008-09-09

    Features seen in portions of a typical midlatitude Martian impact crater show that gully formation follows a geologically recent period of midlatitude glaciation. Geological evidence indicates that, in the relatively recent past, sufficient snow and ice accumulated on the pole-facing crater wall to cause glacial flow and filling of the crater floor with debris-covered glaciers. As glaciation waned, debris-covered glaciers ceased flowing, accumulation zones lost ice, and newly exposed wall alcoves continued as the location for limited snow/frost deposition, entrapment, and preservation. Analysis of the insolation geometry of this pole-facing crater wall, and similar occurrences in other craters at these latitudes on Mars, shows that they are uniquely favored for accumulation of snow and ice, and a relatively more rapid exposure to warmer summer temperatures. We show that, after the last glaciation, melting of residual snow and ice in alcoves could have formed the fluvial channels and sedimentary fans of the gullies. Recent modeling shows that top-down melting can occur in these microenvironments under conditions similar to those currently observed on Mars, if small amounts of snow or frost accumulate in alcoves and channels. Accumulation and melting is even more favored in the somewhat wetter, relatively recent geological past of Mars, after the period of active glaciation.

  16. Origin of osteoclasts: Mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells

    SciTech Connect

    Udagawa, Nobuyuki; Takahashi, Naoyuki; Akatsu, Takuhiko; Tanaka, Hirofumi; Sasaki, Takahisa; Suda, Tatsuo ); Nishihara, Tatsuji; Koga, Toshihiko ); Martin, T.J. )

    1990-09-01

    The authors previously reported that osteoclast-like cells were formed in cocultures of a mouse marrow-derived stromal cell line (ST2) with mouse spleen cells in the presence of 1{alpha},25-dihydroxyvitamin D{sub 3} and dexamethasone. In this study, they developed a new coculture system to determine the origin of osteoclasts. When relatively small numbers of mononuclear cells obtained from mouse bone marrow, spleen, thymus, or peripheral blood were cultured for 12 days on the ST2 cell layers, they formed colonies with a linear relationship between the number of colonies formed and the number of hemopoietic cells inoculated. Tartrate-resistant acid phosphatase (TRAPase)-positive monoculear and multinucleated cells appeared in the colonies (TRAPase-positive colonies) in response to 1{alpha},25-dihydroxyvitamin D{sub 3} and dexamethasone. When hemopoietic cells suspended in a collagen-gel solution were cultured on the ST2 cell layers to prevent their movement, TRAPase-positive colonies were similarly formed, indicating that each colony originated from a single cell. Salmon {sup 125}I-labeled calcitonin specifically bound to the TRAPase-positive cells. Resorption lacunae were formed on dentine slices on which cocultures were performed. These results indicate that osteoclasts are also derived from the mature monocytes and macrophages when a suitable microenvironment is provided by bone marrow-derived stromal cells.

  17. Genomic sequence of infectious hypodermal and hematopoietic necrosis virus (IHHNV) KLV-2010-01 originating from the first Korean outbreak in cultured Litopenaeus vannamei.

    PubMed

    Kim, J H; Kim, H K; Nguyen, V G; Park, B K; Choresca, C H; Shin, S P; Han, J E; Jun, J W; Park, S C

    2012-02-01

    Due to the need to track and monitor genetic diversity, the genome of the infectious hypodermal and hematopoietic necrosis virus (IHHNV) strain KLV-2010-01 in cultured Litopenaeus vannamei shrimp that originated from the first Korean outbreak in 2010 was sequenced and analyzed. The genome, with a length of 3914 nucleotides, was sequenced from the Korean IHHNV. The genome encoded three large and overlapping open reading frames: ORF1 (NS-1) of 2001 bp, ORF2 (NS-2) of 1092 bp and ORF3 (capsid protein) of 990 bp. The overall organization, size and predicted amino acid sequence of the three ORFs in Korean IHHNV were highly similar to those of members of the infectious IHHNV group, and the most closely related strains were IHHNVs described from Ecuador and Hawaii. Additionally, phylogenetic analysis showed that the Korean IHHNV was clustered with lineage III in the infectious IHHNV group and was most similar to IHHNV isolates from Ecuador, China and Taiwan.

  18. Distinguishing autocrine and paracrine signals in hematopoietic stem cell culture using a biofunctional microcavity platform

    NASA Astrophysics Data System (ADS)

    Müller, Eike; Wang, Weijia; Qiao, Wenlian; Bornhäuser, Martin; Zandstra, Peter W.; Werner, Carsten; Pompe, Tilo

    2016-08-01

    Homeostasis of hematopoietic stem cells (HSC) in the mammalian bone marrow stem cell niche is regulated by signals of the local microenvironment. Besides juxtacrine, endocrine and metabolic cues, paracrine and autocrine signals are involved in controlling quiescence, proliferation and differentiation of HSC with strong implications on expansion and differentiation ex vivo as well as in vivo transplantation. Towards this aim, a cell culture analysis on a polymer microcavity carrier platform was combined with a partial least square analysis of a mechanistic model of cell proliferation. We could demonstrate the discrimination of specific autocrine and paracrine signals from soluble factors as stimulating and inhibitory effectors in hematopoietic stem and progenitor cell culture. From that we hypothesize autocrine signals to be predominantly involved in maintaining the quiescent state of HSC in single-cell niches and advocate our analysis platform as an unprecedented option for untangling convoluted signaling mechanisms in complex cell systems being it of juxtacrine, paracrine or autocrine origin.

  19. Distinguishing autocrine and paracrine signals in hematopoietic stem cell culture using a biofunctional microcavity platform

    PubMed Central

    Müller, Eike; Wang, Weijia; Qiao, Wenlian; Bornhäuser, Martin; Zandstra, Peter W.; Werner, Carsten; Pompe, Tilo

    2016-01-01

    Homeostasis of hematopoietic stem cells (HSC) in the mammalian bone marrow stem cell niche is regulated by signals of the local microenvironment. Besides juxtacrine, endocrine and metabolic cues, paracrine and autocrine signals are involved in controlling quiescence, proliferation and differentiation of HSC with strong implications on expansion and differentiation ex vivo as well as in vivo transplantation. Towards this aim, a cell culture analysis on a polymer microcavity carrier platform was combined with a partial least square analysis of a mechanistic model of cell proliferation. We could demonstrate the discrimination of specific autocrine and paracrine signals from soluble factors as stimulating and inhibitory effectors in hematopoietic stem and progenitor cell culture. From that we hypothesize autocrine signals to be predominantly involved in maintaining the quiescent state of HSC in single-cell niches and advocate our analysis platform as an unprecedented option for untangling convoluted signaling mechanisms in complex cell systems being it of juxtacrine, paracrine or autocrine origin. PMID:27535453

  20. Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment.

    PubMed

    Camacho, Virginia; McClearn, Victoria; Patel, Sweta; Welner, Robert S

    2017-05-01

    Leukemias depend on transformed stem cells for their growth and thus these cells represent important therapeutic targets. However, leukemic stem cells resemble normal hematopoietic stem cells (HSCs) with respect to most surface markers, gene expression patterns, and ability to be transplanted. Furthermore, the microenvironment that supports healthy HSCs non-hematopoietic populations, and immune cells correspondingly, the cytokines, adhesion molecules and signal transduction pathways are also impaired during leukemogenesis. This altered environment promotes leukemic growth specifically through pro-inflammatory cytokines. Here, we characterize normal and leukemic signaling, as well as the instructive cues from the neighboring hematopoietic cells and the microenvironment that promote stem cell self-renewal and differentiation.

  1. Evaluation of the efficacy and safety of original filgrastim (Neupogen®), biosimilar filgrastim (Leucostim®) and Lenograstim (Granocyte®) in CD34(+) peripheral hematopoietic stem cell mobilization procedures for allogeneic hematopoietic stem cell transplant donors.

    PubMed

    Sivgin, Serdar; Karakus, Esen; Keklik, Muzaffer; Zararsiz, Gokmen; Solmaz, Musa; Kaynar, Leylagul; Eser, Bulent; Cetin, Mustafa; Unal, Ali

    2016-06-01

    In this study, we aimed to compare the potency of different G-CSF agents including original filgrastim (Neupogen®), biosimilar filgrastim (Leucostim®) and Lenograstim (Granocyte®) on CD34(+) cell mobilization in patients that underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). The data of 243 donors for alloHSCT recipients diagnosed with mostly acute leukemia and myelodsyplastic syndromes (MDS) were analyzed, retrospectively. Data for stem cell mobilization have been recorded from patients' files. Donors who received Filgrastim (Neupogen®, Group I), biosimilar Filgrastim (Leucostim®, Group II) and Lenograstim (Granocyte®, Group III) were analyzed for total CD34(+) cell count at the end of mobilization procedures. A total of 243 donors and patients for alloHSCT were analyzed retrospectively. The diagnosis of the patients were; acute myeloid leukemia (AML) (110 patients, 45.2%), acute lymphoid leukemia (ALL) (61 patients, 25.1%), aplastic anemia (AA) (38 patients, 15.6%), lymphomas (14 patients, 5.7%) and others (20 patients, 8.4%). The median number of total collected PB CD34(+) cells (×10(6)/kg) was 7.12 (min-max: 5.38-7.90) in the Neupogen® group, 7.27 (min-max: 6.79-7.55) in the Leucostim® group and 7.15 (min-max: 5.34-7.58) in the Granocyte® group. There was no statistically significant difference among groups in terms of total collected PB CD34(+) cells (p = 0.919). The median doses of G-CSF agents (µg/kg/day) in PBSC collection in Neupogen® group was; 11.00 (10.00-12.00) in Leucostim® group10.35 (min-max: 10.00-11.10) and in Granocyte® group11.00 (min-max: 10.00-11.00). There was no statistical significance among groups (p = 0.215). Biosimilar filgrastim (Leucostim®) was found comparable to original Filgrastim (Neupogen®) and Lenograstim (Granocyte®) for PBSC mobilization in donors of the patients that underwent alloHSCT. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI

    PubMed Central

    Jin, Hao; Sood, Raman; Xu, Jin; Zhen, Fenghua; English, Milton A.; Liu, P. Paul; Wen, Zilong

    2009-01-01

    Summary One unique feature of vertebrate definitive hematopoiesis is the ontogenic switching of hematopoietic stem cells from one anatomical compartment or niche to another. In mice, hematopoietic stem cells are believed to originate in the aorta-gonad-mesonephros (AGM), subsequently migrate to the fetal liver (FL) and finally colonize the bone marrow (BM). Yet, the differentiation potential of hematopoietic stem cells within early niches such as the AGM and FL remains incompletely defined. Here, we present in vivo analysis to delineate the differentiation potential of definitive hematopoietic stem/progenitor cells (HSPCs) in the zebrafish AGM and FL analogies, namely the ventral wall of dorsal aorta (VDA) and the posterior blood island (PBI), respectively. Cell fate mapping and analysis of zebrafish runx1w84x and vlad tepes (vltm651) mutants revealed that HSPCs in the PBI gave rise to both erythroid and myeloid lineages. However, we surprisingly found that HSPCs in the VDA were not quiescent but were uniquely adapted to generate myeloid but not erythroid lineage cells. We further showed that such distinct differentiation output of HSPCs was, at least in part, ascribed to the different micro-environments present in these two niches. Our results highlight the importance of niche in shaping the differentiation output of developing HSPCs. PMID:19168679

  3. Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI.

    PubMed

    Jin, Hao; Sood, Raman; Xu, Jin; Zhen, Fenghua; English, Milton A; Liu, P Paul; Wen, Zilong

    2009-02-01

    One unique feature of vertebrate definitive hematopoiesis is the ontogenic switching of hematopoietic stem cells from one anatomical compartment or niche to another. In mice, hematopoietic stem cells are believed to originate in the aorta-gonad-mesonephros (AGM), subsequently migrate to the fetal liver (FL) and finally colonize the bone marrow (BM). Yet, the differentiation potential of hematopoietic stem cells within early niches such as the AGM and FL remains incompletely defined. Here, we present in vivo analysis to delineate the differentiation potential of definitive hematopoietic stem/progenitor cells (HSPCs) in the zebrafish AGM and FL analogies, namely the ventral wall of dorsal aorta (VDA) and the posterior blood island (PBI), respectively. Cell fate mapping and analysis of zebrafish runx1(w84x) and vlad tepes (vlt(m651)) mutants revealed that HSPCs in the PBI gave rise to both erythroid and myeloid lineages. However, we surprisingly found that HSPCs in the VDA were not quiescent but were uniquely adapted to generate myeloid but not erythroid lineage cells. We further showed that such distinct differentiation output of HSPCs was, at least in part, ascribed to the different micro-environments present in these two niches. Our results highlight the importance of niche in shaping the differentiation output of developing HSPCs.

  4. Hematopoietic cytokines.

    PubMed

    Metcalf, Donald

    2008-01-15

    The production of hematopoietic cells is under the tight control of a group of hematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating the various responses-survival, proliferation, differentiation commitment, maturation, and functional activation. Individual cytokines can be lineage specific or can regulate cells in multiple lineages, and for some cell types, such as stem cells or megakaryocyte progenitors, the simultaneous action of multiple cytokines is required for proliferative responses. The same cytokines control basal and emergency hematopoietic cell proliferation. Three cytokines, erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, have now been in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. In this little review, discussion will be restricted to those cytokines well established as influencing the production of hematopoietic cells and will exclude newer candidate regulators and those active on lymphoid cells. As requested, this account will describe the cytokines in a historical manner, using a sequential format of discovery, understanding, validation, and puzzlement, a sequence that reflects the evolving views on these cytokines over the past 50 years.

  5. ADVANCES IN UNDERSTANDING THE LEUKEMIA MICROENVIRONMENT

    PubMed Central

    Tabe, Yoko; Konopleva, Marina

    2015-01-01

    SUMMARY Dynamic interactions between leukemic cells and cells of the bone marrow are a feature of hematological malignancies. Two distinct microenvironmental niches in the bone marrow, the “osteoblastic (endosteal)” and “vascular” niches, provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistance. Key components of the bone marrow microenvironment as a home for normal hematopoietic stem cells and the leukemia stem cell niches, and the molecular pathways critical for microenvironment/leukemia interactions via cytokines, chemokines, and adhesion molecules as well as hypoxic conditions, are described in this review. Finally, the genetic abnormalities of leukemia-associated stroma are discussed. Further understanding of the contribution of the bone marrow niche to the process of leukemogenesis may provide new targets that allow destruction of leukemia stem cells without adversely affecting normal stem cell self-renewal. PMID:24405087

  6. Lymphoma Microenvironment and Immunotherapy.

    PubMed

    Xu, Mina L; Fedoriw, Yuri

    2016-03-01

    Understanding of the lymphoma tumor microenvironment is poised to expand in the era of next-generation sequencing studies of the tumor cells themselves. Successful therapies of the future will rely on deeper appreciation of the interactions between elements of the microenvironment. Although the phenotypic, cytogenetic, and molecular characterization of tumor cells in lymphomas has progressed faster than most other solid organ tumors, concrete advancements in understanding the lymphoma microenvironment have been fewer. This article explores the composition of the lymphoma tumor microenvironment; its role in immune surveillance, evasion, and drug resistance; and its potential role in the development of targeted therapies. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Comparison of transplant outcomes and economic costs between biosimilar and originator filgrastim in allogeneic hematopoietic stem cell transplantation.

    PubMed

    Harada, Kaito; Yamada, Yuta; Konishi, Tatsuya; Nagata, Akihito; Takezaki, Toshiaki; Kaito, Satoshi; Kurosawa, Shuhei; Sakaguchi, Masahiro; Yasuda, Shunichiro; Yoshioka, Kosuke; Watakabe-Inamoto, Kyoko; Igarashi, Aiko; Najima, Yuho; Hagino, Takeshi; Muto, Hideharu; Kobayashi, Takeshi; Doki, Noriko; Kakihana, Kazuhiko; Sakamaki, Hisashi; Ohashi, Kazuteru

    2016-12-01

    From January 2012 to September 2015, 49 patients received biosimilar filgrastim (BF) after allogeneic bone marrow transplantation (BMT, n = 31) or peripheral stem cell transplantation (PBSCT, n = 18) in our institution. To evaluate the clinical impact of BF on transplant outcomes of these patients, we compared hematological recovery, overall survival (OS), disease-free survival (DFS), transplantation-related mortality (TRM), cumulative incidence of relapse (CIR), and acute and chronic graft-versus-host disease (GVHD) with those of control patients who received originator filgrastim (OF) after BMT (n = 31) or PBSCT (n = 18). All cases were randomly selected from a clinical database in our institution. In both the BMT and PBSCT settings, neutrophil recovery (17 vs. 19 days in BMT; 13 vs. 15 days in PBSCT) and platelet recovery (27 vs. 31 days in BMT; 17 vs. 28 days in PBSCT) were essentially the same between BF and OF. They were also comparable in terms of OS, DFS, TRM, CIR, and the incidence of acute GVHD and chronic GVHD. On multivariate analysis, the use of BF in both BMT and PBSCT was not a significant factor for adverse transplant outcomes. Although BF significantly reduced filgrastim costs in both BMT and PBSCT, total hospitalization costs were not significantly different between BF and OF.

  8. The role of CD44 in fetal and adult hematopoietic stem cell regulation.

    PubMed

    Cao, Huimin; Heazlewood, Shen Y; Williams, Brenda; Cardozo, Daniela; Nigro, Julie; Oteiza, Ana; Nilsson, Susan K

    2016-01-01

    Throughout development, hematopoietic stem cells migrate to specific microenvironments, where their fate is, in part, extrinsically controlled. CD44 standard as a member of the cell adhesion molecule family is extensively expressed within adult bone marrow and has been previously reported to play important roles in adult hematopoietic regulation via CD44 standard-ligand interactions. In this manuscript, CD44 expression and function are further assessed and characterized on both fetal and adult hematopoietic stem cells. Using a CD44(-/-) mouse model, conserved functional roles of CD44 are revealed throughout development. CD44 is critical in the maintenance of hematopoietic stem and progenitor pools, as well as in hematopoietic stem cell migration. CD44 expression on hematopoietic stem cells as well as other hematopoietic cells within the bone marrow microenvironment is important in the homing and lodgment of adult hematopoietic stem cells isolated from the bone/bone marrow interface. CD44 is also involved in fetal hematopoietic stem cell migration out of the liver, via a process involving stromal cell-derived factor-1α. The absence of CD44 in neonatal bone marrow has no impact on the size of the long-term reconstituting hematopoietic stem cell pool, but results in an enhanced long-term engraftment potential of hematopoietic stem cells.

  9. The role of CD44 in fetal and adult hematopoietic stem cell regulation

    PubMed Central

    Cao, Huimin; Heazlewood, Shen Y.; Williams, Brenda; Cardozo, Daniela; Nigro, Julie; Oteiza, Ana; Nilsson, Susan K.

    2016-01-01

    Throughout development, hematopoietic stem cells migrate to specific microenvironments, where their fate is, in part, extrinsically controlled. CD44 standard as a member of the cell adhesion molecule family is extensively expressed within adult bone marrow and has been previously reported to play important roles in adult hematopoietic regulation via CD44 standard-ligand interactions. In this manuscript, CD44 expression and function are further assessed and characterized on both fetal and adult hematopoietic stem cells. Using a CD44−/− mouse model, conserved functional roles of CD44 are revealed throughout development. CD44 is critical in the maintenance of hematopoietic stem and progenitor pools, as well as in hematopoietic stem cell migration. CD44 expression on hematopoietic stem cells as well as other hematopoietic cells within the bone marrow microenvironment is important in the homing and lodgment of adult hematopoietic stem cells isolated from the bone/bone marrow interface. CD44 is also involved in fetal hematopoietic stem cell migration out of the liver, via a process involving stromal cell-derived factor-1α. The absence of CD44 in neonatal bone marrow has no impact on the size of the long-term reconstituting hematopoietic stem cell pool, but results in an enhanced long-term engraftment potential of hematopoietic stem cells. PMID:26546504

  10. The CLL cell microenvironment.

    PubMed

    Burger, Jan A

    2013-01-01

    Cross talk between CLL cells and accessory stromal cells in specialized tissue microenvironments, such as the secondary lymphoid organs, favors CLL progression by promoting malignant B cell growth and drug resistance. Disrupting the cross talk between CLL cells and their milieu is an attractive, novel strategy for treating CLL patients. This chapter summarizes current knowledge about cellular and molecular interactions between CLL cells and their supportive tissue microenvironment and the therapeutic targets that are emerging, focusing on the CXCR4-CXCL12 axis and small molecule inhibitors that are targeting the B cell receptor-associated kinases SYK, BTK, and PI3Kδ. Clinically relevant aspects of these new therapeutics will be discussed, along with an outlook into future biologically oriented therapeutic strategies. The rapid progress in dissecting the CLL microenvironment and the promising early results of these new targeted treatments in CLL indicate that CLL has become a role model for microenvironment-dependent cancers.

  11. Leukemia microvesicles affect healthy hematopoietic stem cells.

    PubMed

    Razmkhah, Farnaz; Soleimani, Masoud; Mehrabani, Davood; Karimi, Mohammad Hossein; Amini Kafi-Abad, Sedigheh; Ramzi, Mani; Iravani Saadi, Mahdiyar; Kakoui, Javad

    2017-02-01

    Microvesicles are released by different cell types and shuttle mRNAs and microRNAs which have the possibility to transfer genetic information to a target cell and alter its function. Acute myeloid leukemia is a malignant disorder, and leukemic cells occupy all the bone marrow microenvironment. In this study, we investigate the effect of leukemia microvesicles on healthy umbilical cord blood hematopoietic stem cells to find evidence of cell information transferring. Leukemia microvesicles were isolated from acute myeloid leukemia patients and were co-incubated with healthy hematopoietic stem cells. After 7 days, cell count, hematopoietic stem cell-specific cluster of differentiation (CD) markers, colony-forming unit assay, and some microRNA gene expressions were assessed. Data showed a higher number of hematopoietic stem cells after being treated with leukemia microvesicles compared with control (treated with no microvesicles) and normal (treated with normal microvesicles) groups. Also, increased levels of microRNA-21 and microRNA-29a genes were observed in this group, while colony-forming ability was still maintained and high ranges of CD34(+), CD34(+)CD38(-), CD90(+), and CD117(+) phenotypes were observed as stemness signs. Our results suggest that leukemia microvesicles are able to induce some effects on healthy hematopoietic stem cells such as promoting cell survival and some microRNAs deregulation, while stemness is maintained.

  12. The mesenchymal tumor microenvironment

    PubMed Central

    Cukierman, Edna; Bassi, Daniel E.

    2012-01-01

    Drug and radiation resistance represent a challenge for most anticancer therapies. Diverse experimental approaches have provided evidence that the tumor-associated microenvironment constitutes both a protective shell that impedes drug or radiation access and a permissive or promotive microenvironment that encourages a nurturing cancer (i.e., cancer stem cell) niche where tumor cells overcome treatment- and cancer-induced stresses. Better understanding of the effects of the tumor microenvironment on cancer cells before, during and immediately after chemo- or radiotherapy is imperative to design new therapies aimed at targeting this tumor-protective niche. This review summarizes some of the known mesenchymal stromal effects that account for drug resistance, the main signal transduction pathways associated with this resistance and the therapeutic efforts directed to increase the success of current therapies. Special emphasis is given to environment-mediated drug resistance in general and to cell adhesion-mediated drug resistance in particular. PMID:22568991

  13. The Role of Toll-Like Receptors in Hematopoietic Malignancies

    PubMed Central

    Monlish, Darlene A.; Bhatt, Sima T.; Schuettpelz, Laura G.

    2016-01-01

    Toll-like receptors (TLRs) are a family of pattern recognition receptors that shape the innate immune system by identifying pathogen-associated molecular patterns and host-derived damage-associated molecular patterns. TLRs are widely expressed on both immune cells and non-immune cells, including hematopoietic stem and progenitor cells, effector immune cell populations, and endothelial cells. In addition to their well-known role in the innate immune response to acute infection or injury, accumulating evidence supports a role for TLRs in the development of hematopoietic and other malignancies. Several hematopoietic disorders, including lymphoproliferative disorders and myelodysplastic syndromes, which possess a high risk of transformation to leukemia, have been linked to aberrant TLR signaling. Furthermore, activation of TLRs leads to the induction of a number of proinflammatory cytokines and chemokines, which can promote tumorigenesis by driving cell proliferation and migration and providing a favorable microenvironment for tumor cells. Beyond hematopoietic malignancies, the upregulation of a number of TLRs has been linked to promoting tumor cell survival, proliferation, and metastasis in a variety of cancers, including those of the colon, breast, and lung. This review focuses on the contribution of TLRs to hematopoietic malignancies, highlighting the known direct and indirect effects of TLR signaling on tumor cells and their microenvironment. In addition, the utility of TLR agonists and antagonists as potential therapeutics in the treatment of hematopoietic malignancies is discussed. PMID:27733853

  14. Bone microenvironment signals in osteosarcoma development.

    PubMed

    Alfranca, Arantzazu; Martinez-Cruzado, Lucia; Tornin, Juan; Abarrategi, Ander; Amaral, Teresa; de Alava, Enrique; Menendez, Pablo; Garcia-Castro, Javier; Rodriguez, Rene

    2015-08-01

    The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is finely balanced through the processes of bone formation and bone remodeling, which regulates the production and biological activity of many soluble factors and extracellular matrix components needed to maintain the bone homeostasis in terms of cell proliferation, differentiation and apoptosis. Osteosarcoma (OS) emerges in this complex environment as a result of poorly defined oncogenic events arising in osteogenic lineage precursors. Increasing evidence supports that similar to normal development, the bone microenvironment (BME) underlies OS initiation and progression. Here, we recapitulate the physiological processes that regulate bone homeostasis and review the current knowledge about how OS cells and BME communicate and interact, describing how these interactions affect OS cell growth, metastasis, cancer stem cell fate and therapy outcome.

  15. Immunotherapeutic modulation of the suppressive liver and tumor microenvironments

    PubMed Central

    Chan, Tim; Wiltrout, Robert H.; Weiss, Jonathan M.

    2011-01-01

    The liver is an immunologically unique organ, consisting of resident hematopoietic and parenchymal cells which often contribute to a relatively tolerant microenvironment. It is also becoming increasingly clear that tumor-induced immunosuppression occurs via many of the same cellular mechanisms which contribute to the tolerogenic liver microenvironment. Myeloid cells, consisting of dendritic cells (DC), macrophages and myeloid-derived suppressor cells (MDSC), have been implicated in providing a tolerogenic liver environment and immune dysfunction within the tumor microenvironment which can favor tumor progression. As we increase our understanding of the biological mechanisms involved for each phenotypic and/or functionally distinct leukocyte subset, immunotherapeutic strategies can be developed to overcome the inherent barriers to the development of improved strategies for the treatment of liver disease and tumors. In this review, we discuss the principal myeloid cell-based contributions to immunosuppression that are shared between the liver and tumor microenvironments. We further highlight immune-based strategies shown to modulate immunoregulatory cells within each microenvironment and enhance anti-tumor responses. PMID:21241810

  16. Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation.

    PubMed

    Reddehase, Matthias J

    2016-01-01

    Hematopoietic cell transplantation (HCT) is a therapy option for aggressive forms of hematopoietic malignancies that are resistant to standard antitumoral therapies. Hematoablative treatment preceding HCT, however, opens a "window of opportunity" for latent Cytomegalovirus (CMV) by releasing it from immune control with the consequence of reactivation of productive viral gene expression and recurrence of infectious virus. A "window of opportunity" for the virus represents a "window of risk" for the patient. In the interim between HCT and reconstitution of antiviral immunity, primarily mediated by CD8(+) T cells, initially low amounts of reactivated virus can expand exponentially, disseminate to essentially all organs, and cause multiple organ CMV disease, with interstitial pneumonia (CMV-IP) representing the most severe clinical manifestation. Here, I will review predictions originally made in the mouse model of experimental HCT and murine CMV infection, some of which have already paved the way to translational preclinical research and promising clinical trials of a preemptive cytoimmunotherapy of human CMV disease. Specifically, the mouse model has been pivotal in providing "proof of concept" for preventing CMV disease after HCT by adoptive transfer of preselected, virus epitope-specific effector and memory CD8(+) T cells bridging the critical interim. However, CMV is not a "passive antigen" but is a pathogen that actively interferes with the reconstitution of protective immunity by infecting bone marrow (BM) stromal cells that otherwise form niches for hematopoiesis by providing the structural microenvironment and by producing hematopoietically active cytokines, the hemopoietins. Depending on the precise conditions of HCT, reduced homing of transplanted hematopoietic stem- and progenitor cells to infected BM stroma and impaired colony growth and lineage differentiation can lead to "graft failure." In consequence, uncontrolled virus spread causes morbidity and

  17. Human Olfactory Mucosa Multipotent Mesenchymal Stromal Cells Promote Survival, Proliferation, and Differentiation of Human Hematopoietic Cells

    PubMed Central

    Diaz-Solano, Dylana; Wittig, Olga; Ayala-Grosso, Carlos; Pieruzzini, Rosalinda

    2012-01-01

    Multipotent mesenchymal stromal cells (MSCs) from the human olfactory mucosa (OM) are cells that have been proposed as a niche for neural progenitors. OM-MSCs share phenotypic and functional properties with bone marrow (BM) MSCs, which constitute fundamental components of the hematopoietic niche. In this work, we investigated whether human OM-MSCs may promote the survival, proliferation, and differentiation of human hematopoietic stem cells (HSCs). For this purpose, human bone marrow cells (BMCs) were co-cultured with OM-MSCs in the absence of exogenous cytokines. At different intervals, nonadherent cells (NACs) were harvested from BMC/OM-MSC co-cultures, and examined for the expression of blood cell markers by flow cytometry. OM-MSCs supported the survival (cell viability >90%) and proliferation of BMCs, after 54 days of co-culture. At 20 days of co-culture, flow cytometric and microscopic analyses showed a high percentage (73%) of cells expressing the pan-leukocyte marker CD45, and the presence of cells of myeloid origin, including polymorphonuclear leukocytes, monocytes, basophils, eosinophils, erythroid cells, and megakaryocytes. Likewise, T (CD3), B (CD19), and NK (CD56/CD16) cells were detected in the NAC fraction. Colony-forming unit–granulocyte/macrophage (CFU-GM) progenitors and CD34+ cells were found, at 43 days of co-culture. Reverse transcriptase–polymerase chain reaction (RT-PCR) studies showed that OM-MSCs constitutively express early and late-acting hematopoietic cytokines (i.e., stem cell factor [SCF] and granulocyte- macrophage colony-stimulating factor [GM-CSF]). These results constitute the first evidence that OM-MSCs may provide an in vitro microenvironment for HSCs. The capacity of OM-MSCs to support the survival and differentiation of HSCs may be related with the capacity of OM-MSCs to produce hematopoietic cytokines. PMID:22471939

  18. Cancer Cell Colonisation in the Bone Microenvironment

    PubMed Central

    Kan, Casina; Vargas, Geoffrey; Le Pape, François; Clézardin, Philippe

    2016-01-01

    Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow epithelial-to-mesenchymal transition, extravasation and migration. Within the bone metastatic niche, disseminated tumour cells may enter a dormancy stage or proliferate to adapt and survive, interacting with bone cells such as hematopoietic stem cells, osteoblasts and osteoclasts. Cross-talk with the bone may alter tumour cell properties and, conversely, tumour cells may also acquire characteristics of the surrounding microenvironment, in a process known as osteomimicry. Alternatively, these cells may also express osteomimetic genes that allow cell survival or favour seeding to the bone marrow. The seeding of tumour cells in the bone disrupts bone-forming and bone-resorbing activities, which can lead to macrometastasis in bone. At present, bone macrometastases are incurable with only palliative treatment available. A better understanding of how these processes influence the early onset of bone metastasis may give insight into potential therapies. This review will focus on the early steps of bone colonisation, once disseminated tumour cells enter the bone marrow. PMID:27782035

  19. Hematopoietic stem cell fate decisions are regulated by Wnt antagonists: comparisons and current controversies.

    PubMed

    Cain, Corey J; Manilay, Jennifer O

    2013-01-01

    Wingless and int (Wnt) proteins are secreted proteins that are important for regulating hematopoietic stem cell self-renewal and differentiation in the bone marrow microenvironment in mice. The mechanisms by which Wnt signaling regulates these hematopoietic cell fate decisions are not fully understood. Secreted Wnt antagonists, which are expressed in bone and bone marrow stromal cells, either bind to Wnt ligands directly or block Wnt receptors and co-receptors to halt Wnt-mediated signal transduction in both osteolineage and hematopoietic cell types. Secreted frizzled related proteins-1 and -2, Wnt inhibitory factor-1, Dickkopf-1, and Sclerostin are Wnt antagonists that influence hematopoietic cell fate decisions in the bone marrow niche. In this review, we compare and contrast the roles of these Wnt antagonists and their effects on hematopoietic development in mice, and also discuss the clinical significance of targeting Wnt antagonists within the context of hematopoietic disease.

  20. 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

  1. Cell cycle regulation in hematopoietic stem cells.

    PubMed

    Pietras, Eric M; Warr, Matthew R; Passegué, Emmanuelle

    2011-11-28

    Hematopoietic stem cells (HSCs) give rise to all lineages of blood cells. Because HSCs must persist for a lifetime, the balance between their proliferation and quiescence is carefully regulated to ensure blood homeostasis while limiting cellular damage. Cell cycle regulation therefore plays a critical role in controlling HSC function during both fetal life and in the adult. The cell cycle activity of HSCs is carefully modulated by a complex interplay between cell-intrinsic mechanisms and cell-extrinsic factors produced by the microenvironment. This fine-tuned regulatory network may become altered with age, leading to aberrant HSC cell cycle regulation, degraded HSC function, and hematological malignancy.

  2. Crystalline calcium carbonate and hydrogels as microenvironment for stem cells.

    PubMed

    Astachov, Liliana; Nevo, Zvi; Aviv, Moran; Vago, Razi

    2011-01-01

    Stem cell development and fate decisions are dictated by the microenvironment in which the stem cell is embedded. Among the advanced goals of tissue engineering is the creation of a microenvironment that will support the maintenance and differentiation of the stem cell--based on embryonic and adult stem cells as potent, cellular sources--for a variety of clinical applications. This review discusses some of the approaches used to create regulatory and instructive microenvironments for the directed differentiation of mesenchymal stem cells (MSCs) using three-dimensional crystalline calcium carbonate biomaterials of marine origin combined with a hydrated gel based on hyaluronan.

  3. Integrating the glioblastoma microenvironment into engineered experimental models

    PubMed Central

    Xiao, Weikun; Sohrabi, Alireza; Seidlits, Stephanie K

    2017-01-01

    Glioblastoma (GBM) is the most lethal cancer originating in the brain. Its high mortality rate has been attributed to therapeutic resistance and rapid, diffuse invasion – both of which are strongly influenced by the unique microenvironment. Thus, there is a need to develop new models that mimic individual microenvironmental features and are able to provide clinically relevant data. Current understanding of the effects of the microenvironment on GBM progression, established experimental models of GBM and recent developments using bioengineered microenvironments as ex vivo experimental platforms that mimic the biochemical and physical properties of GBM tumors are discussed. PMID:28883992

  4. Targeting the tumor microenvironment

    PubMed Central

    Bournazou, Eirini; Bromberg, Jacqueline

    2013-01-01

    Persistent JAK-STAT3 signaling is implicated in many aspects of tumorigenesis. Apart from its tumor-intrinsic effects, STAT3 also exerts tumor-extrinsic effects, supporting tumor survival and metastasis. These involve the regulation of paracrine cytokine signaling, alterations in metastatic sites rendering these permissive for the growth of cancer cells and subversion of host immune responses to create an immunosuppressive environment. Targeting this signaling pathway is considered a novel promising therapeutic approach, especially in the context of tumor immunity. In this article, we will review to what extent JAK-STAT3-targeted therapies affect the tumor microenvironment and whether the observed effects underlie responsiveness to therapy. PMID:24058812

  5. Targeting the tumor microenvironment

    SciTech Connect

    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

    2006-11-07

    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  6. The microenvironment matters

    PubMed Central

    Weaver, Valerie Marie

    2014-01-01

    The physical and biochemical properties of the microenvironment regulate cell behavior and modulate tissue development and homeostasis. Likewise, the physical and interpersonal cues a trainee receives profoundly influence his or her scientific development, research perspective, and future success. My cell biology career has been greatly impacted by the flavor of the scientific environments I have trained within and the diverse research mentoring I have received. Interactions with physical and life scientists and trainees and exposure to a diverse assortment of interdisciplinary environments have and continue to shape my research vision, guide my experimental trajectory, and contribute to my scientific success and personal happiness. PMID:25360044

  7. Optical imaging of tumor microenvironment

    PubMed Central

    Wu, Yihan; Zhang, Wenjie; Li, Jinbo; Zhang, Yan

    2013-01-01

    Tumor microenvironment plays important roles in tumor development and metastasis. Features of the tumor microenvironment that are significantly different from normal tissues include acidity, hypoxia, overexpressed proteases and so on. Therefore, these features can serve as not only biomarkers for tumor diagnosis but also theraputic targets for tumor treatment. Imaging modalities such as optical, positron emission tomography (PET) and magnetic resonance imaging (MRI) have been intensively applied to investigate tumor microenvironment. Various imaging probes targeting pH, hypoxia and proteases in tumor microenvironment were thus well developed. In this review, we will focus on recent examples on fluorescent probes for optical imaging of tumor microenvironment. Construction of these fluorescent probes were based on characteristic feature of pH, hypoxia and proteases in tumor microenvironment. Strategies for development of these fluorescent probes and applications of these probes in optical imaging of tumor cells or tissues will be discussed in this review paper. PMID:23342297

  8. Sympathetic nervous system regulation of the tumour microenvironment

    PubMed Central

    Cole, Steven W.; Nagaraja, Archana S.; Lutgendorf, Susan K.; Green, Paige A.; Sood, Anil K.

    2016-01-01

    The peripheral autonomic nervous system (ANS) is known to regulate gene expression in primary tumours and their surrounding microenvironment. Activation of the sympathetic division of the ANS in particular modulates gene expression programs that promote metastasis of solid tumours by stimulating macrophage infiltration, inflammation, angiogenesis, epithelial-mesenchymal transition, and tumour invasion, and by inhibiting cellular immune responses and programmed cell death. Haematological cancers are modulated by sympathetic nervous system (SNS) regulation of stem cell biology and hematopoietic differentiation programs. In addition to identifying a molecular basis for physiologic stress effects on cancer, these findings have also identified new pharmacologic strategies to inhibit cancer progression in vivo. PMID:26299593

  9. Microenvironment and Radiation Therapy

    PubMed Central

    Yoshimura, Michio; Itasaka, Satoshi; Harada, Hiroshi; Hiraoka, Masahiro

    2013-01-01

    Dependency on tumor oxygenation is one of the major features of radiation therapy and this has led many radiation biologists and oncologists to focus on tumor hypoxia. The first approach to overcome tumor hypoxia was to improve tumor oxygenation by increasing oxygen delivery and a subsequent approach was the use of radiosensitizers in combination with radiation therapy. Clinical use of some of these approaches was promising, but they are not widely used due to several limitations. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is activated by hypoxia and induces the expression of various genes related to the adaptation of cellular metabolism to hypoxia, invasion and metastasis of cancer cells and angiogenesis, and so forth. HIF-1 is a potent target to enhance the therapeutic effects of radiation therapy. Another approach is antiangiogenic therapy. The combination with radiation therapy is promising, but several factors including surrogate markers, timing and duration, and so forth have to be optimized before introducing it into clinics. In this review, we examined how the tumor microenvironment influences the effects of radiation and how we can enhance the antitumor effects of radiation therapy by modifying the tumor microenvironment. PMID:23509762

  10. Reprogramming Human Endothelial to Hematopoietic Cells Requires Vascular Induction

    PubMed Central

    Sandler, Vladislav M.; Lis, Raphael; Liu, Ying; Kedem, Alon; James, Daylon; Elemento, Olivier; Butler, Jason M.; Scandura, Joseph M.; Rafii, Shahin

    2014-01-01

    Summary Generating engraftable human hematopoietic cells from autologous tissues promises new therapies for blood diseases. Directed differentiation of pluripotent stem cells yields hematopoietic cells that poorly engraft. Here, we devised a method to phenocopy the vascular-niche microenvironment of hemogenic cells, thereby enabling reprogramming of human endothelial cells (ECs) into engraftable hematopoietic cells without transition through a pluripotent intermediate. Highly purified non-hemogenic human umbilical vein-ECs (HUVECs) or adult dermal microvascular ECs (hDMECs) were transduced with transcription factors (TFs), FOSB, GFI1, RUNX1, and SPI1 (FGRS), and then propagated on serum-free instructive vascular niche monolayers to induce outgrowth of hematopoietic colonies containing cells with functional and immunophenotypic features of multipotent progenitor cells (MPP). These reprogrammed ECs- into human-MPPs (rEC-hMPPs) acquire colony-forming cell (CFC) potential and durably engraft in immune-deficient mice after primary and secondary transplantation, producing long-term rEC-hMPP-derived myeloid (granulocytic/monocytic, erythroid, megakaryocytic) and lymphoid (NK, B) progeny. Conditional expression of FGRS transgenes, combined with vascular-induction, activates endogenous FGRS genes endowing rEC-hMPPs with a transcriptional and functional profile similar to self-renewing MPPs. Our approach underscores the role of inductive cues from vascular-niche in orchestrating and sustaining hematopoietic specification and may prove useful for engineering autologous hematopoietic grafts to treat inherited and acquired blood disorders. PMID:25030167

  11. The Role of the Bone Marrow Stromal Compartment in the Hematopoietic Response to Microbial Infections

    PubMed Central

    Nombela-Arrieta, César; Isringhausen, Stephan

    2017-01-01

    Continuous production of blood cells unfolds within a complex three-dimensional tissue scaffold established by highly organized stromal cell networks of mesenchymal, neural, and vascular origin inside bone marrow (BM) cavities. Collectively, stromal cells have been shown to serve two principal roles; first as primary participants of bone remodeling and metabolism and second as master regulators of different stages of blood cell development and production. Indeed, ample evidence demonstrates that stromal cells can sense and integrate systemic signals to shape hematopoietic responses and that these regulatory mechanisms are subverted in multiple pathologic conditions. Microbial infections are stressors that elicit potent inflammatory reactions and induce substantial alterations of hematopoietic output. Whether the cellular components of the BM stromal microenvironment are targeted by infections and participate in infection-induced hematopoiesis has not been investigated in sufficient detail to date. In this manuscript, we provide a succinct updated overview of the different cell populations that are currently known to form BM stroma. We discuss experimental evidence demonstrating that different stromal components are actively damaged or functionally altered by pathogens and/or ensuing inflammatory signals and review how these effects are known to contribute to the hematologic manifestations observed during infections. PMID:28163704

  12. The effect of environmental chemicals on the tumor microenvironment

    PubMed Central

    Casey, Stephanie C.; Vaccari, Monica; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Barcellos-Hoff, Mary Helen; Brown, Dustin G.; Chapellier, Marion; Christopher, Joseph; Curran, Colleen S.; Forte, Stefano; Hamid, Roslida A.; Heneberg, Petr; Koch, Daniel C.; Krishnakumar, P.K.; Laconi, Ezio; Maguer-Satta, Veronique; Marongiu, Fabio; Memeo, Lorenzo; Mondello, Chiara; Raju, Jayadev; Roman, Jesse; Roy, Rabindra; Ryan, Elizabeth P.; Ryeom, Sandra; Salem, Hosni K.; Scovassi, A.Ivana; Singh, Neetu; Soucek, Laura; Vermeulen, Louis; Whitfield, Jonathan R.; Woodrick, Jordan; Colacci, Anna Maria; Bisson, William H.; Felsher, Dean W.

    2015-01-01

    Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis. PMID:26106136

  13. The effect of environmental chemicals on the tumor microenvironment.

    PubMed

    Casey, Stephanie C; Vaccari, Monica; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Barcellos-Hoff, Mary Helen; Brown, Dustin G; Chapellier, Marion; Christopher, Joseph; Curran, Colleen S; Forte, Stefano; Hamid, Roslida A; Heneberg, Petr; Koch, Daniel C; Krishnakumar, P K; Laconi, Ezio; Maguer-Satta, Veronique; Marongiu, Fabio; Memeo, Lorenzo; Mondello, Chiara; Raju, Jayadev; Roman, Jesse; Roy, Rabindra; Ryan, Elizabeth P; Ryeom, Sandra; Salem, Hosni K; Scovassi, A Ivana; Singh, Neetu; Soucek, Laura; Vermeulen, Louis; Whitfield, Jonathan R; Woodrick, Jordan; Colacci, Annamaria; Bisson, William H; Felsher, Dean W

    2015-06-01

    Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Tumor microenvironment and therapeutic response.

    PubMed

    Wu, Ting; Dai, Yun

    2017-02-28

    The tumor microenvironment significantly influences therapeutic response and clinical outcome. Microenvironment-mediated drug resistance can be induced by soluble factors secreted by tumor or stromal cells. The adhesion of tumor cells to stromal fibroblasts or to components of the extracellular matrix can also blunt therapeutic response. Microenvironment-targeted therapy strategies include inhibition of the extracellular ligand-receptor interactions and downstream pathways. Immune cells can both improve and obstruct therapeutic efficacy and may vary in their activation status within the tumor microenvironment; thus, re-programme of the immune response would be substantially more beneficial. The development of rational drug combinations that can simultaneously target tumor cells and the microenvironment may represent a solution to overcome therapeutic resistance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Obesity and inflammation and the effect on the hematopoietic system.

    PubMed

    Benites, Bruno Deltreggia; Gilli, Simone Cristina Olenscki; Saad, Sara Teresinha Olalla

    2014-03-01

    Bone marrow is organized in specialized microenvironments known as 'marrow niches'. These are important for the maintenance of stem cells and their hematopoietic progenitors whose homeostasis also depends on other cell types present in the tissue. Extrinsic factors, such as infection and inflammatory states, may affect this system by causing cytokine dysregulation (imbalance in cytokine production) and changes in cell proliferation and self-renewal rates, and may also induce changes in the metabolism and cell cycle. Known to relate to chronic inflammation, obesity is responsible for systemic changes that are best studied in the cardiovascular system. Little is known regarding the changes in the hematopoietic system induced by the inflammatory state carried by obesity or the cell and molecular mechanisms involved. The understanding of the biological behavior of hematopoietic stem cells under obesity-induced chronic inflammation could help elucidate the pathophysiological mechanisms involved in other inflammatory processes, such as neoplastic diseases and bone marrow failure syndromes.

  16. Expansion of CD133+ Umbilical Cord Blood Derived Hematopoietic Stem Cells on a Biocompatible Microwells

    PubMed Central

    Soufizomorrod, Mina; Soleimani, Masoud; Hajifathali, Abbas; Mohammadi, Majid Mossahebi; Abroun, Saeed

    2013-01-01

    Umbilical cord Blood (UCB) as a source of Hematopoietic Stem/Progenitor cells (HSPCs) used for Umbilical cord blood transplantation (UCBT). The main obstacle in application of this source as an appropriate source of HSPCs is low volume of this product. So ex vivo expansion of these cells in a microenvironment which mimic body condition is important. In current study we designed biocompatible microwells in which collagene type I is coated by softlitography method. Our findings designated that in 3-Dimensional (3D) microenvironment CD133+ UCB derived HSC expanded significantly compared to 2-Dimensional (2D) microenvironment. PMID:24505514

  17. LDEF microenvironments, observed and predicted

    NASA Technical Reports Server (NTRS)

    Bourassa, R. J.; Pippin, H. G.; Gillis, J. R.

    1993-01-01

    A computer model for prediction of atomic oxygen exposure of spacecraft in low earth orbit, referred to as the primary atomic oxygen model, was originally described at the First Long Duration Exposure Facility (LDEF) Post-Retrieval Symposium. The primary atomic oxygen model accounts for variations in orbit parameters, the condition of the atmosphere, and for the orientation of exposed surfaces relative to the direction of spacecraft motion. The use of the primary atomic oxygen model to define average atomic oxygen exposure conditions for a spacecraft is discussed and a second microenvironments computer model is described that accounts for shadowing and scattering of atomic oxygen by complex surface protrusions and indentations. Comparisons of observed and predicted erosion of fluorinated ethylene propylene (FEP) thermal control blankets using the models are presented. Experimental and theoretical results are in excellent agreement. Work is in progress to expand modeling capability to include ultraviolet radiation exposure and to obtain more detailed information on reflecting and scattering characteristics of material surfaces.

  18. [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.

  19. Origins.

    PubMed

    Weinberg, S

    1985-10-04

    The farthest of the galaxies that can be seen through the large ground-based telescopes of modern astronomy, such as those on La Palma in the Canary Islands, are so far away that they appear as they did close to the time of the origin of the universe, perhaps some 10 billion years ago. Much has been learned, and much has still to be learned, about the young universe from optical and radio telescopes, but these instruments cannot be used to look directly at the universe in its first few hundred thousand years. Instead, they are used to search the relatively recent past for relics of much earlier times. Together with experiments planned for the next generation of elementary particle accelerators, astronomical observations should continue to extend what is known about the universe backward in time to the Big Bang and may eventually help to reveal the origins of the physical laws that govern the universe.

  20. Segmentation of vascular structures and hematopoietic cells in 3D microscopy images and quantitative analysis

    NASA Astrophysics Data System (ADS)

    Mu, Jian; Yang, Lin; Kamocka, Malgorzata M.; Zollman, Amy L.; Carlesso, Nadia; Chen, Danny Z.

    2015-03-01

    In this paper, we present image processing methods for quantitative study of how the bone marrow microenvironment changes (characterized by altered vascular structure and hematopoietic cell distribution) caused by diseases or various factors. We develop algorithms that automatically segment vascular structures and hematopoietic cells in 3-D microscopy images, perform quantitative analysis of the properties of the segmented vascular structures and cells, and examine how such properties change. In processing images, we apply local thresholding to segment vessels, and add post-processing steps to deal with imaging artifacts. We propose an improved watershed algorithm that relies on both intensity and shape information and can separate multiple overlapping cells better than common watershed methods. We then quantitatively compute various features of the vascular structures and hematopoietic cells, such as the branches and sizes of vessels and the distribution of cells. In analyzing vascular properties, we provide algorithms for pruning fake vessel segments and branches based on vessel skeletons. Our algorithms can segment vascular structures and hematopoietic cells with good quality. We use our methods to quantitatively examine the changes in the bone marrow microenvironment caused by the deletion of Notch pathway. Our quantitative analysis reveals property changes in samples with deleted Notch pathway. Our tool is useful for biologists to quantitatively measure changes in the bone marrow microenvironment, for developing possible therapeutic strategies to help the bone marrow microenvironment recovery.

  1. Bioprinting the Cancer Microenvironment.

    PubMed

    Zhang, Yu Shrike; Duchamp, Margaux; Oklu, Rahmi; Ellisen, Leif W; Langer, Robert; Khademhosseini, Ali

    2016-10-10

    Cancer is intrinsically complex, comprising both heterogeneous cellular compositions and microenvironmental cues. During the various stages of cancer initiation, development, and metastasis, cell-cell interactions (involving vascular and immune cells besides cancerous cells) as well as cell-extracellular matrix (ECM) interactions (e.g., alteration in stiffness and composition of the surrounding matrix) play major roles. Conventional cancer models both two- and three-dimensional (2D and 3D) present numerous limitations as they lack good vascularization and cannot mimic the complexity of tumors, thereby restricting their use as biomimetic models for applications such as drug screening and fundamental cancer biology studies. Bioprinting as an emerging biofabrication platform enables the creation of high-resolution 3D structures and has been extensively used in the past decade to model multiple organs and diseases. More recently, this versatile technique has further found its application in studying cancer genesis, growth, metastasis, and drug responses through creation of accurate models that recreate the complexity of the cancer microenvironment. In this review we will focus first on cancer biology and limitations with current cancer models. We then detail the current bioprinting strategies including the selection of bioinks for capturing the properties of the tumor matrices, after which we discuss bioprinting of vascular structures that are critical toward construction of complex 3D cancer organoids. We finally conclude with current literature on bioprinted cancer models and propose future perspectives.

  2. Molecular pathology of myelodysplastic syndromes: biology of medullary stromal and hematopoietic cells (review).

    PubMed

    Kitagawa, Masanobu; Kurata, Morito; Yamamoto, Kouhei; Abe, Shinya; Suzuki, Shiho; Umeda, Shigeaki

    2011-01-01

    Myelodysplastic syndromes (MDS) have been defined as a disease entity based on clinical features and morphological findings. Despite similarities in clinical manifestations, genetic abnormalities occurring in hematopoietic cells are heterogeneous among the syndromes. However, recent investigations have revealed that there are common biological events in the bone marrow of MDS cases. Most notably, excessive apoptosis of hematopoietic cells was observed to be induced by the bone marrow microenvironment. The apoptosis was mediated by paracrine as well as autocrine factors, suggesting that medullary stromal and hematopoietic cells play a role in the pathology of disease. Pro-inflammatory cytokines, such as TNFα, in the bone marrow microenvironment are predominantly paracrine mediators of apoptosis. Regarding autocrine stimulation mechanisms, it has recently been shown that the deregulation of ribosomal protein is capable of initiating a stress response in the hematopoietic cell through a p53-mediated signaling pathway. Thus, both the stromal cells of the bone marrow microenvironment and hematopoietic cells themselves possess a common and characteristic biology in this heterogeneous disease entity.

  3. Innate lymphoid cells and their stromal microenvironments.

    PubMed

    Kellermayer, Zoltán; Vojkovics, Dóra; Balogh, Péter

    2017-09-01

    In addition to the interaction between antigen presenting cells, T and B lymphocytes, recent studies have revealed important roles for a diverse set of auxiliary cells that profoundly influence the induction and regulation of immune responses against pathogens. Of these the stromal cells composed of various non-hematopoietic constituents are crucial for the creation and maintenance of specialized semi-static three-dimensional lymphoid tissue microenvironment, whereas the more recently described innate lymphoid cells are generated by the diversification of committed lymphoid precursor cells independently from clonally rearranged antigen receptor genes. Recent findings have revealed important contributions by innate lymphoid cells in inflammation and protection against pathogens in a tissue-specific manner. Importantly, lymphoid stromal cells also influence the onset of immune responses in tissue-specific fashion, raising the possibility of tissue-specific stromal - innate lymphoid cell collaboration. In this review we summarize the main features and interactions between these two cells types, with particular emphasis on ILC type 3 cells and their microenvironmental partners. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  4. Niche contributions to oncogenesis: emerging concepts and implications for the hematopoietic system

    PubMed Central

    Raaijmakers, Marc H.G.P.

    2011-01-01

    The field of hematopoietic oncology has traditionally focused on the study of hematopoietic cell autonomous genetic events in an effort to understand malignant transformation and develop therapeutics. Although highly rewarding in both aspects, this cell autonomous approach has failed to fully satisfy our need to understand tumor cell behavior and related clinical observations. In recent years, it has been increasingly recognized that the tumor microenvironment plays a pivotal role in cancer initiation and progression. This review will discuss recent experimental evidence in support of this view derived from investigations in both epithelial and hematopoietic systems. Based on this, conceptual views and therapeutic implications will be provided on the emerging role of the bone marrow microenvironment in leukemogenesis. PMID:21459792

  5. Functional anatomy of the thymic microenvironment.

    PubMed Central

    Kendall, M D

    1991-01-01

    This paper presents a review of our current understanding of the nature of the thymic microenvironment, after briefly considering the major role of the gland. The epithelial cells and their products are of fundamental importance, and other cells of the macrophage series are implicated in most functional events. The embryological origin of the epithelium is still not clear, although disease conditions would suggest a single origin. Immigration and emigration of thymocytes is considered, and also the passage of antigens into the gland. The events within the thymus are under the control of the CNS acting through the innervation or via hormonal pathways. Both of these areas are considered in detail, especially thymic hormone origins, functions and interactions. Images Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 11 PMID:1769884

  6. A method to establish a mouse model of bone marrow microenvironment injury.

    PubMed

    Cheng, Wenzhe; Ge, Quanhu; Wan, Longfei; Wang, Xiaoyi; Chen, Xueling; Wu, Xiangwei

    2017-06-13

    A normal bone marrow microenvironment plays a very important role in the normal functioning of hematopoietic stem cells. Once disturbed, this microenvironment can become favorable for the occurrence of blood disorders, cancers, and other diseases. Therefore, further studies on the bone marrow microenvironment should be performed to reveal regulatory and stem cell fate determination mechanisms and promote the development of bone marrow transplantation, tissue repair and regenerative medicine, and other fields. A small animal model for further research is also urgently needed. In this study, an electric shock device was designed to elicit a femur bone marrow microenvironment injury in mice. A wire was inserted into the distal femur but not into the proximal femur, and the bone marrow microenvironment was evidently damaged by application of 100 ± 10 V for 1.5 ± 0.5 min; mortality, however, was low in the mice. Gross observation, hematoxylin and eosin staining, immunohistochemistry, bright-field microscopy, and micro-CT scanning were also conducted. A large number of new blood capillaries and sinusoids appeared in the injured distal femur after 2 weeks. The capillaries in the injured femur disappeared after 4 weeks, and mature blood vessels were scattered throughout the injured area. Red blood cells disappeared, and the cellular structure and trabecular bone were better than those observed 2 weeks previously. Thus, we developed a simply operated, accurate, reliable, and easily controlled small animal model as a good technical platform to examine angiogenesis and segmentation damage in the bone marrow microenvironment.

  7. The impact of chronic intermittent hypoxia on hematopoiesis and the bone marrow microenvironment.

    PubMed

    Alvarez-Martins, Inês; Remédio, Leonor; Matias, Inês; Diogo, Lucília N; Monteiro, Emília C; Dias, Sérgio

    2016-05-01

    Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder which is associated with patient morbidity and an elevated risk of developing hypertension and cardiovascular diseases. There is ample evidence for the involvement of bone marrow (BM) cells in the pathophysiology of cardiovascular diseases but a connection between OSA and modulation of the BM microenvironment had not been established. Here, we studied how chronic intermittent hypoxia (CIH) affected hematopoiesis and the BM microenvironment, in a rat model of OSA. We show that CIH followed by normoxia increases the bone marrow hypoxic area, increases the number of multipotent hematopoietic progenitors (CFU assay), promotes erythropoiesis, and increases monocyte counts. In the BM microenvironment of CIH-subjected animals, the number of VE-cadherin-expressing blood vessels, particularly sinusoids, increased, accompanied by increased smooth muscle cell coverage, while vWF-positive vessels decreased. Molecularly, we investigated the expression of endothelial cell-derived genes (angiocrine factors) that could explain the cellular phenotypes. Accordingly, we observed an increase in colony-stimulating factor 1, vascular endothelium growth factor, delta-like 4, and angiopoietin-1 expression. Our data shows that CIH induces vascular remodeling in the BM microenvironment, which modulates hematopoiesis, increasing erythropoiesis, and circulating monocytes. Our study reveals for the first time the effect of CIH in hematopoiesis and suggests that hematopoietic changes may occur in OSA patients.

  8. Analysis of the hematopoietic stem cell niche.

    PubMed

    Lo Celso, Cristina; Klein, Rachael J; Scadden, David T

    2007-11-01

    Hematopoietic stem cells (HSCs) continuously replenish all blood cell lineages not only to maintain the normal rapid turnover of differentiated cells but also to respond to injury and stress. Cell-extrinsic mechanisms are critical determinants of the fine balance between HSC self-renewal and differentiation. The bone marrow microenvironment has emerged as a new area of intense study to identify which of its many components constitute the HSC niche and regulate HSC fate. While HSCs have been isolated, characterized and used in clinical practice for many years thanks to the development of very specific assays and technology (i.e., bone marrow transplants and fluorescence activated cell sorting), study of the HSC niche has evolved by combining experimental designs developed in different fields. In this unit we describe a collection of protocols spanning a wide range of techniques that can help every researcher tackling questions regarding the nature of the HSC niche. Copyright 2007 by John Wiley & Sons, Inc.

  9. Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation

    PubMed Central

    Reddehase, Matthias J.

    2016-01-01

    Hematopoietic cell transplantation (HCT) is a therapy option for aggressive forms of hematopoietic malignancies that are resistant to standard antitumoral therapies. Hematoablative treatment preceding HCT, however, opens a “window of opportunity” for latent Cytomegalovirus (CMV) by releasing it from immune control with the consequence of reactivation of productive viral gene expression and recurrence of infectious virus. A “window of opportunity” for the virus represents a “window of risk” for the patient. In the interim between HCT and reconstitution of antiviral immunity, primarily mediated by CD8+ T cells, initially low amounts of reactivated virus can expand exponentially, disseminate to essentially all organs, and cause multiple organ CMV disease, with interstitial pneumonia (CMV-IP) representing the most severe clinical manifestation. Here, I will review predictions originally made in the mouse model of experimental HCT and murine CMV infection, some of which have already paved the way to translational preclinical research and promising clinical trials of a preemptive cytoimmunotherapy of human CMV disease. Specifically, the mouse model has been pivotal in providing “proof of concept” for preventing CMV disease after HCT by adoptive transfer of preselected, virus epitope-specific effector and memory CD8+ T cells bridging the critical interim. However, CMV is not a “passive antigen” but is a pathogen that actively interferes with the reconstitution of protective immunity by infecting bone marrow (BM) stromal cells that otherwise form niches for hematopoiesis by providing the structural microenvironment and by producing hematopoietically active cytokines, the hemopoietins. Depending on the precise conditions of HCT, reduced homing of transplanted hematopoietic stem- and progenitor cells to infected BM stroma and impaired colony growth and lineage differentiation can lead to “graft failure.” In consequence, uncontrolled virus spread

  10. Dynamic microenvironments: the fourth dimension.

    PubMed

    Tibbitt, Mark W; Anseth, Kristi S

    2012-11-14

    The extracellular space, or cell microenvironment, choreographs cell behavior through myriad controlled signals, and aberrant cues can result in dysfunction and disease. For functional studies of human cell biology or expansion and delivery of cells for therapeutic purposes, scientists must decipher this intricate map of microenvironment biology and develop ways to mimic these functions in vitro. In this Perspective, we describe technologies for four-dimensional (4D) biology: cell-laden matrices engineered to recapitulate tissue and organ function in 3D space and over time.

  11. Nanomedicine as a potent strategy in melanoma tumor microenvironment.

    PubMed

    Pautu, Vincent; Leonetti, Daniela; Lepeltier, Elise; Clere, Nicolas; Passirani, Catherine

    2017-02-20

    Melanoma originated from melanocytes is the most aggressive type of skin cancer. Despite considerable progresses in clinical treatment with the discovery of BRAF or MEK inhibitors and monoclonal antibodies, the durability of response to treatment is often limited to the development of acquired resistance and systemic toxicity. The limited success of conventional treatment highlights the importance of understanding the role of melanoma tumor microenvironment in tumor developement and drug resistance. Nanoparticles represent a promising strategy for the development of new cancer treatments able to improve the bioavailability of drugs and increase their penetration by targeting specifically tumors cells and/or tumor environment. In this review, we will discuss the main influence of tumor microenvironment in melanoma growth and treatment outcome. Furthermore, third generation loaded nanotechnologies represent an exciting tool for detection, treatment, and escape from possible mechanism of resistance mediated by tumor microenvironment, and will be highlighted in this review.

  12. Tumor microenvironment-associated modifications of alternative splicing.

    PubMed

    Brosseau, Jean-Philippe; Lucier, Jean-François; Nwilati, Hanad; Thibault, Philippe; Garneau, Daniel; Gendron, Daniel; Durand, Mathieu; Couture, Sonia; Lapointe, Elvy; Prinos, Panagiotis; Klinck, Roscoe; Perreault, Jean-Pierre; Chabot, Benoit; Abou-Elela, Sherif

    2014-02-01

    Pre-mRNA alternative splicing is modified in cancer, but the origin and specificity of these changes remain unclear. Here, we probed ovarian tumors to identify cancer-associated splicing isoforms and define the mechanism by which splicing is modified in cancer cells. Using high-throughput quantitative PCR, we monitored the expression of splice variants in laser-dissected tissues from ovarian tumors. Surprisingly, changes in alternative splicing were not limited to the tumor tissues but were also found in the tumor microenvironment. Changes in the tumor-associated splicing events were found to be regulated by splicing factors that are differentially expressed in cancer tissues. Overall, ∼20% of the alternative splicing events affected by the down-regulation of the splicing factors QKI and RBFOX2 were altered in the microenvironment of ovarian tumors. Together, our results indicate that the tumor microenvironment undergoes specific changes in alternative splicing orchestrated by a limited number of splicing factors.

  13. Kinetics of hematopoietic stem cells and supportive activities of stromal cells in a three-dimensional bone marrow culture system.

    PubMed

    Harada, Tomonori; Hirabayashi, Yukio; Hatta, Yoshihiro; Tsuboi, Isao; Glomm, Wilhelm Robert; Yasuda, Masahiro; Aizawa, Shin

    2015-01-01

    In the bone marrow, hematopoietic cells proliferate and differentiate in close association with a three-dimensional (3D) hematopoietic microenvironment. Previously, we established a 3D bone marrow culture system. In this study, we analyzed the kinetics of hematopoietic cells, and more than 50% of hematopoietic progenitor cells, including CFU-Mix, CFU-GM and BFU-E in 3D culture were in a resting (non-S) phase. Furthermore, we examined the hematopoietic supportive ability of stromal cells by measuring the expression of various mRNAs relevant to hematopoietic regulation. Over the 4 weeks of culture, the stromal cells in the 3D culture are not needlessly activated and "quietly" regulate hematopoietic cell proliferation and differentiation during the culture, resulting in the presence of resting hematopoietic stem cells in the 3D culture for a long time. Thus, the 3D culture system may be a new tool for investigating hematopoietic stem cell-stromal cell interactions in vitro.

  14. Bone marrow mesenchymal stromal cells induce nitric oxide synthase-dependent differentiation of CD11b+ cells that expedite hematopoietic recovery.

    PubMed

    Trento, Cristina; Marigo, Ilaria; Pievani, Alice; Galleu, Antonio; Dolcetti, Luigi; Wang, Chun-Yin; Serafini, Marta; Bronte, Vincenzo; Dazzi, Francesco

    2017-02-09

    Bone marrow microenvironment is fundamental for hematopoietic homeostasis. Numerous efforts have been made to reproduce or manipulate its activity to facilitate engraftment after hematopoietic stem cell transplantation but clinical results remain unconvincing. This probably reflects the complexity of the hematopoietic niche. Recent data have demonstrated the fundamental role of stromal and myeloid cells in regulating hematopoietic stem cell self-renewal and mobilization in the bone marrow. In this study we unveil a novel interaction by which bone marrow mesenchymal stromal cells induce the rapid differentiation of CD11b+ myeloid cells from bone marrow progenitors. Such an activity requires the expression of nitric oxide synthase-2. Importantly, the administration of these mesenchymal stromal cells-educated CD11b+ cells accelerates hematopoietic reconstitution in bone marrow transplant recipients. We conclude that the liaison between mesenchymal stromal cells and myeloid cells is fundamental in hematopoietic homeostasis and suggests that it can be harnessed in clinical transplantation.

  15. Therapeutic targets in malignant glioblastoma microenvironment.

    PubMed

    Barcellos-Hoff, Mary Helen; Newcomb, Elizabeth W; Zagzag, David; Narayana, Ashwatha

    2009-07-01

    There is considerable evidence that the tissue microenvironment can suppress cancer and that microenvironment disruption is required for cancer growth and progression. Distortion of the microenvironment by tumor cells can promote growth, recruit nonmalignant cells that provide physiological resources, and facilitate invasion. Compared with the variable routes taken by cells to become cancers, the response of normal tissue to cancer is relatively consistent such that controlling cancer may be more readily achieved indirectly via the microenvironment. Here, we discuss 3 ideas about how the microenvironment, consisting of a vasculature, inflammatory cells, immune cells, growth factors, and extracellular matrix, might provide therapeutic targets in glioblastoma (GBM) in the context of radiotherapy (RT): (1) viable therapeutic targets exist in the GBM microenvironment, (2) RT alters the microenvironment of tissues and tumors; and (3) a potential benefit may be achieved by targeting the microenvironments induced by RT.

  16. [Research progress on visual observations of hematopoietic stem cell homing].

    PubMed

    Wu, Meng-Yao; Chen, Tong

    2014-02-01

    Hematopoietic stem cell transplantation (HSCT) is an important mean for clinical treatment to many of hematological diseases, malignant diseases, hereditary diseases and autoimmune diseases. Whether the implanted hematopoietic stem cells (HSC) can home to bone marrow (BM) smoothly and reconstitute the hematopoiesis is the key to successful HSCT. With the cognition of HSC homing mechanism, the visual observation of HSC homing to BM is attracting more and more attention and helps to clarify the micro-dialogue between HSC and BM microenvironment. In recent years, with the development of imaging technology, confocal laser scanning microscope (CLSM) and two-photon microscope are able to make 3D reconstruction and real-time observation of the tissue or cells. Researches on HSC homing process visibly become reality. In this article the methods of visual research and their application in HSC homing observation are reviewed.

  17. DEFECTS IN HEMATOPOIETIC DIFFERENTIATION IN NZB AND NZC MICE

    PubMed Central

    Warner, Noel L.; Moore, Malcolm A. S.

    1971-01-01

    Hematopoietic stem cell activity in inbred NZB and NZC mice has been determined by transplantation and endogenous spleen colony assays. Whereas NZB mice show normal colony-forming unit (CFU) activity in the transplantation assay, they show markedly elevated endogenous CFU. NZC mice also show this markedly elevated endogenous CFU activity, but in the transplantation assay show only about 5–10% of normal CFU counts. When NZC stem cells are tested for CFU activity in irradiated recipients of the H-2d type, almost normal colony numbers occur. NZB stem cells however also cannot form colonies in NZC mice. These results suggest that NZC mice have a defect in the micro-environment of the spleen which renders them incapable of allowing transplanted CFU to form colonies. Genetic analysis of both the NZC defect as a CFU recipient, and the elevated endogenous count in NZB and NZC, shows that both are controlled by single recessive genes which are not linked to either coat color, agouti, H-2 or Ig loci. Of even more relevance is the finding that these hematopoietic abnormalities are not linked to the genes involved in controlling autoantibody formation to red cells in the NZB mice. These mice therefore appear to show two distinct hematopoietic abnormalities, the analysis of which may be of considerable value in understanding the detailed events of hematopoietic stem cell differentiation. PMID:4934499

  18. Targeting the Neural Microenvironment in Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    AD_________________ Award Number: W81XWH-14-1-0505 TITLE: Targeting the Neural Microenvironment in Prostate Cancer PRINCIPAL INVESTIGATOR...SUBTITLE 5a. CONTRACT NUMBER Targeting the Neural Microenvironment in Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0505 5c. PROGRAM ELEMENT NUMBER... microenvironment plays an important role in the initiation and progression of PCa. One important component of this microenvironment is nerves. PCa has a

  19. Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine.

    PubMed Central

    Paul, S R; Bennett, F; Calvetti, J A; Kelleher, K; Wood, C R; O'Hara, R M; Leary, A C; Sibley, B; Clark, S C; Williams, D A

    1990-01-01

    Hematopoiesis occurs in close association with a complex network of cells loosely termed the hematopoietic microenvironment. Analysis of the mechanisms of microenvironmental regulation of hematopoiesis has been hindered by the complexity of the microenvironment as well as the heterogeneity of hematopoietic stem cells and early progenitor cells. We have established immortalized primate bone marrow-derived stromal cell lines to facilitate analysis of the interactions of hematopoietic cells with the microenvironment in a large animal species. One such line, PU-34, was found to produce a variety of growth factors, including an activity that stimulates the proliferation of an interleukin 6-dependent murine plasmacytoma cell line. A cDNA encoding the plasmacytoma stimulatory activity was isolated through functional expression cloning in mammalian cells. The nucleotide sequence contained a single long reading frame of 597 nucleotides encoding a predicted 199-amino acid polypeptide. The amino acid sequence of this cytokine, designated interleukin 11 (IL-11), did not display significant similarity with any other sequence in the GenBank data base. Preliminary biological characterization indicates that in addition to stimulating plasmacytoma proliferation, IL-11 stimulates the T-cell-dependent development of immunoglobulin-producing B cells and synergizes with IL-3 in supporting murine megakaryocyte colony formation. These properties implicate IL-11 as an additional multifunctional regulator in the hematopoietic microenvironment. Images PMID:2145578

  20. Generation of axolotl hematopoietic chimeras

    PubMed Central

    Lopez, David; Scott, Edward W.

    2015-01-01

    Wound repair is an extremely complex process that requires precise coordination between various cell types including immune cells. Unfortunately, in mammals this usually results in scar formation instead of restoration of the original fully functional tissue, otherwise known as regeneration. Various animal models like frogs and salamanders are currently being studied to determine the intracellular and intercellular pathways, controlled by gene expression, that elicit cell proliferation, differentiation, and migration of cells during regenerative healing. Now, the necessary genetic tools to map regenerative pathways are becoming available for the axolotl salamander, thus allowing comparative studies between scarring and regeneration. Here, we describe in detail three methods to produce axolotl hematopoietic cell-tagged chimeras for the study of hematopoiesis and regeneration. PMID:26366424

  1. Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

    PubMed Central

    Coste, Cécile; Neirinckx, Virginie; Gothot, André; Wislet, Sabine; Rogister, Bernard

    2015-01-01

    Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC) function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL) 12-abundant reticular (CAR) cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs), which have been recently identified as neural crest-derived cells (NCSCs). Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system. PMID:26136659

  2. Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

    PubMed

    Coste, Cécile; Neirinckx, Virginie; Gothot, André; Wislet, Sabine; Rogister, Bernard

    2015-01-01

    Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC) function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL) 12-abundant reticular (CAR) cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs), which have been recently identified as neural crest-derived cells (NCSCs). Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

  3. PTEN action in leukemia dictated by the tissue microenvironment

    PubMed Central

    Miething, Cornelius; Scuoppo, Claudio; Bosbach, Benedikt; Appelmann, Iris; Nakitandwe, Joy; Ma, Jing; Wu, Gang; Lintault, Laura; Auer, Martina; Premsrirut, Prem K.; Teruya-Feldstein, Julie; Hicks, James; Benveniste, Helene; Speicher, Michael R.; Downing, James R.; Lowe, Scott W.

    2014-01-01

    PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing1–3. PTEN dephosphorylates phosphatidylinositol 3,4,5-triphosphate (PIP3), thereby opposing the activity of class I phosphatidylinositol 3-kinases (PI3Ks) that mediate growth and survival factors signaling through PI3K effectors such as AKT and mTOR2. To determine whether continued PTEN inactivation is required to maintain malignancy, we generated an RNAi-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal PTEN knockdown in the hematopoietic compartment produced highly disseminated T-cell leukemia (T-ALL). Surprisingly, reactivation of PTEN mainly reduced T-ALL dissemination but had little effect on tumor load in hematopoietic organs. Leukemia infiltration into the intestine was dependent on CCR9 G-protein coupled receptor (GPCR) signaling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, GPCRs may play an unanticipated role in driving tumor growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumor maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype. PMID:24805236

  4. Tumor microenvironment: Sanctuary of the devil.

    PubMed

    Hui, Lanlan; Chen, Ye

    2015-11-01

    Tumor cells constantly interact with the surrounding microenvironment. Increasing evidence indicates that targeting the tumor microenvironment could complement traditional treatment and improve therapeutic outcomes for these malignancies. In this paper, we review new insights into the tumor microenvironment, and summarize selected examples of the cross-talk between tumor cells and their microenvironment, which have enhanced our understanding of pathophysiology of the microenvironment. We believe that this rapidly moving field promises many more to come, and they will guide the rational design of combinational therapies for success in cancer eradication. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Targeting microenvironment in cancer therapeutics

    PubMed Central

    Martin, Matthew; Wei, Han; Lu, Tao

    2016-01-01

    During development of a novel treatment for cancer patients, the tumor microenvironment and its interaction with the tumor cells must be considered. Aspects such as the extracellular matrix (ECM), the epithelial-mesenchymal transition (EMT), secreted factors, cancer-associated fibroblasts (CAFs), the host immune response, and tumor-associated microphages (TAM) are critical for cancer progression and metastasis. Additionally, signaling pathways such as the nuclear factor κB (NF-κB), transforming growth factor β (TGFβ), and tumor necrosis factor α (TNFα) can promote further cytokine release in the tumor environment, and impact tumor progression greatly. Importantly, cytokine overexpression has been linked to drug resistance in cancers and is therefore an attractive target for combinational therapies. Specific inhibitors of cytokines involved in signaling between tumor cells and the microenvironment have not been studied in depth and have great potential for use in personalized medicines. Together, the interactions between the microenvironment and tumors are critical for tumor growth and promotion and should be taken into serious consideration for future novel therapeutic approaches. PMID:27270649

  6. Concise review: hematopoietic stem cells and tissue stem cells: current concepts and unanswered questions.

    PubMed

    Metcalf, Donald

    2007-10-01

    The term hematopoietic stem cells has at times been used to include a miscellany of precursor cells ranging from multipotential self-generating cells to lineage-restricted progenitors with little capacity for self-generation. It is probable that the stem cells of other tissues also vary widely in their multipotentiality and proliferative capacity. This review questions several dogmas regarding the self-generative capacity of various hematopoietic cells, the single episodic origin of hematopoietic cells, and the irreversible nature of progressive mature cell formation in individual hematopoietic lineages. Disclosure of potential conflicts of interest is found at the end of this article.

  7. Hematopoietic Stem Cells Therapies.

    PubMed

    Chivu-Economescu, Mihaela; Rubach, Martin

    2017-01-01

    Stem cell-based therapies are recognized as a new way to treat various diseases and injuries, with a wide range of health benefits. The goal is to heal or replace diseased or destroyed organs or body parts with healthy new cells provided by stem cell transplantation. The current practical form of stem cell therapy is the hematopoietic stem cells transplant applied for the treatment of hematological disorders. There are over 2100 clinical studies in progress concerning hematopoietic stem cell therapies. All of them are using hematopoietic stem cells to treat various diseases like: cancers, leukemia, lymphoma, cardiac failure, neural disorders, auto-immune diseases, immunodeficiency, metabolic or genetic disorders. Several challenges are to be addressed prior to developing and applying large scale cell therapies: 1) to explain and control the mechanisms of differentiation and development toward a specific cell type needed to treat the disease, 2) to obtain a sufficient number of desired cell type for transplantation, 3) to overcome the immune rejection and 4) to show that transplanted cells fulfill their normal functions in vivo after transplants.

  8. Reprogramming Malignant Cancer Cells toward a Benign Phenotype following Exposure to Human Embryonic Stem Cell Microenvironment

    PubMed Central

    Arena, Vincenzo; Arena, Manuel; Arena, Goffredo Orazio

    2017-01-01

    The embryonic microenvironment is well known to be non-permissive for tumor development because early developmental signals naturally suppress the expression of proto-oncogenes. In an analogous manner, mimicking an early embryonic environment during embryonic stem cell culture has been shown to suppress oncogenic phenotypes of cancer cells. Exosomes derived from human embryonic stem cells harbor substances that mirror the content of the cells of origin and have been reported to reprogram hematopoietic stem/progenitor cells via horizontal transfer of mRNA and proteins. However, the possibility that these embryonic stem cells-derived exosomes might be the main effectors of the anti-tumor effect mediated by the embryonic stem cells has not been explored yet. The present study aims to investigate whether exosomes derived from human embryonic stem cells can reprogram malignant cancer cells to a benign stage and reduce their tumorigenicity. We show that the embryonic stem cell-conditioned medium contains factors that inhibit cancer cell growth and tumorigenicity in vitro and in vivo. Moreover, we demonstrate that exosomes derived from human embryonic stem cells display anti-proliferation and pro-apoptotic effects, and decrease tumor size in a xenograft model. These exosomes are also able to transfer their cargo into target cancer cells, inducing a dose-dependent increase in SOX2, OCT4 and Nanog proteins, leading to a dose-dependent decrease of cancer cell growth and tumorigenicity. This study shows for the first time that human embryonic stem cell-derived exosomes play an important role in the tumor suppressive activity displayed by human embryonic stem cells. PMID:28068409

  9. Reprogramming Malignant Cancer Cells toward a Benign Phenotype following Exposure to Human Embryonic Stem Cell Microenvironment.

    PubMed

    Zhou, Shufeng; Abdouh, Mohamed; Arena, Vincenzo; Arena, Manuel; Arena, Goffredo Orazio

    2017-01-01

    The embryonic microenvironment is well known to be non-permissive for tumor development because early developmental signals naturally suppress the expression of proto-oncogenes. In an analogous manner, mimicking an early embryonic environment during embryonic stem cell culture has been shown to suppress oncogenic phenotypes of cancer cells. Exosomes derived from human embryonic stem cells harbor substances that mirror the content of the cells of origin and have been reported to reprogram hematopoietic stem/progenitor cells via horizontal transfer of mRNA and proteins. However, the possibility that these embryonic stem cells-derived exosomes might be the main effectors of the anti-tumor effect mediated by the embryonic stem cells has not been explored yet. The present study aims to investigate whether exosomes derived from human embryonic stem cells can reprogram malignant cancer cells to a benign stage and reduce their tumorigenicity. We show that the embryonic stem cell-conditioned medium contains factors that inhibit cancer cell growth and tumorigenicity in vitro and in vivo. Moreover, we demonstrate that exosomes derived from human embryonic stem cells display anti-proliferation and pro-apoptotic effects, and decrease tumor size in a xenograft model. These exosomes are also able to transfer their cargo into target cancer cells, inducing a dose-dependent increase in SOX2, OCT4 and Nanog proteins, leading to a dose-dependent decrease of cancer cell growth and tumorigenicity. This study shows for the first time that human embryonic stem cell-derived exosomes play an important role in the tumor suppressive activity displayed by human embryonic stem cells.

  10. TopBP1 Governs Hematopoietic Stem/Progenitor Cells Survival in Zebrafish Definitive Hematopoiesis

    PubMed Central

    Gao, Lei; Li, Dantong; Ma, Ke; Zhang, Wenjuan; Xu, Tao; Fu, Cong; Jing, Changbin; Jia, Xiaoe; Wu, Shuang; Sun, Xin; Dong, Mei; Deng, Min; Chen, Yi; Zhu, Wenge; Peng, Jinrong; Wan, Fengyi; Zhou, Yi; Zon, Leonard I.; Pan, Weijun

    2015-01-01

    In vertebrate definitive hematopoiesis, nascent hematopoietic stem/progenitor cells (HSPCs) migrate to and reside in proliferative hematopoietic microenvironment for transitory expansion. In this process, well-established DNA damage response pathways are vital to resolve the replication stress, which is deleterious for genome stability and cell survival. However, the detailed mechanism on the response and repair of the replication stress-induced DNA damage during hematopoietic progenitor expansion remains elusive. Here we report that a novel zebrafish mutantcas003 with nonsense mutation in topbp1 gene encoding topoisomerase II β binding protein 1 (TopBP1) exhibits severe definitive hematopoiesis failure. Homozygous topbp1cas003 mutants manifest reduced number of HSPCs during definitive hematopoietic cell expansion, without affecting the formation and migration of HSPCs. Moreover, HSPCs in the caudal hematopoietic tissue (an equivalent of the fetal liver in mammals) in topbp1cas003 mutant embryos are more sensitive to hydroxyurea (HU) treatment. Mechanistically, subcellular mislocalization of TopBP1cas003 protein results in ATR/Chk1 activation failure and DNA damage accumulation in HSPCs, and eventually induces the p53-dependent apoptosis of HSPCs. Collectively, this study demonstrates a novel and vital role of TopBP1 in the maintenance of HSPCs genome integrity and survival during hematopoietic progenitor expansion. PMID:26131719

  11. First steps to define murine amniotic fluid stem cell microenvironment

    PubMed Central

    Bertin, E.; Piccoli, M.; Franzin, C.; Spiro, G.; Donà, S.; Dedja, A.; Schiavi, F.; Taschin, E.; Bonaldo, P.; Braghetta, P.; De Coppi, P.; Pozzobon, M.

    2016-01-01

    Stem cell niche refers to the microenvironment where stem cells reside in living organisms. Several elements define the niche and regulate stem cell characteristics, such as stromal support cells, gap junctions, soluble factors, extracellular matrix proteins, blood vessels and neural inputs. In the last years, different studies demonstrated the presence of cKit+ cells in human and murine amniotic fluid, which have been defined as amniotic fluid stem (AFS) cells. Firstly, we characterized the murine cKit+ cells present both in the amniotic fluid and in the amnion. Secondly, to analyze the AFS cell microenvironment, we injected murine YFP+ embryonic stem cells (ESC) into the amniotic fluid of E13.5 wild type embryos. Four days after transplantation we found that YFP+ sorted cells maintained the expression of pluripotency markers and that ESC adherent to the amnion were more similar to original ESC in respect to those isolated from the amniotic fluid. Moreover, cytokines evaluation and oxygen concentration analysis revealed in this microenvironment the presence of factors that are considered key regulators in stem cell niches. This is the first indication that AFS cells reside in a microenvironment that possess specific characteristics able to maintain stemness of resident and exogenous stem cells. PMID:27845396

  12. First steps to define murine amniotic fluid stem cell microenvironment.

    PubMed

    Bertin, E; Piccoli, M; Franzin, C; Spiro, G; Donà, S; Dedja, A; Schiavi, F; Taschin, E; Bonaldo, P; Braghetta, P; De Coppi, P; Pozzobon, M

    2016-11-15

    Stem cell niche refers to the microenvironment where stem cells reside in living organisms. Several elements define the niche and regulate stem cell characteristics, such as stromal support cells, gap junctions, soluble factors, extracellular matrix proteins, blood vessels and neural inputs. In the last years, different studies demonstrated the presence of cKit(+) cells in human and murine amniotic fluid, which have been defined as amniotic fluid stem (AFS) cells. Firstly, we characterized the murine cKit(+) cells present both in the amniotic fluid and in the amnion. Secondly, to analyze the AFS cell microenvironment, we injected murine YFP(+) embryonic stem cells (ESC) into the amniotic fluid of E13.5 wild type embryos. Four days after transplantation we found that YFP(+) sorted cells maintained the expression of pluripotency markers and that ESC adherent to the amnion were more similar to original ESC in respect to those isolated from the amniotic fluid. Moreover, cytokines evaluation and oxygen concentration analysis revealed in this microenvironment the presence of factors that are considered key regulators in stem cell niches. This is the first indication that AFS cells reside in a microenvironment that possess specific characteristics able to maintain stemness of resident and exogenous stem cells.

  13. The spleen microenvironment influences disease transformation in a mouse model of KITD816V-dependent myeloproliferative neoplasm

    PubMed Central

    Pelusi, Natalie; Kosanke, Maike; Riedt, Tamara; Rösseler, Corinna; Seré, Kristin; Li, Jin; Gütgemann, Ines; Zenke, Martin; Janzen, Viktor; Schorle, Hubert

    2017-01-01

    Activating mutations leading to ligand-independent signaling of the stem cell factor receptor KIT are associated with several hematopoietic malignancies. One of the most common alterations is the D816V mutation. In this study, we characterized mice, which conditionally express the humanized KITD816V receptor in the adult hematopoietic system to determine the pathological consequences of unrestrained KIT signaling during blood cell development. We found that KITD816V mutant animals acquired a myeloproliferative neoplasm similar to polycythemia vera, marked by a massive increase in red blood cells and severe splenomegaly caused by excessive extramedullary erythropoiesis. Moreover, we found mobilization of stem cells from bone marrow to the spleen. Splenectomy prior to KITD816V induction prevented expansion of red blood cells, but rapidly lead to a state of aplastic anemia and bone marrow fibrosis, reminiscent of post polycythemic myeloid metaplasia, the spent phase of polycythemia vera. Our results show that the extramedullary hematopoietic niche microenvironment significantly influences disease outcome in KITD816V mutant mice, turning this model a valuable tool for studying the interplay between functionally abnormal hematopoietic cells and their microenvironment during development of polycythemia vera-like disease and myelofibrosis. PMID:28128288

  14. Biomimetic microenvironments for regenerative endodontics.

    PubMed

    Kaushik, Sagar N; Kim, Bogeun; Walma, Alexander M Cruz; Choi, Sung Chul; Wu, Hui; Mao, Jeremy J; Jun, Ho-Wook; Cheon, Kyounga

    2016-01-01

    Regenerative endodontics has been proposed to replace damaged and underdeveloped tooth structures with normal pulp-dentin tissue by providing a natural extracellular matrix (ECM) mimicking environment; stem cells, signaling molecules, and scaffolds. In addition, clinical success of the regenerative endodontic treatments can be evidenced by absence of signs and symptoms; no bony pathology, a disinfected pulp, and the maturation of root dentin in length and thickness. In spite of the various approaches of regenerative endodontics, there are several major challenges that remain to be improved: a) the endodontic root canal is a strong harbor of the endodontic bacterial biofilm and the fundamental etiologic factors of recurrent endodontic diseases, (b) tooth discolorations are caused by antibiotics and filling materials, (c) cervical root fractures are caused by endodontic medicaments, (d) pulp tissue is not vascularized nor innervated, and (e) the dentin matrix is not developed with adequate root thickness and length. Generally, current clinical protocols and recent studies have shown a limited success of the pulp-dentin tissue regeneration. Throughout the various approaches, the construction of biomimetic microenvironments of pulp-dentin tissue is a key concept of the tissue engineering based regenerative endodontics. The biomimetic microenvironments are composed of a synthetic nano-scaled polymeric fiber structure that mimics native pulp ECM and functions as a scaffold of the pulp-dentin tissue complex. They will provide a framework of the pulp ECM, can deliver selective bioactive molecules, and may recruit pluripotent stem cells from the vicinity of the pulp apex. The polymeric nanofibers are produced by methods of self-assembly, electrospinning, and phase separation. In order to be applied to biomedical use, the polymeric nanofibers require biocompatibility, stability, and biodegradability. Therefore, this review focuses on the development and application of the

  15. The origin and development of the immune system with a view to stem cell therapy.

    PubMed

    Anastassova-Kristeva, Marlene

    2003-04-01

    Careful study of the phylogeny and ontogeny of the three components of the immune system reveals that the macrophage, lymphatic, and hematopoietic systems originate independently of each other. Chronologically, the most ancient is the macrophage system, which arises in the coelomic cavity as mesenchymal ameboid cells having the properties to recognize self from non-self and to ingest foreign particles. The lymphatic system later develops from the endoderm of pharyngeal pouches, where the thymic anlage differentiates. The lymphocytes that originate here seed all lymphatic organs and retain the ability to divide and thereby form multiple colonies (lymphatic nodules) in the respiratory and digestive tract; further diversification of lymphocytes follows after confrontation with antigens. The last component of the immune system to appear is the hematopoietic system, which originates from the splanchnic mesoderm of the yolk sac as hematogenic tissue, containing hemangioblasts. The hematogenic tissue remains attached to the outer wall of the vitelline vessels, which provides an efficient mechanism for introducing the hematogenic tissue into the embryo. In an appropriate microenvironment, the hemangioblasts give rise to sinusoidal endothelium and to hemocytoblasts - the bone marrow stem cells for erythrocytes, myeloid cells, and megakaryocytes. The facts and opinions presented in this article are not in agreement with the currently accepted dogma that a common "hematolymphatic stem cell" localized in the marrow generates all of the cellular components of blood and the immune system.

  16. Dissecting the Multiple Myeloma-bone microenvironment reveals new therapeutic opportunities

    PubMed Central

    Shay, G; Hazlehurst, L; Lynch, CC

    2015-01-01

    Multiple myeloma is a plasma cell skeletal malignancy. While therapeutic agents such as bortezomib and lenalidomide have significantly improved overall survival, the disease is currently incurable with the emergence of drug resistance limiting the efficacy of chemotherapeutic strategies. Failure to cure the disease is in part due to the underlying genetic heterogeneity of the cancer. Myeloma progression is critically dependent on the surrounding microenvironment. Defining the interactions between myeloma cells and the more genetically stable hematopoietic and mesenchymal components of the bone microenvironment is critical for the development of new therapeutic targets. In this review, we discuss recent advances in our understanding of how microenvironmental elements contribute to myeloma progression and therapeutically, how those elements can or are currently being targeted in a bid to eradicate the disease. PMID:26423531

  17. Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation, differentiation, and maintenance of hematopoietic stem and progenitor cells

    PubMed Central

    Stopp, Sabine; Bornhäuser, Martin; Ugarte, Fernando; Wobus, Manja; Kuhn, Matthias; Brenner, Sebastian; Thieme, Sebastian

    2013-01-01

    The melanoma cell adhesion molecule defines mesenchymal stromal cells in the human bone marrow that regenerate bone and establish a hematopoietic microenvironment in vivo. The role of the melanoma cell adhesion molecule in primary human mesenchymal stromal cells and the maintenance of hematopoietic stem and progenitor cells during ex vivo culture has not yet been demonstrated. We applied RNA interference or ectopic overexpression of the melanoma cell adhesion molecule in human mesenchymal stromal cells to evaluate the effect of the melanoma cell adhesion molecule on their proliferation and differentiation as well as its influence on co-cultivated hematopoietic stem and progenitor cells. Knockdown and overexpression of the melanoma cell adhesion molecule affected several characteristics of human mesenchymal stromal cells related to osteogenic differentiation, proliferation, and migration. Furthermore, knockdown of the melanoma cell adhesion molecule in human mesenchymal stromal cells stimulated the proliferation of hematopoietic stem and progenitor cells, and strongly reduced the formation of long-term culture-initiating cells. In contrast, melanoma cell adhesion molecule-overexpressing human mesenchymal stromal cells provided a supportive microenvironment for hematopoietic stem and progenitor cells. Expression of the melanoma cell adhesion molecule increased the adhesion of hematopoietic stem and progenitor cells to human mesenchymal stromal cells and their migration beneath the monolayer of human mesenchymal stromal cells. Our results demonstrate that the expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells determines their fate and regulates the maintenance of hematopoietic stem and progenitor cells through direct cell-cell contact. PMID:22801967

  18. Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation, differentiation, and maintenance of hematopoietic stem and progenitor cells.

    PubMed

    Stopp, Sabine; Bornhäuser, Martin; Ugarte, Fernando; Wobus, Manja; Kuhn, Matthias; Brenner, Sebastian; Thieme, Sebastian

    2013-04-01

    The melanoma cell adhesion molecule defines mesenchymal stromal cells in the human bone marrow that regenerate bone and establish a hematopoietic microenvironment in vivo. The role of the melanoma cell adhesion molecule in primary human mesenchymal stromal cells and the maintenance of hematopoietic stem and progenitor cells during ex vivo culture has not yet been demonstrated. We applied RNA interference or ectopic overexpression of the melanoma cell adhesion molecule in human mesenchymal stromal cells to evaluate the effect of the melanoma cell adhesion molecule on their proliferation and differentiation as well as its influence on co-cultivated hematopoietic stem and progenitor cells. Knockdown and overexpression of the melanoma cell adhesion molecule affected several characteristics of human mesenchymal stromal cells related to osteogenic differentiation, proliferation, and migration. Furthermore, knockdown of the melanoma cell adhesion molecule in human mesenchymal stromal cells stimulated the proliferation of hematopoietic stem and progenitor cells, and strongly reduced the formation of long-term culture-initiating cells. In contrast, melanoma cell adhesion molecule-overexpressing human mesenchymal stromal cells provided a supportive microenvironment for hematopoietic stem and progenitor cells. Expression of the melanoma cell adhesion molecule increased the adhesion of hematopoietic stem and progenitor cells to human mesenchymal stromal cells and their migration beneath the monolayer of human mesenchymal stromal cells. Our results demonstrate that the expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells determines their fate and regulates the maintenance of hematopoietic stem and progenitor cells through direct cell-cell contact.

  19. Mobilization and homing of hematopoietic stem cells.

    PubMed

    Suárez-Álvarez, Beatriz; López-Vázquez, Antonio; López-Larrea, Carlos

    2012-01-01

    Hematopoietic stem cells (HSC) are a population of precursor cells that posses the capacity for self-renewal and multilineage differentiation. In the bone marrow (BM), HSCs warrant blood cell homeostasis, but at the same time a stable pool of functional cells must be constantly maintained. For this, HSCs constitute a model in which subpopulations of quiescent and active adult stem cells co-exist in the same tissue, in specific microenvironment called stem-cell "niches." These microenvironments keep the stem cells at quiescent (osteoblastic niche) for its self-renewal and activate the stem cells (vascular niche) for proliferation and/or injury repair, maintaining a dynamic balance between self-renewal and differentiation. HSC reside in the bone marrow but can be forces into the blood, a process termed mobilization used clinically to harvest large number of cells for transplantation. At the same time, homing to the BM is necessary to optimize cell engraftment. Here, we summarize current understanding of HSC niche characteristics, and the physiological and pathological mechanisms that guide HSC mobilization both within the BM and to distant niches in the periphery. Mobilization and Homing are mirror process depending on an interplay between chemokines, chemokine receptors, intracellular signaling, adhesion moleculas and proteases. The interaction between SDF-1/CXCL12 and its receptor CXCR4 is critical to retain HSCs within the bone marrow. Current mobilization strategies used in clinic, mainly G-CSF cytokine, are well tolerated but often produce suboptimal number of collected HSCs. Novel agents (AMD3100, stem cell factor, GROßT.) are being developed to enhance the mobilization to modify the signaling into the niche and boost the stem cell harvest, increasing the number of HSCs available for the transplant.

  20. The microenvironment of wound healing.

    PubMed

    Junker, Johan P E; Caterson, E J; Eriksson, Elof

    2013-01-01

    This review summarizes experiments performed by us and others, examining the importance of the microenvironment to wound healing. The development of a sealed polyurethane wound chamber has allowed us to perform studies evaluating the effects of growth factors, transplanted cells, and other bioactive substances on wound healing. Studies have compared wet, moist, and dry healing, with the conclusion that a wet, incubator-like microenvironment provides the fastest healing with fewest aberrations and least scar formation. The wet environment is also paramount for the survival and proliferation of transplanted cells or tissue, which has been shown in studies of porcine and human wounds. Moreover, high concentrations of antibiotics and other agents can be introduced in the wound chamber, thereby effectively fighting infection, while maintaining safe systemic concentrations. These findings have been used in clinical settings to treat wounds of different types. A titanium chamber has been developed to create an in vivo incubator, which will serve as a regenerative platform for in vivo tissue engineering.

  1. Microenvironments Dictating Tumor Cell Dormancy

    PubMed Central

    Bragado, Paloma; Sosa, Maria Soledad; Keely, Patricia; Condeelis, John

    2012-01-01

    The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support three potential scenarios contributing to tumor cell dormancy. The first scenario proposes that DTCs from invasive cancers activate stress signals in response to the dissemination process and/or a growth suppressive target organ microenvironment inducing dormancy. The second scenario asks whether therapy and/or micro-environmental stress conditions (e.g. hypoxia) acting on primary tumor cells carrying specific gene signatures prime new DTCs to enter dormancy in a matching target organ microenvironment that can also control the timing of DTC dormancy. The third and final scenario proposes that early dissemination contributes a population of DTCs that are unfit for immediate expansion and survive mostly in an arrested state well after primary tumor surgery, until genetic and/or epigenetic mechanisms activate their proliferation. We propose that DTC dormancy is ultimately a survival strategy that when targeted will eradicate dormant DTCs preventing metastasis. For these non-mutually exclusive scenarios we review experimental and clinical evidence in their support. PMID:22527492

  2. LDEF microenvironments, observed and predicted

    NASA Technical Reports Server (NTRS)

    Bourassa, R. J.

    1992-01-01

    Complex protrusions and surface indentations on spacecraft equipment alter exposure environments by casting shadows, producing reflections and scattering incident atomic oxygen flux and UV radiation. A computer model is being developed to predict these effects. The model accounts for any arbitrary shape, size, orientation, or curvature of exposed objects. LDEF offers a unique opportunity to compare model prediction with observations. For this purpose, a study is underway on twelve of LDEF's copper grounding straps. These straps were exposed at various angles from the ram vector during the LDEF flight. Microenvironment variables include shadowing and reflections from clamps and fasteners, and varying exposure caused by bending of the straps. Strap measurements include optical properties, surface film composition by ESCA, and film thickness measurements by optical interference techniques. The features of the microenvironment model and the analytical methods used to examine the straps are discussed. Data are presented showing predicted microenvironmental variations. These variations are compared with observed point to point differences in surface properties of the straps.

  3. Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting.

    PubMed

    Chiarini, Francesca; Lonetti, Annalisa; Evangelisti, Camilla; Buontempo, Francesca; Orsini, Ester; Evangelisti, Cecilia; Cappellini, Alessandra; Neri, Luca M; McCubrey, James A; Martelli, Alberto M

    2016-03-01

    The bone marrow (BM) microenvironment regulates the properties of healthy hematopoietic stem cells (HSCs) localized in specific niches. Two distinct microenvironmental niches have been identified in the BM, the "osteoblastic (endosteal)" and "vascular" niches. Nevertheless, these niches provide sanctuaries where subsets of leukemic cells escape chemotherapy-induced death and acquire a drug-resistant phenotype. Moreover, it is emerging that leukemia cells are able to remodel the BM niches into malignant niches which better support neoplastic cell survival and proliferation. This review focuses on the cellular and molecular biology of microenvironment/leukemia interactions in acute lymphoblastic leukemia (ALL) of both B- and T-cell lineage. We shall also highlight the emerging role of exosomes/microvesicles as efficient messengers for cell-to-cell communication in leukemia settings. Studies on the interactions between the BM microenvironment and ALL cells have led to the discovery of potential therapeutic targets which include cytokines/chemokines and their receptors, adhesion molecules, signal transduction pathways, and hypoxia-related proteins. The complex interplays between leukemic cells and BM microenvironment components provide a rationale for innovative, molecularly targeted therapies, designed to improve ALL patient outcome. A better understanding of the contribution of the BM microenvironment to the process of leukemogenesis and leukemia persistence after initial remission, may provide new targets that will allow destruction of leukemia cells without adversely affecting healthy HSCs. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis,Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. The evolving view of the hematopoietic stem cell niche.

    PubMed

    Beerman, Isabel; Luis, Tiago C; Singbrant, Sofie; Lo Celso, Cristina; Méndez-Ferrer, Simon

    2017-06-01

    Hematopoietic stem cells (HSCs) reside in specialized microenvironments known as niches. The niche is essential to support HSC function and to maintain a correct balance between self-renewal and differentiation. Recent advances in defining different mesenchymal and endothelial bone marrow cell populations, as well as hematopoietic stem and progenitor cells, greatly enhanced our understanding of these niches and of the molecular mechanisms by which they regulate HSC function. In addition to the role in maintaining HSC homeostasis, the niche has also been implicated in the pathogenesis of blood disorders including hematological malignancies. Characterizing the extrinsic regulators and the cellular context in which the niches interact with HSCs will be crucial to define new strategies to enhance blood regeneration. Furthermore, a better understanding of the role of the niche in leukemia development will open new possibilities for the treatment of these disorders by using therapies aiming to target the leukemic niche specifically. To update on recent findings on this topic, the International Society for Experimental Hematology (ISEH) organized a webinar, presented by Prof. Sean J. Morrison and Dr. Simón Méndez-Ferrer and moderated by Dr. Cristina Lo Celso, entitled "The evolving view of the hematopoietic stem cell niche," which we summarize here. Published by Elsevier Inc.

  5. Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance

    PubMed Central

    Alonso, Salvador; Hernandez, Daniela; Chang, Yu-ting; Gocke, Christian B.; McCray, Megan; Varadhan, Ravi; Matsui, William H.; Jones, Richard J.

    2016-01-01

    Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in bortezomib (BTZ) resistance. However, the mechanisms involved in these interactions are not completely understood. We previously showed that expression of CYP26 in BM stromal cells maintains a retinoic acid–low (RA-low) microenvironment that prevents the differentiation of normal and malignant hematopoietic cells. Since a low secretory B cell phenotype is associated with BTZ resistance in MM and retinoid signaling promotes plasma cell differentiation and Ig production, we investigated whether stromal expression of the cytochrome P450 monooxygenase CYP26 modulates BTZ sensitivity in the BM niche. CYP26-mediated inactivation of RA within the BM microenvironment prevented plasma cell differentiation and promoted a B cell–like, BTZ-resistant phenotype in human MM cells that were cocultured on BM stroma. Moreover, paracrine Hedgehog secretion by MM cells upregulated stromal CYP26 and further reinforced a protective microenvironment. These results suggest that crosstalk between Hedgehog and retinoid signaling modulates BTZ sensitivity in the BM niche. Targeting these pathological interactions holds promise for eliminating minimal residual disease in MM. PMID:27775549

  6. Bone marrow extracellular matrix molecules improve gene transfer into human hematopoietic cells via retroviral vectors.

    PubMed

    Moritz, T; Patel, V P; Williams, D A

    1994-04-01

    Direct contact between hematopoietic cells and viral packaging cell lines or other sources of stroma has been shown to increase the efficiency of retroviral-mediated gene transfer into these target cells compared with infection with viral supernatant. We have investigated the role of defined bone marrow extracellular matrix molecules (ECM) in this phenomenon. Here we report that infection of cells adhering to the carboxy-terminal 30/35-kD fragment of the fibronectin molecule (30/35 FN), which contains the alternatively spliced CS-1 cell adhesion domain, significantly increases gene transfer into hematopoietic cells. Two retroviral vectors differing in recombinant viral titer were used. Gene transfer into committed progenitor cells and long-term culture-initiating cells, an in vitro assay for human stem cells, was significantly increased when the cells were infected while adherent to 30/35 FN-coated plates compared with cells infected on BSA-coated control plates or plates coated with other bone marrow ECM molecules. Although gene transfer into committed progenitor cells and to a lesser degree into long-term culture-initiating cells was increased on intact fibronectin as well, increased gene transfer efficiency into hematopoietic cells on 30/35 FN was dependent on CS-1 sequence since infection on a similar FN fragment lacking CS-1 (42 FN) was suboptimal. 30/35 FN has previously been shown by our laboratory and other investigators to mediate adhesion of primitive murine and human hematopoietic stem cells to the hematopoietic microenvironment. Additional studies showed that neither soluble 30/35 FN nor nonspecific binding of hematopoietic cells to poly-L-lysine-coated plates had any appreciable effect on the infection efficiency of these cells. Our findings indicate that hematopoietic stem cell adhesion to specific ECM molecules alters retroviral infection efficiency. These findings should aid in the design of gene transfer protocols using hematopoietic progenitor and

  7. The external microenvironment of healing skin wounds.

    PubMed

    Kruse, Carla R; Nuutila, Kristo; Lee, Cameron C Y; Kiwanuka, Elizabeth; Singh, Mansher; Caterson, Edward J; Eriksson, Elof; Sørensen, Jens A

    2015-01-01

    The skin wound microenvironment can be divided into two main components that influence healing: the external wound microenvironment, which is outside the wound surface; and the internal wound microenvironment, underneath the surface, to which the cells within the wound are exposed. Treatment methods that directly alter the features of the external wound microenvironment indirectly affect the internal wound microenvironment due to the exchange between the two compartments. In this review, we focus on the effects of temperature, pressure (positive and negative), hydration, gases (oxygen and carbon dioxide), pH, and anti-microbial treatment on the wound. These factors are well described in the literature and can be modified with treatment methods available in the clinic. Understanding the roles of these factors in wound pathophysiology is of central importance in wound treatment. © 2015 by the Wound Healing Society.

  8. Shaping Tumor Microenvironment for Improving Nanoparticle Delivery.

    PubMed

    Gao, Huile

    2016-01-01

    Tumor microenvironment is so complex that involves in many factors of tumor. Although enhanced permeability and retention effect is a main driving force of tumor targeted nanoparticles, the tumor microenvironment greatly affects the delivery efficiency of nanoparticles. A careful search of the scientific database was performed to find the tumor microenvironment related papers. Then the papers were concluded and reviewed. In tumor, elevated interstitial fluid pressure, abnormal tumor vasculature, dense tumor extracellular matrix and elevated solid stress considerably hinder the extravasation and intratumor penetration of nanoparticles. Therefore, shaping the tumor microenvironment could improve nanoparticle delivery, including vascular normalization, vasculature promotion therapy, lymph normalization, reducing tumor stroma components, elevating blood pressure, elevating receptor expression, cell cycle arrest and priming by cytotoxic therapy. Shaping the tumor microenvironment could considerably enhance the nanoparticles delivery.

  9. The Hematopoietic Niche in Myeloproliferative Neoplasms

    PubMed Central

    Schmitt-Graeff, Annette H.; Nitschke, Roland; Zeiser, Robert

    2015-01-01

    Specialized microanatomical areas of the bone marrow provide the signals that are mandatory for the maintenance and regulation of hematopoietic stem cells (HSCs) and progenitor cells. A complex microenvironment adjacent to the marrow vasculature (vascular niche) and close to the endosteum (endosteal niche) harbors multiple cell types including mesenchymal stromal cells and their derivatives such as CAR cells expressing high levels of chemokines C-X-C motif ligand 12 and early osteoblastic lineage cells, endothelial cells, and megakaryocytes. The characterization of the cellular and molecular networks operating in the HSC niche has opened new perspectives for the understanding of the bidirectional cross-talk between HSCs and stromal cell populations in normal and malignant conditions. A structural and functional remodeling of the niche may contribute to the development of myeloproliferative neoplasms (MPN). Malignant HSCs may alter the function and survival of MSCs that do not belong to the neoplastic clone. For example, a regression of nestin+ MSCs by apoptosis has been attributed to neuroglial damage in MPN. Nonneoplastic MSCs in turn can promote aggressiveness and drug resistance of malignant cells. In the future, strategies to counteract the pathological interaction between the niche and neoplastic HSCs may offer additional treatment strategies for MPN patients. PMID:26696752

  10. Hematopoietic stem cells for cancer immunotherapy.

    PubMed

    Gschweng, Eric; De Oliveira, Satiro; Kohn, Donald B

    2014-01-01

    Hematopoietic stem cells (HSCs) provide an attractive target for immunotherapy of cancer and leukemia by the introduction of genes encoding T-cell receptors (TCRs) or chimeric antigen receptors (CARs) directed against tumor-associated antigens. HSCs engraft for long-term blood cell production and could provide a continuous source of targeted anti-cancer effector cells to sustain remissions. T cells produced de novo from HSCs may continuously replenish anti-tumor T cells that have become anergic or exhausted from ex vivo expansion or exposure to the intratumoral microenvironment. In addition, transgenic T cells produced in vivo undergo allelic exclusion, preventing co-expression of an endogenous TCR that could mis-pair with the introduced TCR chains and blunt activity or even cause off-target reactivity. CAR-engineered HSCs may produce myeloid and natural killer cells in addition to T cells expressing the CAR, providing broader anti-tumor activity that arises quickly after transplant and does not solely require de novo thymopoiesis. Use of TCR- or CAR-engineered HSCs would likely require cytoreductive conditioning to achieve long-term engraftment, and this approach may be used in clinical settings where autologous HSC transplant is being performed to add a graft-versus-tumor effect. Results of experimental and preclinical studies performed to date are reviewed.

  11. Fas transduces dual apoptotic and trophic signals in hematopoietic progenitors.

    PubMed

    Pearl-Yafe, Michal; Stein, Jerry; Yolcu, Esma S; Farkas, Daniel L; Shirwan, Haval; Yaniv, Isaac; Askenasy, Nadir

    2007-12-01

    Stem cells and progenitors are often required to realize their differentiation potential in hostile microenvironments. The Fas/Fas ligand (FasL) interaction is a major effector pathway of apoptosis, which negatively regulates the expansion of differentiated hematopoietic cells. The involvement of this molecular interaction in the function of hematopoietic stem and progenitor cells is not well understood. In the murine syngeneic transplant setting, both Fas and FasL are acutely upregulated in bone marrow-homed donor cells; however, the Fas(+) cells are largely insensitive to FasL-induced apoptosis. In heterogeneous populations of lineage-negative (lin(-)) bone marrow cells and progenitors isolated by counterflow centrifugal elutriation, trimerization of the Fas receptor enhanced the clonogenic activity. Inhibition of caspases 3 and 8 did not affect the trophic signals mediated by Fas, yet it efficiently blocked the apoptotic pathways. Fas-mediated tropism appears to be of physiological significance, as pre-exposure of donor cells to FasL improved the radioprotective qualities of hematopoietic progenitors, resulting in superior survival of myeloablated hosts. Under these conditions, the activity of long-term reconstituting cells was not affected, as determined in sequential secondary and tertiary transplants. Dual caspase-independent tropic and caspase-dependent apoptotic signaling place the Fas receptor at an important junction of activation and death. This regulatory mechanism of hematopoietic homeostasis activates progenitors to promote the recovery from aplasia and converts into a negative regulator in distal stages of cell differentiation. Disclosure of potential conflicts of interest is found at the end of this article.

  12. [Glioblastomas: gliomagenesis, genetics, angiogenesis, and microenvironment].

    PubMed

    Figarella-Branger, D; Colin, C; Tchoghandjian, A; Baeza, N; Bouvier, C

    2010-12-01

    Glioblastomas are the most malignant gliomas of the central nervous system. Currently, numerous studies are attempting to decipher their genetic and epigenetic modifications, to identify the cells at the origin of gliomagenesis, and to better understand the molecular bases responsible for invasion and angiogenesis processes. This article reviews recent data on the cellular and molecular biology of gliomas delineated by several teams including ours. We and others have underlined the role played by cancer stem cells in gliomagenesis; the Cancer Genome Atlas Network has described most glioblastoma genetic alterations. According to many studies, glioblastomas derive from malignant transformation of stem cells and/or glial precursor cells. Moreover, the topographic microenvironment is important regarding invasion and angiogenesis processes. Finally, it is now well established, thanks to IDH1 mutation identification, that primary and secondary glioblastomas are two different clinical and genetic entities. Interestingly, IDH1 mutation seems to be a very early genomic modification in astrocytoma, oligodendroglioma, and secondary glioblastoma tumorigenic processes. Regarding all these data, we suggest a hypothetical model of glioma initiation, growth, and progression. Moreover, the histomolecular glioma classification has been substantially revised and new therapeutic targets have been identified. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  13. Endothelial cells mitigate DNA damage and promote the regeneration of hematopoietic stem cells after radiation injury

    PubMed Central

    Zachman, Derek K.; Leon, Ronald P.; Das, Prerna; Goldman, Devorah C.; Hamlin, Kimberly L.; Guha, Chandan; Fleming, William H.

    2014-01-01

    Endothelial cells (ECs) are an essential component of the hematopoietic microenvironment, which maintains and regulates hematopoietic stem cells (HSCs). Although ECs can support the regeneration of otherwise lethally-irradiated HSCs, the mechanisms are not well understood. To further understand this phenomenon, we studied HSC regeneration from irradiated bone marrow using co-culture with human aortic endothelial cells (HAECs). Co-culture with HAECs induced a 24-fold expansion of long-term HSCs (CD150+, lineagelo, Sca-1+, c-Kit+; CD150+LSK cells) in vitro. These cells gave rise to functional hematopoietic stem and progenitor cells (HSPCs) with colony-forming activity, multilineage reconstitution and serial transplantation potential. Furthermore, HAECs significantly reduced DNA damage in irradiated LSK cells within 24 hours. Remarkably, we were able to delay the exposure of irradiated bone marrow to the regenerative, HAEC-derived signals for up to 48 hours and still rescue functional HSCs. G-CSF is the gold standard for promoting hematopoietic regeneration in vivo. However, when compared to HAECs, in vitro G-CSF treatment promoted lineage differentiation and regenerated 5-fold fewer CD150+LSK cells. Together, our results show that HAECs are powerful, direct mitigators of HSC injury and DNA damage. Identification of the HAEC-derived factors that rescue HSCs may lead to improved therapies for hematopoietic regeneration after radiation injury. PMID:23939266

  14. The tale of early hematopoietic cell seeding in the bone marrow niche.

    PubMed

    Yaniv, Isaac; Stein, Jerry; Farkas, Daniel L; Askenasy, Nadir

    2006-02-01

    Since introduction of the notion of a "niche" that hosts engraftment and activity of hematopoietic cells, there is a massive effort to discover its structure and decipher its function. Our understanding of the niche is continuously changing with reinterpretation of traditional concepts and apprehension of new insights into the biology of hematopoietic cell homing, seeding, and engraftment. Here we discuss some of the early events in hematopoietic stem cell seeding and engraftment and propose a perspective based on visualization of labeled bone marrow cells in real time in vivo. Primary seeding of hematopoietic cells in the bone marrow niches evolves as a complex and dynamic process; however, it follows discrete topological and chronological patterns. Initial seeding occurs on the endosteal surface of the marrow, which includes heterogeneous niches for primary seeding. Several days after transplantation the endosteal niches become more restrictive, hosting primarily mitotically quiescent cells, and gradual centripetal migration is accompanied by engagement in proliferation and differentiation. The hematopoietic niches evolve as heterogeneous three-dimensional microenvironments that are continuously changing over time.

  15. Myelomagenesis: capturing early microenvironment changes.

    PubMed

    Korde, Neha; Maric, Irina

    2011-01-01

    Plasma cell neoplasms result from the clonal expansion of terminally differentiated, immunoglobulin heavy-chain class switched B cells that typically secrete a monoclonal immunoglobulin. The 2008 World Health Organization (WHO) classification of plasma cell neoplasms encompasses a broad spectrum of disorders, from the precursor disorder monoclonal gammopathy of undetermined significance (MGUS) to plasma cell leukemia. The classification includes, in addition to precursor lesion MGUS, plasma cell myeloma, plasmacytoma, immunoglobulin deposition diseases, and osteosclerotic myeloma. Plasma cell myeloma is further divided into symptomatic plasma cell myeloma or multiple myeloma (MM), asymptomatic smoldering myeloma (SMM), non-secretory myeloma, and plasma cell leukemia. Although histopathologic cut-off criteria are incorporated into the classification schema, distinction between MGUS, SMM, and MM depends primarily on the presence or absence of end-organ damage, as defined by "CRAB" criteria (hypercalcemia, renal insufficiency, anemia, lytic bone lesions, or a combination of these). Systematic evaluation of pathogenetic differences between MGUS and MM should offer invaluable insights into early myelomagenesis. Given the complex, intertwined nature of the malignant plasma cell and its surroundings, multiple pathogenetic mechanisms play a critical role in interactions between neoplastic cells and their microenvironment. Understanding the events leading to end-organ damage, like anemia and bone remodeling, is a critical part of investigating early myelomagenesis and should provide us with better tools for early identification and treatment of these patients. Published by Elsevier Inc.

  16. Bone Marrow Microenvironment Modulation of Acute Lymphoblastic Leukemia Phenotype

    PubMed Central

    Moses, Blake S; Slone, William L; Thomas, Patrick; Evans, Rebecca; Piktel, Debbie; Angel, Peggi M; Walsh, Callee M; Cantrell, Pamela S; Rellick, Stephanie L; Martin, Karen H; Simpkins, James W; Gibson, Laura F

    2015-01-01

    Acute lymphoblastic leukemia (ALL) treatment regimens have dramatically improved the survival of ALL patients. However, chemoresistant minimal residual disease (MRD) that persists following cessation of therapy contributes to aggressive relapse. The bone marrow microenvironment (BMM) is an established “site of sanctuary” for ALL as well as myeloid lineage hematopoietic disease, with signals in this unique anatomical location contributing to drug resistance. Several models have been developed to recapitulate the interactions between the BMM and ALL cells. However, many in vitro models fail to accurately reflect the level of protection afforded to the most resistant sub-set of leukemic cells during co-culture with BMM elements. Pre-clinical in vivo models have advantages, but can be costly, and are often not fully informed by optimal in vitro studies. In the current report we describe an innovative extension of 2D co-culture wherein ALL cells uniquely interact with bone marrow derived stromal cells. Tumor cells in this model bury beneath primary human bone marrow derived stromal cells or osteoblasts, termed “phase dim” (PD) ALL, and exhibit a unique phenotype characterized by altered metabolism, distinct protein expression profiles, increased quiescence, and pronounced chemotherapy resistance. Investigation focused on the PD subpopulation may more efficiently inform pre-clinical design and investigation of MRD and relapse that arises from BMM supported leukemic tumor cells. PMID:26407636

  17. The Aged Microenvironment Influences Prostate Carcinogenesis

    DTIC Science & Technology

    2008-12-01

    endometrial stromal fibroblast is regulated by paracrine factors secreted by leukocytes8, this finding suggests that the aged smooth-muscle...Poster title: “The Aged Prostate Microenvironment: Implications for Prostate Carcinogenesis” Presented at the MCB Graduate Student Reception

  18. Regulation of invadopodia by the tumor microenvironment

    PubMed Central

    Gould, Christine M; Courtneidge, Sara A

    2014-01-01

    The tumor microenvironment consists of stromal cells, extracellular matrix (ECM), and signaling molecules that communicate with cancer cells. As tumors grow and develop, the tumor microenvironment changes. In addition, the tumor microenvironment is not only influenced by signals from tumor cells, but also stromal components contribute to tumor progression and metastasis by affecting cancer cell function. One of the mechanisms that cancer cells use to invade and metastasize is mediated by actin-rich, proteolytic structures called invadopodia. Here, we discuss how signals from the tumor environment, including growth factors, hypoxia, pH, metabolism, and stromal cell interactions, affect the formation and function of invadopodia to regulate cancer cell invasion and metastasis. Understanding how the tumor microenvironment affects invadopodia biology could aid in the development of effective therapeutics to target cancer cell invasion and metastasis. PMID:24714597

  19. Microenvironment Tracker (MicroTrac) Factsheet

    EPA Pesticide Factsheets

    MicroTrac is a model developed by EPA that uses GPS data to estimate time of day and duration that people spend in different microenvironments, such as indoors and outdoors at home, work, school, and inside vehicles.

  20. Combining Intravital Fluorescent Microscopy (IVFM) with Genetic Models to Study Engraftment Dynamics of Hematopoietic Cells to Bone Marrow Niches.

    PubMed

    Wang, Lin; Kamocka, Malgorzata M; Zollman, Amy; Carlesso, Nadia

    2017-03-21

    Increasing evidence indicates that normal hematopoiesis is regulated by distinct microenvironmental cues in the BM, which include specialized cellular niches modulating critical hematopoietic stem cell (HSC) functions(1)(,)(2). Indeed, a more detailed picture of the hematopoietic microenvironment is now emerging, in which the endosteal and the endothelial niches form functional units for the regulation of normal HSC and their progeny(3)(,)(4)(,)(5). New studies have revealed the importance of perivascular cells, adipocytes and neuronal cells in maintaining and regulating HSC function(6)(,)(7)(,)(8). Furthermore, there is evidence that cells from different lineages, i.e. myeloid and lymphoid cells, home and reside in specific niches within the BM microenvironment. However, a complete mapping of the BM microenvironment and its occupants is still in progress. Transgenic mouse strains expressing lineage specific fluorescent markers or mice genetically engineered to lack selected molecules in specific cells of the BM niche are now available. Knock-out and lineage tracking models, in combination with transplantation approaches, provide the opportunity to refine the knowledge on the role of specific "niche" cells for defined hematopoietic populations, such as HSC, B-cells, T-cells, myeloid cells and erythroid cells. This strategy can be further potentiated by merging the use of two-photon microscopy of the calvarium. By providing in vivo high resolution imaging and 3-D rendering of the BM calvarium, we can now determine precisely the location where specific hematopoietic subsets home in the BM and evaluate the kinetics of their expansion over time. Here, Lys-GFP transgenic mice (marking myeloid cells)(9) and RBPJ knock-out mice (lacking canonical Notch signaling)(10) are used in combination with IVFM to determine the engraftment of myeloid cells to a Notch defective BM microenvironment.

  1. CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells

    PubMed Central

    Vacca, Paola; Vitale, Chiara; Montaldo, Elisa; Conte, Romana; Cantoni, Claudia; Fulcheri, Ezio; Darretta, Valeria; Moretta, Lorenzo; Mingari, Maria Cristina

    2011-01-01

    Natural killer (NK) cells are the main lymphoid population in the maternal decidua during the first trimester of pregnancy. Decidual NK (dNK) cells display a unique functional profile and play a key role in promoting tissue remodeling, neoangiogenesis, and immune modulation. However, little information exists on their origin and development. Here we discovered CD34+ hematopoietic precursors in human decidua (dCD34+). We show that dCD34+ cells differ from cord blood- or peripheral blood-derived CD34+ precursors. The expression of IL-15/IL-2 receptor common β-chain (CD122), IL-7 receptor α-chain (CD127), and mRNA for E4BP4 and ID2 transcription factors suggested that dCD34+ cells are committed to the NK cell lineage. Moreover, they could undergo in vitro differentiation into functional (i.e., IL-8– and IL-22–producing) CD56brightCD16−KIR+/− NK cells in the presence of growth factors or even upon coculture with decidual stromal cells. Their NK cell commitment was further supported by the failure to undergo myeloid differentiation in the presence of GM-CSF. Our findings strongly suggest that decidual NK cells may directly derive from CD34+ cell precursors present in the decidua upon specific cellular interactions with components of the decidual microenvironment. PMID:21248224

  2. Microenvironment of liver regeneration in liver cancer.

    PubMed

    Li, Han-Min; Ye, Zhi-Hua

    2017-07-01

    The occurrence and development of liver cancer are essentially the most serious outcomes of uncontrolled liver regeneration. The progression of liver cancer is inevitably related to the abnormal microenvironment of liver regeneration. The deterioration observed in the microenvironment of liver regeneration is a necessary condition for the occurrence, development and metastasis of cancer. Therefore, the use of a technique to prevent and treat liver cancer via changes in the microenvironment of liver regeneration is a novel strategy. This strategy would be an effective way to delay, prevent or even reverse cancer occurrence, development and metastasis through an improvement in the liver regeneration microenvironment along with the integrated regulation of multiple components, targets, levels, channels and time sequences. In addition, the treatment of "tonifying Shen (Kidney) to regulate liver regeneration and repair by affecting stem cells and their microenvironment" can regulate "the dynamic imbalance between the normal liver regeneration and the abnormal liver regeneration"; this would improve the microenvironment of liver regeneration, which is also a mechanism by which liver cancer may be prevented or treated.

  3. Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation.

    PubMed

    Taya, Yuki; Ota, Yasunori; Wilkinson, Adam C; Kanazawa, Ayano; Watarai, Hiroshi; Kasai, Masataka; Nakauchi, Hiromitsu; Yamazaki, Satoshi

    2016-12-02

    A specialized bone marrow microenvironment (niche) regulates hematopoietic stem cell (HSC) self-renewal and commitment. For successful donor-HSC engraftment, the niche must be emptied via myeloablative irradiation or chemotherapy. However, myeloablation can cause severe complications and even mortality. Here we report that the essential amino acid valine is indispensable for the proliferation and maintenance of HSCs. Both mouse and human HSCs failed to proliferate when cultured in valine-depleted conditions. In mice fed a valine-restricted diet, HSC frequency fell dramatically within 1 week. Furthermore, dietary valine restriction emptied the mouse bone marrow niche and afforded donor-HSC engraftment without chemoirradiative myeloablation. These findings indicate a critical role for valine in HSC maintenance and suggest that dietary valine restriction may reduce iatrogenic complications in HSC transplantation. Copyright © 2016, American Association for the Advancement of Science.

  4. Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function

    PubMed Central

    Kosan, Christian; Godmann, Maren

    2016-01-01

    All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC) have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation. The stem cell niche provides the microenvironment to keep HSC in a quiescent state. Furthermore, several transcription factors and epigenetic modifiers are involved in this process. These create modifications that regulate the cell fate in a more or less reversible and dynamic way and contribute to HSC homeostasis. In addition, HSC respond in a unique way to DNA damage. These mechanisms also contribute to the regulation of HSC function and are essential to ensure viability after DNA damage. How HSC maintain their quiescent stage during the entire life is still matter of ongoing research. Here we will focus on the molecular mechanisms that regulate HSC function. PMID:26798358

  5. Bone Niches, Hematopoietic Stem Cells, and Vessel Formation

    PubMed Central

    Tamma, Roberto; Ribatti, Domenico

    2017-01-01

    Bone marrow (BM) is a source of hematopoietic stem cells (HSCs). HSCs are localized in both the endosteum, in the so-called endosteal niche, and close to thin-walled and fenestrated sinusoidal vessel in the center of BM, in the so-called vascular niche. HSCs give rise to all types of mature blood cells through a process finely controlled by numerous signals emerging from the bone marrow niches where HSCs reside. This review will focus on the description of the role of BM niches in the control of the fate of HSCs and will also highlight the role of the BM niches in the regulation of vasculogenesis and angiogenesis. Moreover, alterations of the signals in niche microenvironment are involved in many aspects of tumor progression and vascularization and further knowledge could provide the basis for the development of new therapeutic strategies. PMID:28098778

  6. Transcriptomic Microenvironment of Lung Adenocarcinoma.

    PubMed

    Bossé, Yohan; Sazonova, Olga; Gaudreault, Nathalie; Bastien, Nathalie; Conti, Massimo; Pagé, Sylvain; Trahan, Sylvain; Couture, Christian; Joubert, Philippe

    2017-03-01

    Background: Tissues surrounding tumors are increasingly studied to understand the biology of cancer development and identify biomarkers.Methods: A unique geographic tissue sampling collection was obtained from patients that underwent curative lobectomy for stage I pulmonary adenocarcinoma. Tumor and nontumor lung samples located at 0, 2, 4, and 6 cm away from the tumor were collected. Whole-genome gene expression profiling was performed on all samples (n = 5 specimens × 12 patients = 60). Analyses were carried out to identify genes differentially expressed in the tumor compared with adjacent nontumor lung tissues at different distances from the tumor as well as to identify stable and transient genes in nontumor tissues with respect to tumor proximity.Results: The magnitude of gene expression changes between tumor and nontumor sites was similar with increasing distance from the tumor. A total of 482 up- and 843 downregulated genes were found in tumors, including 312 and 566 that were consistently differentially expressed across nontumor sites. Twenty-nine genes induced and 34 knocked-down in tumors were also identified. Tumor proximity analyses revealed 15,700 stable genes in nontumor lung tissues. Gene expression changes across nontumor sites were subtle and not statistically significant.Conclusions: This study describes the transcriptomic microenvironment of lung adenocarcinoma and adjacent nontumor lung tissues collected at standardized distances relative to the tumor.Impact: This study provides further insights about the molecular transitions that occur from normal tissue to lung adenocarcinoma and is an important step to develop biomarkers in nonmalignant lung tissues. Cancer Epidemiol Biomarkers Prev; 26(3); 389-96. ©2016 AACR.

  7. Catalog of gene expression in adult neural stem cells and their in vivo microenvironment

    SciTech Connect

    Williams, Cecilia; Wirta, Valtteri; Meletis, Konstantinos; Wikstroem, Lilian; Carlsson, Leif; Frisen, Jonas; Lundeberg, Joakim . E-mail: joakim.lundeberg@biotech.kth.se

    2006-06-10

    Stem cells generally reside in a stem cell microenvironment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique stemness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research.

  8. Osteoblastic and Vascular Endothelial Niches, Their Control on Normal Hematopoietic Stem Cells, and Their Consequences on the Development of Leukemia

    PubMed Central

    Guerrouahen, Bella S.; Al-Hijji, Ibrahim; Tabrizi, Arash Rafii

    2011-01-01

    Stem cell self-renewal is regulated by intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments called “niches.” The best-characterized stem cell is the hematopoietic stem cell (HSC). Self-renewal and differentiation ability of HSC are regulated by two major elements: endosteal and vascular regulatory elements. The osteoblastic niche localized at the inner surface of the bone cavity might serve as a reservoir for long-term HSC storage in a quiescent state. Whereas the vascular niche, which consists of sinusoidal endothelial cell lining blood vessel, provides an environment for short-term HSC proliferation and differentiation. Both niches act together to maintain hematopoietic homeostasis. In this paper, we provide some principles applying to the hematopoietic niches, which will be useful in the study and understanding of other stem cell niches. We will discuss altered microenvironment signaling leading to myeloid lineage disease. And finally, we will review some data on the development of acute myeloid leukemia from a subpopulation called leukemia-initiating cells (LIC), and we will discuss on the emerging evidences supporting the influence of the microenvironment on chemotherapy resistance. PMID:22190963

  9. Hematopoietic Processes in Eosinophilic Asthma.

    PubMed

    Salter, Brittany M; Sehmi, Roma

    2017-08-01

    Airway eosinophilia is a hallmark of allergic asthma, and understanding mechanisms that promote increases in lung eosinophil numbers is important for effective pharmacotherapeutic development. It has become evident that expansion of hematopoietic compartments in the bone marrow (BM) promotes differentiation and trafficking of mature eosinophils to the airways. Hematopoietic progenitor cells egress the BM and home to the lungs, where in situ differentiation within the tissue provides an ongoing source of proinflammatory cells. In addition, hematopoietic progenitor cells in the airways can respond to locally derived alarmins to produce a panoply of cytokines, thereby themselves acting as effector proinflammatory cells that potentiate type 2 responses in eosinophilic asthma. In this review, we provide evidence for these findings and discuss novel targets for modulating eosinophilopoietic processes, migration, and effector function of precursor cells. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  10. Perturbation of single hematopoietic stem cell fates in artificial niches†

    PubMed Central

    Havenstrite, Karen; Koleckar, Kassie

    2010-01-01

    Hematopoietic stem cells (HSCs) are capable of extensive self-renewal in vivo and are successfully employed clinically to treat hematopoietic malignancies, yet are in limited supply as in culture this self-renewal capacity is lost. Using an approach at the interface of stem cell biology and bioengineering, here we describe a novel platform of hydrogel microwell arrays for assessing the effects of either secreted or tethered proteins characteristic of the in vivo microenvironment, or niche, on HSC fate in vitro. Time-lapse microscopic analyses of single cells were crucial to overcoming inevitable heterogeneity of FACS-enriched HSCs. A reduction in proliferation kinetics or an increase in asynchronous division of single HSCs in microwells in response to specific proteins (Wnt3a and N-Cadherin) correlated well with subsequent serial long-term blood reconstitution in mice in vivo. Single cells that divided once in the presence of a given protein were capable of in vivo reconstitution, providing evidence of self-renewal divisions of HSCs in vitro. These results validate the hydrogel microwell platform as a broadly applicable paradigm for dissecting the regulatory role of specific signals within a complex stem cell niche. PMID:20023792

  11. Effects of erythropoietin on the bone microenvironment.

    PubMed

    McGee, S J; Havens, A M; Shiozawa, Y; Jung, Y; Taichman, R S

    2012-02-01

    It has been well established that blood and bone share a unique, regulatory relationship with one another, though the specifics of this relationship still remain unanswered. Erythropoietin (Epo) is known primarily for its role as a hematopoietic hormone. However, after the discovery of Epo receptor outside the hematopoietic tissues, Epo has been avidly studied for its possible nonhematopoietic effects. It has been proposed that Epo interacts with bone both directly, by activating bone marrow stromal cells, and indirectly, through signaling pathways on hematopoietic stem cells. Yet, the role of Epo in regulating skeletal maintenance and regeneration remains controversial. Here, we review the current state of knowledge pertaining to the effects of Epo on the skeleton.

  12. The combined influence of substrate elasticity and ligand density on the viability and biophysical properties of hematopoietic stem and progenitor cells.

    PubMed

    Choi, Ji S; Harley, Brendan A C

    2012-06-01

    Hematopoietic stem cells (HSCs) are adult stem cells with the capacity to give rise to all blood and immune cells in the body. HSCs are housed in a specialized microenvironment known as the stem cell niche, which provides intrinsic and extrinsic signals to regulate HSC fate: quiescence, self-renewal, differentiation, mobilization, homing, and apoptosis. These niches provide a complex, three dimensional (3D) microenvironment consisting of cells, the extracellular matrix (ECM), and ECM-bound or soluble biomolecules that provides cellular, structural, and molecular signals that regulate HSC fate decisions. In this study, we examined the decoupled effects of substrate elasticity, construct dimensionality, and ligand concentration on the biophysical properties of primary hematopoietic stem and progenitor cells (HSPCs) using homologous series of two and three dimensional microenvironments. Microenvironments were chosen to span the range of biophysical environments presented physiologically within the bone marrow, ranging from soft marrow and adipose tissue (<1 kPa), to surrounding cell membranes (1-3 kPa), to developing osteoid (>30 kPa). We additionally investigated the influence of collagen ligand density on HSPC biophysical parameters and compared these behaviors to those observed in HSPCs grown in culture on stiff glass substrates. This work suggests the potential for substrate stiffness and ligand density to directly affect the biophysical properties of primary hematopoietic stem and progenitor cells at the single cell level and that these parameters may be critical design criteria for the development of artificial HSC niches.

  13. Engineering the hematopoietic stem cell niche: Frontiers in biomaterial science.

    PubMed

    Choi, Ji Sun; Mahadik, Bhushan P; Harley, Brendan A C

    2015-10-01

    Hematopoietic stem cells (HSCs) play a crucial role in the generation of the body's blood and immune cells. This process takes place primarily in the bone marrow in specialized 'niche' microenvironments, which provide signals responsible for maintaining a balance between HSC quiescence, self-renewal, and lineage specification required for life-long hematopoiesis. While our understanding of these signaling mechanisms continues to improve, our ability to engineer them in vitro for the expansion of clinically relevant HSC populations is still lacking. In this review, we focus on development of biomaterials-based culture platforms for in vitro study of interactions between HSCs and their local microenvironment. The tools and techniques used for both examining HSC-niche interactions as well as applying these findings towards controlled HSC expansion or directed differentiation in 2D and 3D platforms are discussed. These novel techniques hold the potential to push the existing boundaries of HSC cultures towards high-throughput, real-time, and single-cell level biomimetic approaches that enable a more nuanced understanding of HSC regulation and function. Their application in conjunction with innovative biomaterial platforms can pave the way for engineering artificial bone marrow niches for clinical applications as well as elucidating the pathology of blood-related cancers and disorders. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Engineering the hematopoietic stem cell niche: Frontiers in biomaterial science

    PubMed Central

    Choi, Ji Sun; Mahadik, Bhushan P.; Harley, Brendan A. C.

    2016-01-01

    Hematopoietic stem cells (HSCs) play a crucial role in the generation of the body’s blood and immune cells. This process takes place primarily in the bone marrow in specialized ‘niche’ microenvironments, which provide signals responsible for maintaining a balance between HSC quiescence, self-renewal, and lineage specification required for life-long hematopoiesis. While our understanding of these signaling mechanisms continues to improve, our ability to engineer them in vitro for the expansion of clinically relevant HSC populations is still lacking. In this review, we focus on development of biomaterials-based culture platforms for in vitro study of interactions between HSCs and their local microenvironment. The tools and techniques used for both examining HSC-niche interactions as well as applying these findings towards controlled HSC expansion or directed differentiation in 2D and 3D platforms are discussed. These novel techniques hold the potential to push the existing boundaries of HSC cultures towards high-throughput, real-time, and single-cell level biomimetic approaches that enable a more nuanced understanding of HSC regulation and function. Their application in conjunction with innovative biomaterial platforms can pave the way for engineering artificial bone marrow niches for clinical applications as well as elucidating the pathology of blood-related cancers and disorders. PMID:26356030

  15. Engineering biomolecular microenvironments for cell instructive biomaterials.

    PubMed

    Custódio, Catarina A; Reis, Rui L; Mano, João F

    2014-06-01

    Engineered cell instructive microenvironments with the ability to stimulate specific cellular responses are a topic of high interest in the fabrication and development of biomaterials for application in tissue engineering. Cells are inherently sensitive to the in vivo microenvironment that is often designed as the cell "niche." The cell "niche" comprising the extracellular matrix and adjacent cells, influences not only cell architecture and mechanics, but also cell polarity and function. Extensive research has been performed to establish new tools to fabricate biomimetic advanced materials for tissue engineering that incorporate structural, mechanical, and biochemical signals that interact with cells in a controlled manner and to recapitulate the in vivo dynamic microenvironment. Bioactive tunable microenvironments using micro and nanofabrication have been successfully developed and proven to be extremely powerful to control intracellular signaling and cell function. This Review is focused in the assortment of biochemical signals that have been explored to fabricate bioactive cell microenvironments and the main technologies and chemical strategies to encode them in engineered biomaterials with biological information.

  16. Hyaluronan: A modulator of the tumor microenvironment.

    PubMed

    Chanmee, Theerawut; Ontong, Pawared; Itano, Naoki

    2016-05-28

    Tumors are cellular masses formed through dynamic interactions between tumor cells and a mixed population of stromal cells. Crosstalk between oncogenic and adjacent stromal cells contributes to the formation of a "tumor microenvironment" influencing the tumor cell behaviors of proliferation, invasion, and metastatic spread throughout cancer progression. The composition and structure of the tumor microenvironment vary among different types of tumors and are extensively remodeled in close association with tumor advancement. The tumor microenvironment is composed not only of cellular compartments, such as endothelial cells, fibroblasts, inflammatory cells, and immune cells, but also of bioactive substances, including growth factors and the extracellular matrix. Hyaluronan (HA) is a major component of the extracellular matrix, and the degree of HA accumulation is strongly correlated with a poor prognosis in advanced cancer patients. Emerging evidence has suggested that HA creates a specific microenvironment that is favorable for tumor angiogenesis, invasion, and metastasis. This review highlights the prominent roles of HA as a modulator of the tumor microenvironment and addresses the recent advances regarding HA function in cancer stem cell niches. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Molecular imaging of the tumor microenvironment.

    PubMed

    Zhou, Zhuxian; Lu, Zheng-Rong

    2017-04-01

    The tumor microenvironment plays a critical role in tumor initiation, progression, metastasis, and resistance to therapy. It is different from normal tissue in the extracellular matrix, vascular and lymphatic networks, as well as physiologic conditions. Molecular imaging of the tumor microenvironment provides a better understanding of its function in cancer biology, and thus allowing for the design of new diagnostics and therapeutics for early cancer diagnosis and treatment. The clinical translation of cancer molecular imaging is often hampered by the high cost of commercialization of targeted imaging agents as well as the limited clinical applications and small market size of some of the agents. Because many different cancer types share similar tumor microenvironment features, the ability to target these biomarkers has the potential to provide clinically translatable molecular imaging technologies for a spectrum of cancers and broad clinical applications. There has been significant progress in targeting the tumor microenvironment for cancer molecular imaging. In this review, we summarize the principles and strategies of recent advances made in molecular imaging of the tumor microenvironment, using various imaging modalities for early detection and diagnosis of cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. The tumor microenvironment in hepatocellular carcinoma (review).

    PubMed

    Leonardi, Giulia Costanza; Candido, Saverio; Cervello, Melchiorre; Nicolosi, Daria; Raiti, Fabio; Travali, Salvatore; Spandidos, Demetrios A; Libra, Massimo

    2012-06-01

    The tumor microenvironment has been largely studied as a dynamic system orchestrated by inflammatory cells, including cancer cells, stroma as well as the extracellular matrix. It is useful to describe and predict the phenotypic characteristics of cancer. Furthermore, a better understanding of its interplay with the various aspects of the tumor cells may be utilized for the discovery of novel molecular targets. Liver cancer is considered a model of the relation occurring between the tumor micro-environment and tumor development. The chronic inflammatory status of the liver, sustained by the infection of hepatitis viruses, as well as the production of cytokines and growth factors within the parenchyma, lead to an intricate microenvironment. The identification of novel molecular therapeutic targets may improve the outcome of patients with liver cancer as it remains the third leading cause of cancer death worldwide. In the present study, the tumor microenvironment in hepatocellular carcinoma (HCC) was explored by a review of the literature. Studies on hepatitis virus infections and the consequent chronic inflammatory status were examined. In this context, immune-mediated and/or virus-related molecular mechanisms have been hypothesized as being responsible for liver cancer development. The interlink among HCC microenvironment components, comprising cellular elements, cytokines, growth factors and several proteins is also described together with the role of matrix metalloproteinases in HCC development. Finally, the rationale for targeting tumor-stromal interface is summarized in the context of new therapeutic opportunities.

  19. Activated macrophages in the tumour microenvironment – dancing to the tune of TLR and NF-κB

    PubMed Central

    Hallam, Simon; Escorcio-Correia, Monica; Soper, Robin; Schultheiss, Anne; Hagemann, Thorsten

    2010-01-01

    A large number of variables have been identified which appear to influence macrophage phenotype within the tumour microenvironment. These include reciprocal chemical and physical interactions with tumour cells and with non-malignant cells of the tumour microenvironment, tissue oxygen tension, and the origin and prior experience of the particular macrophage population. In this review we outline the key evidence for these influences and consider how macrophage phenotype is acquired and the relevance of the TLR/NF-κB pathway. PMID:19662665

  20. The Hematopoietic System in the Context of Regenerative Medicine

    PubMed Central

    Porada, Christopher D.; Atala, Anthony J.; Almeida-Porada, Graça

    2015-01-01

    Hematopoietic stem cells (HSC) represent the prototype stem cell within the body. Since their discovery, HSC have been the focus of intensive research, and have proven invaluable clinically to restore hematopoiesis following inadvertent radiation exposure and following radio/chemotherapy to eliminate hematologic tumors. While they were originally discovered in the bone marrow, HSC can also be isolated from umbilical cord blood and can be “mobilized” peripheral blood, making them readily available in relatively large quantities. While their ability to repopulate the entire hematopoietic system would already guarantee HSC a valuable place in regenerative medicine, the finding that hematopoietic chimerism can induce immunological tolerance to solid organs and correct autoimmune diseases has dramatically broadened their clinical utility. The demonstration that these cells, through a variety of mechanisms, can also promote repair/regeneration of non-hematopoietic tissues as diverse as liver, heart, and brain has further increased their clinical value. The goal of this review is to provide the reader with a brief glimpse into the remarkable potential HSC possess, and to highlight their tremendous value as therapeutics in regenerative medicine. PMID:26319943

  1. Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View.

    PubMed

    Cavazzana, Marina; Ribeil, Jean-Antoine; Lagresle-Peyrou, Chantal; André-Schmutz, Isabelle

    2017-01-15

    When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject: metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD). In all other settings [X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase deficiency, Wiskott-Aldrich syndrome, and β-hemoglobinopathies], the bone marrow content of the different stem and precursor cells and the cells' relationship with the stroma have very specific characteristics. These peculiarities can influence the cells' harvesting and behavior in culture, and the postgraft uptake and further behavior of the gene-modified hematopoietic/precursor cells. In the present mini-review, we shall briefly summarize these characteristics and outline the possible consequences and challenges.

  2. Hematopoietic stem cell compartment: Acute and late effects of radiation therapy an chemotherapy

    SciTech Connect

    Mauch, P.; Constine, L.; Greenberger, J.

    1995-03-30

    The bone marrow is an important dose-limiting cell renewal tissue for chemotherapy, wide-field irradiation, and autologous bone marrow transplantion. Over the past 5-10 years a great deal has been discovered about the hematopoietic stem cell compartment. Although the toxicity associated with prolonged myelosuppression continue to limit the wider use of chemotherapy and irradiation, ways are being discovered to circumvent this toxicity such as with the increasing use of cytokines. This review describes what is known of how chemotherapy and irradiation damage stem cells and the microenvironment, how cytokines protect hematopoietic cells from radiation damage and speed marrow recovery after chemotherapy or marrow transplantation, and how various types of blood marrow cells contribute to engraftment and long-term hematopoiesis after high doses of cytotoxic agents and/or total body irradiation. 167 refs., 7 figs., 6 tabs.

  3. Bone Marrow Homing and Engraftment Defects of Human Hematopoietic Stem and Progenitor Cells

    PubMed Central

    Caocci, Giovanni; Greco, Marianna; La Nasa, Giorgio

    2017-01-01

    Homing of hematopoietic stem cells (HSC) to their microenvironment niches in the bone marrow is a complex process with a critical role in repopulation of the bone marrow after transplantation. This active process allows for migration of HSC from peripheral blood and their successful anchoring in bone marrow before proliferation. The process of engraftment starts with the onset of proliferation and must, therefore, be functionally dissociated from the former process. In this overview, we analyze the characteristics of stem cells (SCs) with particular emphasis on their plasticity and ability to find their way home to the bone marrow. We also address the problem of graft failure which remains a significant contributor to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Within this context, we discuss non-malignant and malignant hematological disorders treated with reduced-intensity conditioning regimens or grafts from human leukocyte antigen (HLA)-mismatched donors. PMID:28512561

  4. Bone Marrow Homing and Engraftment Defects of Human Hematopoietic Stem and Progenitor Cells.

    PubMed

    Caocci, Giovanni; Greco, Marianna; La Nasa, Giorgio

    2017-01-01

    Homing of hematopoietic stem cells (HSC) to their microenvironment niches in the bone marrow is a complex process with a critical role in repopulation of the bone marrow after transplantation. This active process allows for migration of HSC from peripheral blood and their successful anchoring in bone marrow before proliferation. The process of engraftment starts with the onset of proliferation and must, therefore, be functionally dissociated from the former process. In this overview, we analyze the characteristics of stem cells (SCs) with particular emphasis on their plasticity and ability to find their way home to the bone marrow. We also address the problem of graft failure which remains a significant contributor to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Within this context, we discuss non-malignant and malignant hematological disorders treated with reduced-intensity conditioning regimens or grafts from human leukocyte antigen (HLA)-mismatched donors.

  5. Hyaluronan Is Required for Generation of Hematopoietic Cells during Differentiation of Human Embryonic Stem Cells

    PubMed Central

    Schraufstatter, Ingrid U.; Serobyan, Naira; Loring, Jeanne; Khaldoyanidi, Sophia K.

    2010-01-01

    Hyaluronan (HA) is an important component of the microenvironment in bone marrow, but its role in regulation of the development of hematopoietic cells is not well understood. To address the role of HA in regulation of human embryonic stem cell (hESC) differentiation into the hematopoietic lineage, we screened for genes encoding components of the HA pathway. Using gene arrays, we found that HA synthases and HA receptors are expressed in both undifferentiated and differentiating hESCs. Enzymatic degradation of HA resulted in decreased numbers of hematopoietic progenitors and lower numbers of CD45+ cells generated in HA-deprived embryoid bodies (EBs). In addition, deprivation of HA resulted in the inhibition of generation of CD31+ cells, stromal fibroblast-like cells and contracting myocytes in EBs. RT-PCR and immunocytochemistry revealed that HA deprivation did not influence the dynamics of OCT4 expression, but decreased the expression of BRY, an early mesoderm marker, and BMP2, a later mesoderm marker in differentiating EBs. In addition, the endoderm markers α-FP and SOX17 were decreased, whereas the expression of the ectoderm markers GFAP and FGF5 was higher in HA-deprived cultures. Our findings indicate that endogenously produced HA contributes to the network that regulates the differentiation of hESC and the generation of mesodermal lineage in general and hematopoietic cells specifically. PMID:20861924

  6. Image Analysis of the Tumor Microenvironment.

    PubMed

    Lloyd, Mark C; Johnson, Joseph O; Kasprzak, Agnieszka; Bui, Marilyn M

    2016-01-01

    In the field of pathology it is clear that molecular genomics and digital imaging represent two promising future directions, and both are as relevant to the tumor microenvironment as they are to the tumor itself (Beck AH et al. Sci Transl Med 3(108):108ra113-08ra113, 2011). Digital imaging, or whole slide imaging (WSI), of glass histology slides facilitates a number of value-added competencies which were not previously possible with the traditional analog review of these slides under a microscope by a pathologist. As an important tool for investigational research, digital pathology can leverage the quantification and reproducibility offered by image analysis to add value to the pathology field. This chapter will focus on the application of image analysis to investigate the tumor microenvironment and how quantitative investigation can provide deeper insight into our understanding of the tumor to tumor microenvironment relationship.

  7. Automated Identification and Localization of Hematopoietic Stem Cells in 3D Intravital Microscopy Data

    PubMed Central

    Khorshed, Reema A.; Hawkins, Edwin D.; Duarte, Delfim; Scott, Mark K.; Akinduro, Olufolake A.; Rashidi, Narges M.; Spitaler, Martin; Lo Celso, Cristina

    2015-01-01

    Summary Measuring three-dimensional (3D) localization of hematopoietic stem cells (HSCs) within the bone marrow microenvironment using intravital microscopy is a rapidly expanding research theme. This approach holds the key to understanding the detail of HSC-niche interactions, which are critical for appropriate stem cell function. Due to the complex tissue architecture of the bone marrow and to the progressive introduction of scattering and signal loss at increasing imaging depths, there is no ready-made software to handle efficient segmentation and unbiased analysis of the data. To address this, we developed an automated image analysis tool that simplifies and standardizes the biological interpretation of 3D HSC microenvironment images. The algorithm identifies HSCs and measures their localization relative to surrounding osteoblast cells and bone collagen. We demonstrate here the effectiveness, consistency, and accuracy of the proposed approach compared to current manual analysis and its wider applicability to analyze other 3D bone marrow components. PMID:26120058

  8. Using microenvironment to engineer stem cell function.

    PubMed

    Chen, Christopher S

    2004-01-01

    Stem cells differentiate into different lineages depending on the local cues present in their microenvironment. While soluble cues have been studied in great depth, little is known about the role of insoluble cues such as cell adhesion and mechanical forces. We now show that human mesenchymal stem cells (MSCs) commit to different lineages depending on their physical microenvironment. Using microfabricated tools, we found that cell shape regulates MSCs commitment, and does so through a cytoskeletal tension-dependent pathway. We will discuss the novel tools that we are developing to study these mechanical signals, and how they have informed us about how cells probe and respond to their environment.

  9. Influence of the tumor microenvironment on angiogenesis.

    PubMed

    Payne, Sarah J L; Jones, Louise

    2011-03-01

    It is becoming increasingly recognized that the host microenvironment is essential for regulating tumor cell behavior. The cellular stromal compartment can modulate angiogenesis either directly through enhanced secretion of pro-angiogenic factors or reduced secretion of antiangiogenic factors, or indirectly by modulating the surrounding extracellular matrix. Control of angiogenesis represents a critical step in cancer progression and is a potential therapeutic target. This article focuses on the role of the tumor microenvironment in the control of angiogenesis and how dissection of the molecular interactions may enhance prognostic and predictive power and facilitate therapeutic targeting.

  10. Human and murine amniotic fluid c-Kit+Lin- cells display hematopoietic activity.

    PubMed

    Ditadi, Andrea; de Coppi, Paolo; Picone, Olivier; Gautreau, Laetitia; Smati, Rim; Six, Emmanuelle; Bonhomme, Delphine; Ezine, Sophie; Frydman, René; Cavazzana-Calvo, Marina; André-Schmutz, Isabelle

    2009-04-23

    We have isolated c-Kit(+)Lin(-) cells from both human and murine amniotic fluid (AF) and investigated their hematopoietic potential. In vitro, the c-Kit(+)Lin(-) population in both species displayed a multilineage hematopoietic potential, as demonstrated by the generation of erythroid, myeloid, and lymphoid cells. In vivo, cells belonging to all 3 hematopoietic lineages were found after primary and secondary transplantation of murine c-Kit(+)Lin(-) cells into immunocompromised hosts, thus demonstrating the ability of these cells to self-renew. Gene expression analysis of c-Kit(+) cells isolated from murine AF confirmed these results. The presence of cells with similar characteristics in the surrounding amnion indicates the possible origin of AF c-Kit(+)Lin(-) cells. This is the first report showing that cells isolated from the AF do have hematopoietic potential; our results support the idea that AF may be a new source of stem cells for therapeutic applications.

  11. Genetic modification of hematopoietic stem cells with nonviral systems: past progress and future prospects.

    PubMed

    Papapetrou, E P; Zoumbos, N C; Athanassiadou, A

    2005-10-01

    Serious unwanted complications provoked by retroviral gene transfer into hematopoietic stem cells (HSCs) have recently raised the need for the development and assessment of alternative gene transfer vectors. Within this context, nonviral gene transfer systems are attracting increasing interest. Their main advantages include low cost, ease of handling and large-scale production, large packaging capacity and, most importantly, biosafety. While nonviral gene transfer into HSCs has been restricted in the past by poor transfection efficiency and transient maintenance, in recent years, biotechnological developments are converting nonviral transfer into a realistic approach for genetic modification of cells of hematopoietic origin. Herein we provide an overview of past accomplishments in the field of nonviral gene transfer into hematopoietic progenitor/stem cells and we point at future challenges. We argue that episomally maintained self-replicating vectors combined with physical methods of delivery show the greatest promise among nonviral gene transfer strategies for the treatment of disorders of the hematopoietic system.

  12. Multiple Myeloma and the immune microenvironment.

    PubMed

    Kawano, Yawara; Roccaro, Aldo M; Azzi, Jamil; Ghobrial, Irene M

    2017-02-13

    One of the great advances in the field of cancer therapy in recent years is the emergence of immune therapies. Immune therapies, especially immune checkpoint inhibitors, have shown promising results in pre-clinical models and clinical trials of solid tumors, such as melanoma, breast cancer and lung cancer. Therapeutic strategies targeting the immune microenvironment have also been applied to hematological malignancies such as multiple myeloma (MM), a plasma cell neoplasia characterized by clonal expansion of malignant plasma cells mainly in the bone marrow (BM). MM is associated with both cellular and humoral immune deficiencies, indicating that the evolution of the disease from a precursor state (monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (sMM)) is associated with an immunosuppressive milieu that fosters immune escape and tumor growth. Despite significant advances in treatment, MM is mostly an incurable diseases. Therefore, there is an urgent need of novel therapeutic agents that not only target the tumor clone but also the MM immune microenvironment. However, the complexity of the BM microenvironment and heterogeneity of tumor cell clones make it a difficult task for developing appropriate immune therapies of MM. In this article we review the current knowledge of the interaction between malignant plasma cells and the bone marrow immune microenvironment during disease progression. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Fusion-derived epithelial cancer cells express hematopoietic markers and contribute to stem cell and migratory phenotype in ovarian carcinoma.

    PubMed

    Ramakrishnan, Mallika; Mathur, Sandeep R; Mukhopadhyay, Asok

    2013-09-01

    For a long time, the external milieu of cancer cells was considered to be of secondary importance when compared with its intrinsic properties. That has changed now as the microenvironment is considered to be a major contributing factor toward the progression of tumor. In this study, we show that in human and mouse epithelial ovarian carcinoma and mouse lung carcinoma, the interaction between tumor-infiltrating hematopoietic cells and epithelial cancer cells results in their fusion. Intriguingly, even after the fusion event, cancer cells retain the expression of the pan-hematopoietic marker (CD45) and various markers of hematopoietic lineage, including those of hematopoietic stem cells, indicating that the hematopoietic genome is not completely reprogrammed. This observation may have implications on the bone marrow contribution to the cancer stem cell population. Interestingly, it was seen that in both cancer models, the expression of chemokine receptor CXCR4 was largely contributed to by the fused compartment of cancer cells. We hypothesize that the superior migratory potential gained by the cancer cells due to the fusion helps in its dissemination to various secondary organs upon activation of the CXCR4/CXCL12 axis. We are the first to report the presence of a hemato-epithelial cancer compartment, which contributes to stem cell markers and CXCR4 in epithelial carcinoma. This finding has repercussions on CXCR4-based therapeutics and opens new avenues in discovering novel molecular targets against fusion and metastasis.

  14. Proteomic profiling of the cancer microenvironment by antibody arrays.

    PubMed

    Knezevic, V; Leethanakul, C; Bichsel, V E; Worth, J M; Prabhu, V V; Gutkind, J S; Liotta, L A; Munson, P J; Petricoin, E F; Krizman, D B

    2001-10-01

    Critical changes in protein expression that enable tumors to initiate and progress originate in the local tissue microenvironment, and there are increasing indications that these microenvironmental alterations in protein expression play critical roles in shaping and directing this process. As a model to better understand how patterns of protein expression shape the tissue microenvironment, we analyzed protein expression in tissue derived from squamous cell carcinoma of the oral cavity through an antibody microarray approach for high-throughput proteomic analysis. Utilizing laser capture microdissection to procure total protein from specific microscopic cellular populations, we demonstrate that quantitative, and potentially qualitative, differences in expression patterns of multiple proteins within epithelial cells reproducibly correlate with oral cavity tumor progression. Furthermore, differential expression of multiple proteins was also found in stromal cells surrounding and adjacent to regions of diseased epithelium that directly correlated with tumor progression of the epithelium. Most of the proteins identified in both cell types are involved in signal transduction pathways, thus we hypothesize that extensive molecular communication involving complex cellular signaling between epithelium and stroma play a key role in driving oral cavity cancer progression.

  15. Nanocomposite Membranes Enhance Bone Regeneration Through Restoring Physiological Electric Microenvironment.

    PubMed

    Zhang, Xuehui; Zhang, Chenguang; Lin, Yuanhua; Hu, Penghao; Shen, Yang; Wang, Ke; Meng, Song; Chai, Yuan; Dai, Xiaohan; Liu, Xing; Liu, Yun; Mo, Xiaoju; Cao, Cen; Li, Shue; Deng, Xuliang; Chen, Lili

    2016-08-23

    Physiological electric potential is well-known for its indispensable role in maintaining bone volume and quality. Although implanted biomaterials simulating structural, morphological, mechanical, and chemical properties of natural tissue or organ has been introduced in the field of bone regeneration, the concept of restoring physiological electric microenvironment remains ignored in biomaterials design. In this work, a flexible nanocomposite membrane mimicking the endogenous electric potential is fabricated to explore its bone defect repair efficiency. BaTiO3 nanoparticles (BTO NPs) were first coated with polydopamine. Then the composite membranes are fabricated with homogeneous distribution of Dopa@BTO NPs in poly(vinylidene fluoridetrifluoroethylene) (P(VDF-TrFE)) matrix. The surface potential of the nanocomposite membranes could be tuned up to -76.8 mV by optimizing the composition ratio and corona poling treatment, which conform to the level of endogenous biopotential. Remarkably, the surface potential of polarized nanocomposite membranes exhibited a dramatic stability with more than half of original surface potential remained up to 12 weeks in the condition of bone defect. In vitro, the membranes encouraged bone marrow mesenchymal stem cells (BM-MSCs) activity and osteogenic differentiation. In vivo, the membranes sustainably maintained the electric microenvironment giving rise to rapid bone regeneration and complete mature bone-structure formation. Our findings evidence that physiological electric potential repair should be paid sufficient attention in biomaterials design, and this concept might provide an innovative and well-suited strategy for bone regenerative therapies.

  16. Pulmonary emphysema and tumor microenvironment in primary lung cancer.

    PubMed

    Murakami, Junichi; Ueda, Kazuhiro; Sano, Fumiho; Hayashi, Masataro; Nishimoto, Arata; Hamano, Kimikazu

    2016-02-01

    To clarify the relationship between the presence of pulmonary emphysema and tumor microenvironment and their significance for the clinicopathologic aggressiveness of non-small cell lung cancer. The subjects included 48 patients with completely resected and pathologically confirmed stage I non-small cell lung cancer. Quantitative computed tomography was used to diagnose pulmonary emphysema, and immunohistochemical staining was performed to evaluate the matrix metalloproteinase (MMP) expression status in the intratumoral stromal cells as well as the microvessel density (MVD). Positive MMP-9 staining in the intratumoral stromal cells was confirmed in 17 (35%) of the 48 tumors. These 17 tumors were associated with a high MVD, frequent lymphovascular invasion, a high proliferative activity, and high postoperative recurrence rate (all, P < 0.05). The majority of the tumors (13 of 17) arose in patients with pulmonary emphysema (P = 0.02). Lung cancers arising from pulmonary emphysema were also associated with a high MVD, proliferative activity, and postoperative recurrence rate (all, P < 0.05). The MMP-9 expression in intratumoral stromal cells is associated with the clinicopathologic aggressiveness of lung cancer and is predominantly identified in tumors arising in emphysematous lungs. Further studies regarding the biological links between the intratumoral and extratumoral microenvironment will help to explain why lung cancers originating in emphysematous lung tissues are associated with a poor prognosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Aging promotes neoplastic disease through effects on the tissue microenvironment

    PubMed Central

    Doratiotto, Silvia; Sini, Marcella; Fanti, Maura; Cadoni, Erika; Serra, Monica; Laconi, Ezio

    2016-01-01

    A better understanding of the complex relationship between aging and cancer will provide important tools for the prevention and treatment of neoplasia. In these studies, the hypothesis was tested that aging may fuel carcinogenesis via alterations imposed in the tissue microenvironment. Preneoplastic hepatocytes isolated from liver nodules were orthotopically injected into either young or old syngeneic rats and their fate was followed over time using the dipeptidyl-peptidase type IV (DPPIV) system to track donor-derived-cells. At 3 months post-Tx, the mean size of donor-derived clusters was 11±3 cells in young vs. 42±8 in old recipients. At 8 months post-Tx, no visible lesion were detected in any of 21 young recipients, while 17/18 animals transplanted at old age displayed hepatic nodules, including 7 large tumors. All tumors expressed the DPPIV marker enzyme, indicating that they originated from transplanted cells. Expression of senescence-associated β-galactosidase was common in liver of 18-month old animals, while it was a rare finding in young controls. Finally, both mRNA and IL6 protein were found to be increased in the liver of aged rats compared to young controls. These results are interpreted to indicate that the microenvironment of the aged liver promotes the growth of pre-neoplastic hepatocytes. PMID:27929382

  18. Acquired initiating mutations in early hematopoietic cells of CLL patients.

    PubMed

    Damm, Frederik; Mylonas, Elena; Cosson, Adrien; Yoshida, Kenichi; Della Valle, Véronique; Mouly, Enguerran; Diop, M'boyba; Scourzic, Laurianne; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Kikushige, Yoshikane; Davi, Frederick; Lambert, Jérôme; Gautheret, Daniel; Merle-Béral, Hélène; Sutton, Laurent; Dessen, Philippe; Solary, Eric; Akashi, Koichi; Vainchenker, William; Mercher, Thomas; Droin, Nathalie; Ogawa, Seishi; Nguyen-Khac, Florence; Bernard, Olivier A

    2014-09-01

    Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. ©2014 American Association for Cancer Research.

  19. Nonmyeloablative allogeneic hematopoietic cell transplantation

    PubMed Central

    Storb, Rainer; Sandmaier, Brenda M.

    2016-01-01

    Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens. These regimens enabled allogeneic engraftment, thereby setting the stage for graft-versus-tumor effects. This review summarizes the encouraging early results seen with the new regimens and discusses the two hurdles that need to be overcome for achieving even greater success, disease relapse and graft-versus-host disease. PMID:27132278

  20. Making a Hematopoietic Stem Cell.

    PubMed

    Daniel, Michael G; Pereira, Carlos-Filipe; Lemischka, Ihor R; Moore, Kateri A

    2016-03-01

    Previous attempts to either generate or expand hematopoietic stem cells (HSCs) in vitro have involved either ex vivo expansion of pre-existing patient or donor HSCs or de novo generation from pluripotent stem cells (PSCs), comprising both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). iPSCs alleviated ESC ethical issues but attempts to generate functional mature hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful. New efforts focus on directly reprogramming somatic cells into definitive HSCs and HSPCs. To meet clinical needs and to advance drug discovery and stem cell therapy, alternative approaches are necessary. In this review, we synthesize the strategies used and the key findings made in recent years by those trying to make an HSC. Published by Elsevier Ltd.

  1. bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

    SciTech Connect

    Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Schulz, Robert A.

    2014-10-24

    Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche.

  2. Facilitating cells: Translation of hematopoietic chimerism to achieve clinical tolerance

    PubMed Central

    Ildstad, Suzanne T.; Leventhal, Joseph; Wen, Yujie; Yolcu, Esma

    2015-01-01

    ABSTRACT For over 50 y the association between hematopoietic chimerism and tolerance has been recognized. This originated with the brilliant observation by Dr. Ray Owen that freemartin cattle twins that shared a common placental blood supply were red blood cell chimeras, which led to the discovery that hematopoietic chimerism resulted in actively acquired tolerance. This was first confirmed in neonatal mice by Medawar et al. and subsequently in adult rodents. Fifty years later this concept has been successfully translated to solid organ transplant recipients in the clinic. The field is new, but cell-based therapies are being used with increasing frequency to induce tolerance and immunomodulation. The future is bright. This review focuses on chimerism and tolerance: past, present and prospects for the future. PMID:26745761

  3. Hematopoietic cell transplantation in fetal lambs with ceroid-lipofuscinosis.

    PubMed

    Westlake, V J; Jolly, R D; Jones, B R; Mellor, D J; Machon, R; Zanjani, E D; Krivit, W

    1995-06-05

    Hematopoietic cells from the liver of normal 45-48-day-old fetal lambs (Hb type AA) were transplanted intraperitoneally into 58-60-day-old recipient fetuses (Hb type BB). The recipient fetuses resulted from mating homozygous ceroid-lipofuscinosis affected males with heterozygous, phenotypically normal, females. The sex of the donor fetus was also recorded. At age 2 1/2 months the recipient lambs with ceroid-lipofuscinosis were diagnosed by histopathology of brain biopsies. Monitoring of blood and bone marrow cells showed that an average of 9% of blood cells in ceroid-lipofuscinosis affected recipients were of donor origin. No differences were evident in the clinical course of disease, brain weight, or histopathology of organs between transplanted and non-transplanted lambs with ceroid-lipofuscinosis. Under the conditions of this experiment, transplantation of fetal hematopoietic cells was not beneficial.

  4. Molecular Pathways: Targeting the CXCR4-CXCL12 Axis--Untapped Potential in the Tumor Microenvironment.

    PubMed

    Scala, Stefania

    2015-10-01

    Evidence suggests that the CXC-chemokine receptor-4 pathway plays a role in cancer cell homing and metastasis, and thus represents a potential target for cancer therapy. The homeostatic microenvironment chemokine CXCL12 binds the CXCR4 and CXCR7 receptors, activating divergent signals on multiple pathways, such as ERK1/2, p38, SAPK/JNK, AKT, mTOR, and the Bruton tyrosine kinase (BTK). An activating mutation in CXCR4 is responsible for a rare disease, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), and dominant CXCR4 mutations have also been reported in Waldenstrom macroglobulinemia. The CXCR4-CXCL12 axis regulates the hematopoietic stem cell niche--a property that has led to the approval of the CXCR4 antagonist plerixafor (AMD3100) for mobilization of hematopoietic precursors. In preclinical models, plerixafor has shown antimetastatic potential in vivo, offering proof of concept. Other antagonists are in preclinical and clinical development. Recent evidence demonstrates that inhibiting CXCR4 signaling restores sensitivity to CTLA-4 and PD-1 checkpoint inhibitors, creating a new line for investigation. Targeting the CXCR4-CXCL12 axis thus offers the possibility of affecting CXCR4-expressing primary tumor cells, modulating the immune response, or synergizing with other targeted anticancer therapies. ©2015 American Association for Cancer Research.

  5. Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment.

    PubMed

    Singbrant, Sofie; Russell, Megan R; Jovic, Tanja; Liddicoat, Brian; Izon, David J; Purton, Louise E; Sims, Natalie A; Martin, T John; Sankaran, Vijay G; Walkley, Carl R

    2011-05-26

    Erythropoietin (Epo) has been used in the treatment of anemia resulting from numerous etiologies, including renal disease and cancer. However, its effects are controversial and the expression pattern of the Epo receptor (Epo-R) is debated. Using in vivo lineage tracing, we document that within the hematopoietic and mesenchymal lineage, expression of Epo-R is essentially restricted to erythroid lineage cells. As expected, adult mice treated with a clinically relevant dose of Epo had expanded erythropoiesis because of amplification of committed erythroid precursors. Surprisingly, we also found that Epo induced a rapid 26% loss of the trabecular bone volume and impaired B-lymphopoiesis within the bone marrow microenvironment. Despite the loss of trabecular bone, hematopoietic stem cell populations were unaffected. Inhibition of the osteoclast activity with bisphosphonate therapy blocked the Epo-induced bone loss. Intriguingly, bisphosphonate treatment also reduced the magnitude of the erythroid response to Epo. These data demonstrate a previously unrecognized in vivo regulatory network coordinating erythropoiesis, B-lymphopoiesis, and skeletal homeostasis. Importantly, these findings may be relevant to the clinical application of Epo.

  6. Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

    PubMed

    Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

    2015-02-01

    During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

  7. ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias.

    PubMed

    Ishibashi, Tomohiko; Yokota, Takafumi; Tanaka, Hirokazu; Ichii, Michiko; Sudo, Takao; Satoh, Yusuke; Doi, Yukiko; Ueda, Tomoaki; Tanimura, Akira; Hamanaka, Yuri; Ezoe, Sachiko; Shibayama, Hirohiko; Oritani, Kenji; Kanakura, Yuzuru

    2016-04-01

    Reliable markers are essential to increase our understanding of the biological features of human hematopoietic stem cells and to facilitate the application of hematopoietic stem cells in the field of transplantation and regenerative medicine. We previously identified endothelial cell-selective adhesion molecule (ESAM) as a novel functional marker of hematopoietic stem cells in mice. Here, we found that ESAM can also be used to purify human hematopoietic stem cells from all the currently available sources (adult bone marrow, mobilized peripheral blood, and cord blood). Multipotent colony-forming units and long-term hematopoietic-reconstituting cells in immunodeficient mice were found exclusively in the ESAM(High) fraction of CD34(+)CD38(-) cells. The CD34(+)CD38(-) fraction of cord blood and collagenase-treated bone marrow contained cells exhibiting extremely high expression of ESAM; these cells are likely to be related to the endothelial lineage. Leukemia cell lines of erythroid and megakaryocyte origin, but not those of myeloid or lymphoid descent, were ESAM positive. However, high ESAM expression was observed in some primary acute myeloid leukemia cells. Furthermore, KG-1a myeloid leukemia cells switched from ESAM negative to ESAM positive with repeated leukemia reconstitution in vivo. Thus, ESAM is a useful marker for studying both human hematopoietic stem cells and leukemia cells. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  8. Donor Dependent Variations in Hematopoietic Differentiation among Embryonic and Induced Pluripotent Stem Cell Lines

    PubMed Central

    Féraud, Olivier; Valogne, Yannick; Melkus, Michael W.; Zhang, Yanyan; Oudrhiri, Noufissa; Haddad, Rima; Daury, Aurélie; Rocher, Corinne; Larbi, Aniya; Duquesnoy, Philippe; Divers, Dominique; Gobbo, Emilie; Brunet de la Grange, Philippe; Louache, Fawzia; Bennaceur-Griscelli, Annelise; Mitjavila-Garcia, Maria Teresa

    2016-01-01

    Hematopoiesis generated from human embryonic stem cells (ES) and induced pluripotent stem cells (iPS) are unprecedented resources for cell therapy. We compared hematopoietic differentiation potentials from ES and iPS cell lines originated from various donors and derived them using integrative and non-integrative vectors. Significant differences in differentiation toward hematopoietic lineage were observed among ES and iPS. The ability of engraftment of iPS or ES-derived cells in NOG mice varied among the lines with low levels of chimerism. iPS generated from ES cell-derived mesenchymal stem cells (MSC) reproduce a similar hematopoietic outcome compared to their parental ES cell line. We were not able to identify any specific hematopoietic transcription factors that allow to distinguish between good versus poor hematopoiesis in undifferentiated ES or iPS cell lines. There is a relatively unpredictable variation in hematopoietic differentiation between ES and iPS cell lines that could not be predicted based on phenotype or gene expression of the undifferentiated cells. These results demonstrate the influence of genetic background in variation of hematopoietic potential rather than the reprogramming process. PMID:26938212

  9. Hematopoietic Progenitors from Early Murine Fetal Liver Possess Hepatic Differentiation Potential

    PubMed Central

    Khurana, Satish; Mukhopadhyay, Asok

    2008-01-01

    Bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes during liver development. It is believed that hepatoblasts originate from endodermal tissue. Here, we provide evidence for the presence of hepatic progenitor cells in the hematopoietic compartment at an early stage of liver development. Flow cytometric analysis showed that at early stages of liver development, approximately 13% of CD45+ cells express Δ-like protein-1, a marker of hepatoblasts. Furthermore, reverse transcriptase-PCR data suggest that many hepatic genes are expressed in these cells. Cell culture experiments confirmed the hepatic differentiation potential of these cells with the loss of the CD45 marker. We observed that both hematopoietic activity in Δ-like protein-1+ cells and hepatic activity in CD45+ cells were high at embryonic day 10.5 and declined thereafter. Clonal analysis revealed that the hematopoietic fraction of fetal liver cells at embryonic day 10.5 gave rise to both hepatic and hematopoietic colonies. The above results suggest a common source of these two functionally distinct cell lineages. In utero transplantation experiments confirmed these results, as green fluorescent protein-expressing CD45+ cells at the same stage of development yielded functional hepatocytes and hematopoietic reconstitution. Since these cells were unable to differentiate into cytokeratin-19-expressing cholangiocytes, we distinguished them from hepatoblasts. This preliminary study provides hope to correct many liver diseases during prenatal development via transplantation of fetal liver hematopoietic cells. PMID:18988804

  10. Defined three-dimensional microenvironments boost induction of pluripotency

    NASA Astrophysics Data System (ADS)

    Caiazzo, Massimiliano; Okawa, Yuya; Ranga, Adrian; Piersigilli, Alessandra; Tabata, Yoji; Lutolf, Matthias P.

    2016-03-01

    Since the discovery of induced pluripotent stem cells (iPSCs), numerous approaches have been explored to improve the original protocol, which is based on a two-dimensional (2D) cell-culture system. Surprisingly, nothing is known about the effect of a more biologically faithful 3D environment on somatic-cell reprogramming. Here, we report a systematic analysis of how reprogramming of somatic cells occurs within engineered 3D extracellular matrices. By modulating microenvironmental stiffness, degradability and biochemical composition, we have identified a previously unknown role for biophysical effectors in the promotion of iPSC generation. We find that the physical cell confinement imposed by the 3D microenvironment boosts reprogramming through an accelerated mesenchymal-to-epithelial transition and increased epigenetic remodelling. We conclude that 3D microenvironmental signals act synergistically with reprogramming transcription factors to increase somatic plasticity.

  11. Sinusoidal ephrin receptor EPHB4 controls hematopoietic progenitor cell mobilization from bone marrow

    PubMed Central

    Kwak, Hyeongil; Salvucci, Ombretta; Weigert, Roberto; Martinez-Torrecuadrada, Jorge L.; Henkemeyer, Mark; Poulos, Michael G.; Butler, Jason M.

    2016-01-01

    Hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow. Stress signals from cancer and other conditions promote HSPC mobilization into circulation and subsequent homing to tissue microenvironments. HSPC infiltration into tissue microenvironments can influence disease progression; notably, in cancer, HSPCs encourage tumor growth. Here we have uncovered a mutually exclusive distribution of EPHB4 receptors in bone marrow sinusoids and ephrin B2 ligands in hematopoietic cells. We determined that signaling interactions between EPHB4 and ephrin B2 control HSPC mobilization from the bone marrow. In mice, blockade of the EPHB4/ephrin B2 signaling pathway reduced mobilization of HSPCs and other myeloid cells to the circulation. EPHB4/ephrin B2 blockade also reduced HSPC infiltration into tumors as well as tumor progression in murine models of melanoma and mammary cancer. These results identify EPHB4/ephrin B2 signaling as critical to HSPC mobilization from bone marrow and provide a potential strategy for reducing cancer progression by targeting the bone marrow. PMID:27820703

  12. Lysyl Oxidase and the Tumor Microenvironment

    PubMed Central

    Wang, Tong-Hong; Hsia, Shih-Min; Shieh, Tzong-Ming

    2016-01-01

    The lysyl oxidase (LOX) family of oxidases contains a group of extracellular copper-dependent enzymes that catalyze the cross-linking of collagen and elastin by oxidation, thus maintaining the rigidity and structural stability of the extracellular matrix (ECM). Aberrant expression or activation of LOX alters the cellular microenvironment, leading to many diseases, including atherosclerosis, tissue fibrosis, and cancer. Recently, a number of studies have shown that LOX is overexpressed in most cancers and that it is involved in the regulation of tumor progression and metastasis. In contrast, a few reports have also indicated the tumor-suppressing role of LOX. In this short review, we discuss recent research on the correlations between LOX and cancer. Further, the role of LOX in tumor microenvironment remodeling, tumorigenesis, and metastasis and the underlying mechanisms have also been elucidated. PMID:28036074

  13. Advances in understanding the leukaemia microenvironment.

    PubMed

    Tabe, Yoko; Konopleva, Marina

    2014-03-01

    Dynamic interactions between leukaemic cells and cells of the bone marrow are a feature of haematological malignancies. Two distinct microenvironmental niches in the bone marrow, the 'osteoblastic (endosteal)' and 'vascular' niches, provide a sanctuary for subpopulations of leukaemic cells to evade chemotherapy-induced death and allow acquisition of drug resistance. Key components of the bone marrow microenvironment as a home for normal haematopoietic stem cells and the leukaemia stem cell niches, and the molecular pathways critical for microenvironment/leukaemia interactions via cytokines, chemokines and adhesion molecules as well as hypoxic conditions, are described in this review. Finally, the genetic abnormalities of leukaemia-associated stroma are discussed. Further understanding of the contribution of the bone marrow niche to the process of leukaemogenesis may provide new targets that allow destruction of leukaemia stem cells without adversely affecting normal stem cell self-renewal. © 2014 John Wiley & Sons Ltd.

  14. 3D Neutrophil Tractions in Changing Microenvironments

    NASA Astrophysics Data System (ADS)

    Toyjanova, Jennet; Flores, Estefany; Reichner, Jonathan; Franck, Christian

    2012-02-01

    Neutrophils are well-known as first responders to defend the body against life threatening bacterial diseases, infections and inflammation. The mechanical properties and the local topography of the surrounding microenvironment play a significant role in the regulating neutrophil behavior including cell adhesion, migration and generation of tractions. In navigating to the site of infection, neutrophils are exposed to changing microenvironments that differ in their composition, structure and mechanical properties. Our goal is to investigate neutrophil behavior, specifically migration and cellular tractions in a well-controlled 3D in vitro system. By utilizing an interchangeable 2D-3D sandwich gel structure system with tunable mechanical properties neutrophil migration and cell tractions can be computed as a function of gel stiffness and geometric dimensionality.

  15. Dynamic Reciprocity in the Wound Microenvironment

    PubMed Central

    Schultz, Gregory S.; Davidson, Jeffrey M.; Kirsner, Robert S.; Bornstein, Paul; Herman, Ira M.

    2011-01-01

    Here, we define dynamic reciprocity (DR) as an ongoing, bidirectional interaction amongst cells and their surrounding microenvironment. In the review, we posit that DR is especially meaningful during wound healing as the DR-driven biochemical, biophysical and cellular responses to injury play pivotal roles in regulating tissue regenerative responses. Such cell-extracellular matrix interactions not only guide and regulate cellular morphology, but cellular differentiation, migration, proliferation, and survival during tissue development, including e.g. embryogenesis, angiogenesis, as well as during pathologic processes including cancer diabetes, hypertension and chronic wound healing. Herein, we examine DR within the wound microenvironment while considering specific examples across acute and chronic wound healing. This review also considers how a number of hypotheses that attempt to explain chronic wound pathophysiology, which may be understood within the DR framework. The implications of applying the principles of dynamic reciprocity to optimize wound care practice and future development of innovative wound healing therapeutics are also briefly considered. PMID:21362080

  16. Vascular regeneration: engineering the stem cell microenvironment.

    PubMed

    Sun, Guoming; Gerecht, Sharon

    2009-05-01

    Vascular diseases are a major threat to human health nowadays. While current treatments can cure some vascular diseases, their beneficial effects are only temporary; vascular regeneration holds the promise of permanent, effective treatments for many vascular diseases. Stem cells and endothelial progenitor cells can differentiate into vascular lineages and therefore have the potential to repair vascular systems. However, engineering appropriate microenvironments that will allow cell maturation and delivery remains the major challenge to the successful implementation of this treatment. This review introduces the cells that are being studied for vascular differentiation and regeneration; we then consider recent approaches to engineering microenvironments, including proper signaling cues and biodegradable scaffolds that will guide the development of these cells into vessels suitable for cell-based vascular therapy.

  17. Regulation of the Prostate Cancer Tumor Microenvironment

    DTIC Science & Technology

    2017-06-01

    Award  Number:    W81XWH-11-1-0260   TITLE:      Regulation  of  the  Prostate   Cancer  Tumor  Microenvironment PRINCIPAL  INVESTIGATOR:      Dr... Cancer Tumor Microenvironment 5a.  CONTRACT  NUMBER   5b.  GRANT  NUMBER  W81XWH--11--1-- 0260 5c.  PROGRAM  ELEMENT  NUMBER   6. AUTHOR(S) Arnold  I...immunity  in  prostate   cancer  tumorigenesis  is  unclear.  We  hypothesis  that  innate  immune  pathways   contribute  to  programming  the

  18. Bioinspired Hydrogels to Engineer Cancer Microenvironments.

    PubMed

    Park, Kyung Min; Lewis, Daniel; Gerecht, Sharon

    2017-06-21

    Recent research has demonstrated that tumor microenvironments play pivotal roles in tumor development and metastasis through various physical, chemical, and biological factors, including extracellular matrix (ECM) composition, matrix remodeling, oxygen tension, pH, cytokines, and matrix stiffness. An emerging trend in cancer research involves the creation of engineered three-dimensional tumor models using bioinspired hydrogels that accurately recapitulate the native tumor microenvironment. With recent advances in materials engineering, many researchers are developing engineered tumor models, which are promising platforms for the study of cancer biology and for screening of therapeutic agents for better clinical outcomes. In this review, we discuss the development and use of polymeric hydrogel materials to engineer native tumor ECMs for cancer research, focusing on emerging technologies in cancer engineering that aim to accelerate clinical outcomes.

  19. Medulloblastoma—Biology and Microenvironment: A Review

    PubMed Central

    Byrd, Tiara; Grossman, Robert G.; Ahmed, Nabil

    2014-01-01

    Medulloblastoma (MB) is a cancer of the cerebellum and the most common primary pediatric malignancy of the central nervous system. Classified as a primitive neural ectoderm tumor; it is thought to arise from granule cell precursors in the cerebellum. The standard of care consists of surgery, chemotherapy and age-dependent radiation therapy. Despite aggressive multimodality therapy; approximately 30% of MB patients remain incurable. Moreover, for long-term survivors, the treatment related sequelae are often debilitating. Side effects include cerebellar mutism, sterility, neurocognitive deficits, and a substantial risk of developing secondary cancers. In a quest for more effective and targeted therapies, scientists have begun to investigate the biological events that not only initiate but also sustain the malignant phenotype in MB. Of particular interest is, the role of the tumor microenvironment in tumor pathogenesis. This review seeks to highlight several key processes observed in cancer biology, particularly the involvement of the tumor microenvironment, with relevant examples from MB. PMID:22742590

  20. Biological stoichiometry in tumor micro-environments.

    PubMed

    Kareva, Irina

    2013-01-01

    Tumors can be viewed as evolving ecological systems, in which heterogeneous populations of cancer cells compete with each other and somatic cells for space and nutrients within the ecosystem of the human body. According to the growth rate hypothesis (GRH), increased phosphorus availability in an ecosystem, such as the tumor micro-environment, may promote selection within the tumor for a more proliferative and thus potentially more malignant phenotype. The applicability of the GRH to tumor growth is evaluated using a mathematical model, which suggests that limiting phosphorus availability might promote intercellular competition within a tumor, and thereby delay disease progression. It is also shown that a tumor can respond differently to changes in its micro-environment depending on the initial distribution of clones within the tumor, regardless of its initial size. This suggests that composition of the tumor as a whole needs to be evaluated in order to maximize the efficacy of therapy.

  1. Metastasis Suppressors and the Tumor Microenvironment

    PubMed Central

    Cook, Leah M.; Hurst, Douglas R.; Welch, Danny R.

    2011-01-01

    The most lethal and debilitating attribute of cancer cells is their ability to metastasize. Throughout the process of metastasis, tumor cells interact with other tumor cells, host cells and a variety of molecules. Tumor cells are also faced with a number of insults, such as hemodynamic sheer pressure and immune selection. This brief review explores how metastasis suppressor proteins regulate interactions between tumor cells and the microenvironments in which tumor cells find themselves. PMID:21168504

  2. Analyzing the Tumor Microenvironment by Flow Cytometry.

    PubMed

    Young, Yoon Kow; Bolt, Alicia M; Ahn, Ryuhjin; Mann, Koren K

    2016-01-01

    Flow cytometry is an essential tool for studying the tumor microenvironment. It allows us to quickly quantify and identify multiple cell types in a heterogeneous sample. A brief overview of flow cytometry instrumentation and the appropriate considerations and steps in building a good flow cytometry staining panel are discussed. In addition, a lymphoid tissue and solid tumor leukocyte infiltrate flow cytometry staining protocol and an example of flow cytometry data analysis are presented.

  3. Probing the tumor microenvironment: collection and induction

    NASA Astrophysics Data System (ADS)

    Williams, James K.; Padgen, Michael R.; Wang, Yarong; Entenberg, David; Gertler, Frank; Condeelis, John S.; Castracane, James

    2012-03-01

    The Nano Intravital Device, or NANIVID, is under development as an optically transparent, implantable tool to study the tumor microenvironment. Two etched glass substrates are sealed using a thin polymer membrane to create a reservoir with a single outlet. This reservoir is loaded with a hydrogel blend that contains growth factors or other chemicals to be delivered to the tumor microenvironment. When the device is implanted in the tumor, the hydrogel will swell and release these entrapped molecules, forming a gradient. Validation of the device has been performed in vitro using epidermal growth factor (EGF) and MenaINV, a highly invasive, rat mammary adenocarcinoma cell line. In both 2-D and 3-D environments, cells migrated toward the gradient of EGF released from the device. The chorioallantoic membrane (CAM) of White Leghorn chicken eggs is being utilized to grow xenograft tumors that will be used for ex vivo cell collection. Device optimization is being performed for in vivo use as a tool to collect the invasive cell population. Preliminary cell collection experiments in vivo were performed using a mouse model of breast cancer. As a second application, the device is being explored as a delivery vehicle for chemicals that induce controlled changes in the tumor microenvironment. H2O2 was loaded in the device and generated intracellular reactive oxygen species (ROS) in cells near the device outlet. In the future, other induction targets will be explored, including hypoglycemia and the manipulation of extracellular matrix stiffness.

  4. Effects of laser immunotherapy on tumor microenvironment

    NASA Astrophysics Data System (ADS)

    Acquaviva, Joseph T.; Wood, Ethan W.; Hasanjee, Aamr; Chen, Wei R.; Vaughan, Melville B.

    2014-02-01

    The microenvironments of tumors are involved in a complex and reciprocal dialog with surrounding cancer cells. Any novel treatment must consider the impact of the therapy on the microenvironment. Recently, clinical trials with laser immunotherapy (LIT) have proven to effectively treat patients with late-stage, metastatic breast cancer and melanoma. LIT is the synergistic combination of phototherapy (laser irradiation) and immunological stimulation. One prominent cell type found in the tumor stroma is the fibroblast. Fibroblast cells can secrete different growth factors and extracellular matrix modifying molecules. Furthermore, fibroblast cells found in the tumor stroma often express alpha smooth muscle actin. These particular fibroblasts are coined cancer-associated fibroblast cells (CAFs). CAFs are known to facilitate the malignant progression of tumors. A collagen lattice assay with human fibroblast cells is used to elucidate the effects LIT has on the microenvironment of tumors. Changes in the contraction of the lattice, the differentiation of the fibroblast cells, as well as the proliferation of the fibroblast cells will be determined.

  5. Targeting the tumour microenvironment in ovarian cancer.

    PubMed

    Hansen, Jean M; Coleman, Robert L; Sood, Anil K

    2016-03-01

    The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors

    PubMed Central

    Gonzalez-Nieto, Daniel; Li, Lina; Kohler, Anja; Ghiaur, Gabriel; Ishikawa, Eri; Sengupta, Amitava; Madhu, Malav; Arnett, Jorden L.; Santho, Rebecca A.; Dunn, Susan K.; Fishman, Glenn I.; Gutstein, David E.; Civitelli, Roberto; Barrio, Luis C.; Gunzer, Matthias

    2012-01-01

    Connexin-43 (Cx43), a gap junction protein involved in control of cell proliferation, differentiation and migration, has been suggested to have a role in hematopoiesis. Cx43 is highly expressed in osteoblasts and osteogenic progenitors (OB/P). To elucidate the biologic function of Cx43 in the hematopoietic microenvironment (HM) and its influence in hematopoietic stem cell (HSC) activity, we studied the hematopoietic function in an in vivo model of constitutive deficiency of Cx43 in OB/P. The deficiency of Cx43 in OB/P cells does not impair the steady state hematopoiesis, but disrupts the directional trafficking of HSC/progenitors (Ps) between the bone marrow (BM) and peripheral blood (PB). OB/P Cx43 is a crucial positive regulator of transstromal migration and homing of both HSCs and progenitors in an irradiated microenvironment. However, OB/P Cx43 deficiency in nonmyeloablated animals does not result in a homing defect but induces increased endosteal lodging and decreased mobilization of HSC/Ps associated with proliferation and expansion of Cxcl12-secreting mesenchymal/osteolineage cells in the BM HM in vivo. Cx43 controls the cellular content of the BM osteogenic microenvironment and is required for homing of HSC/Ps in myeloablated animals. PMID:22498741

  7. New insights into the regulation by RUNX1 and GFI1(s) proteins of the endothelial to hematopoietic transition generating primordial hematopoietic cells.

    PubMed

    Thambyrajah, Roshana; Patel, Rahima; Mazan, Milena; Lie-A-Ling, Michael; Lilly, Andrew; Eliades, Alexia; Menegatti, Sara; Garcia-Alegria, Eva; Florkowska, Magdalena; Batta, Kiran; Kouskoff, Valerie; Lacaud, Georges

    2016-08-17

    The first hematopoietic cells are generated very early in ontogeny to support the growth of the embryo and to provide the foundation to the adult hematopoietic system. There is a considerable therapeutic interest in understanding how these first blood cells are generated in order to try to reproduce this process in vitro. This would allow generating blood products, or hematopoietic cell populations from embryonic stem (ES) cells, induced pluripotent stem cells or through directed reprogramming. Recent studies have clearly established that the first hematopoietic cells originate from a hemogenic endothelium (HE) through an endothelial to hematopoietic transition (EHT). The molecular mechanisms underlining this transition remain largely unknown with the exception that the transcription factor RUNX1 is critical for this process. In this Extra Views report, we discuss our recent studies demonstrating that the transcriptional repressors GFI1 and GFI1B have a critical role in the EHT. We established that these RUNX1 transcriptional targets are actively implicated in the downregulation of the endothelial program and the loss of endothelial identity during the formation of the first blood cells. In addition, our results suggest that GFI1 expression provides an ideal novel marker to identify, isolate and study the HE cell population.

  8. New insights into the regulation by RUNX1 and GFI1(s) proteins of the endothelial to hematopoietic transition generating primordial hematopoietic cells

    PubMed Central

    Thambyrajah, Roshana; Patel, Rahima; Mazan, Milena; Lie-a-Ling, Michael; Lilly, Andrew; Eliades, Alexia; Menegatti, Sara; Garcia-Alegria, Eva; Florkowska, Magdalena; Batta, Kiran; Kouskoff, Valerie; Lacaud, Georges

    2016-01-01

    ABSTRACT The first hematopoietic cells are generated very early in ontogeny to support the growth of the embryo and to provide the foundation to the adult hematopoietic system. There is a considerable therapeutic interest in understanding how these first blood cells are generated in order to try to reproduce this process in vitro. This would allow generating blood products, or hematopoietic cell populations from embryonic stem (ES) cells, induced pluripotent stem cells or through directed reprogramming. Recent studies have clearly established that the first hematopoietic cells originate from a hemogenic endothelium (HE) through an endothelial to hematopoietic transition (EHT). The molecular mechanisms underlining this transition remain largely unknown with the exception that the transcription factor RUNX1 is critical for this process. In this Extra Views report, we discuss our recent studies demonstrating that the transcriptional repressors GFI1 and GFI1B have a critical role in the EHT. We established that these RUNX1 transcriptional targets are actively implicated in the downregulation of the endothelial program and the loss of endothelial identity during the formation of the first blood cells. In addition, our results suggest that GFI1 expression provides an ideal novel marker to identify, isolate and study the HE cell population. PMID:27399214

  9. Combined procedure of vascularized bone marrow transplantation and mesenchymal stem cells graft - an effective solution for rapid hematopoietic reconstitution and prevention of graft-versus-host disease.

    PubMed

    Coliţă, Andrei; Coliţă, Anca; Zamfirescu, Dragos; Lupu, Anca Roxana

    2012-09-01

    Hematopoietic stem cell transplantation (HSCT) is a a standard therapeutic option for several diseases. The success of the procedure depends on quality and quantity of transplanted cells and on stromal capacity to create an optimal microenvironment, that supports survival and development of the hematopoietic elements. Conditions associated with stromal dysfunction lead to slower/insufficient engraftment and/or immune reconstitution. A possible solution to this problem is to realize a combined graft of hematopoietic stem cells along with the medular stroma in the form of vascularized bone marrow transplant (VBMT). Another major drawback of HSCT is the risk of graft versus host disease (GVHD). Recently, mesenchymal stromal cells (MSC) have demonstrated the capacity to down-regulate alloreactive T-cell and to enhance the engraftment. Cotransplantation of MSC could be a therapeutic option for a better engraftment and GVHD prevention. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Role of hematopoietic growth factors in angiogenesis.

    PubMed

    Ribatti, D; Vacca, A; De Falco, G; Ria, R; Roncali, L; Dammacco, F

    2001-01-01

    In early ontogeny, hematopoiesis is closely associated with angiogenesis. This article reviews recent studies of the effect of hematopoietic growth factors on several endothelial cell functions together with recent findings about angiogenesis and antiangiogenic therapies in hematopoietic malignancies such as leukemia, lymphoma and myeloma. Copyright 2001 S. Karger AG, Basel

  11. Hypoxia and Metabolic Properties of Hematopoietic Stem Cells

    PubMed Central

    2014-01-01

    Abstract Significance: The effect of redox signaling on hematopoietic stem cell (HSC) function is not clearly understood. Recent Advances: A growing body of evidence suggests that adult HSCs reside in the hypoxic bone marrow microenvironment or niche during homeostasis. It was recently shown that primitive HSCs in the bone marrow prefer to utilize anaerobic glycolysis to meet their energy demands and have lower rates of oxygen consumption and lower ATP levels. Hypoxia-inducible factor-α (Hif-1α) is a master regulator of cellular metabolism. With hundreds of downstream target genes and crosstalk with other signaling pathways, it regulates various aspects of metabolism from the oxidative stress response to glycolysis and mitochondrial respiration. Hif-1α is highly expressed in HSCs, where it regulates their function and metabolic phenotype. However, the regulation of Hif-1α in HSCs is not entirely understood. The homeobox transcription factor myeloid ecotropic viral integration site 1 (Meis1) is expressed in the most primitive HSCs populations, and it is required for primitive hematopoiesis. Recent reports suggest that Meis1 is required for normal adult HSC function by regulating the metabolism and redox state of HSCs transcriptionally through Hif-1α and Hif-2α. Critical Issues: Given the profound effect of redox status on HSC function, it is critical to fully characterize the intrinsic, and microenvironment-related mechanisms of metabolic and redox regulation in HSCs. Future Directions: Future studies will be needed to elucidate the link between HSC metabolism and HSC fates, including quiescence, self-renewal, differentiation, apoptosis, and migration. Antioxid. Redox Signal. 20, 1891–1901. PMID:23621582

  12. 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.

  13. 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

  14. Embryonic hematopoiesis in vertebrate somites gives rise to definitive hematopoietic stem cells

    PubMed Central

    Qiu, Juhui; Fan, Xiaoying; Wang, Yixia; Jin, Hongbin; Song, Yixiao; Han, Yang; Huang, Shenghong; Meng, Yaping; Tang, Fuchou; Meng, Anming

    2016-01-01

    Hematopoietic stem cells (HSCs) replenish all types of blood cells. It is debating whether HSCs in adults solely originate from the aorta-gonad-mesonephros (AGM) region, more specifically, the dorsal aorta, during embryogenesis. Here, we report that somite hematopoiesis, a previously unwitnessed hematopoiesis, can generate definitive HSCs (dHSCs) in zebrafish. By transgenic lineage tracing, we found that a subset of cells within the forming somites emigrate ventromedially and mix with lateral plate mesoderm-derived primitive hematopoietic cells before the blood circulation starts. These somite-derived hematopoietic precursors and stem cells (sHPSCs) subsequently enter the circulation and colonize the kidney of larvae and adults. RNA-seq analysis reveals that sHPSCs express hematopoietic genes with sustained expression of many muscle/skeletal genes. Embryonic sHPSCs transplanted into wild-type embryos expand during growth and survive for life time with differentiation into various hematopoietic lineages, indicating self-renewal and multipotency features. Therefore, the embryonic origin of dHSCs in adults is not restricted to the AGM. PMID:27252540

  15. Tunneling nanotubes mediate the transfer of stem cell marker CD133 between hematopoietic progenitor cells.

    PubMed

    Reichert, Doreen; Scheinpflug, Julia; Karbanová, Jana; Freund, Daniel; Bornhäuser, Martin; Corbeil, Denis

    2016-11-01

    Deciphering all mechanisms of intercellular communication used by hematopoietic progenitors is important, not only for basic stem cell research, but also in view of their therapeutic relevance. Here, we investigated whether these cells can produce the thin F-actin-based plasma membrane protrusions referred to as tunneling nanotubes (TNTs), which are known to bridge cells over long distances without contact with the substratum and transfer cargo molecules along them in various biological processes. We found that human primary CD34(+) hematopoietic progenitors and leukemic KG1a cells develop such structures upon culture on primary mesenchymal stromal cells or specific extracellular-matrix-based substrata. Time-lapse video microscopy revealed that cell dislodgement is the primary mechanism responsible for TNT biogenesis. Surprisingly, we found that, among various cluster of differentiation (CD) markers, only the stem cell antigen CD133 is transferred between cells. It is selectively and directionally transported along the surface of TNTs in small clusters, such as cytoplasmic phospho-myosin light chain 2, suggesting that the latter actin motor protein might be implicated in this process. Our data provide new insights into the biology of hematopoietic progenitors that can contribute to our understanding of all facets of intercellular communication in the bone marrow microenvironment under healthy or cancerous conditions.

  16. Innate immunity as orchestrator of bone marrow homing for hematopoietic stem/progenitor cells.

    PubMed

    Ratajczak, Mariusz Z; Kim, ChiHwa; Ratajczak, Janina; Janowska-Wieczorek, Anna

    2013-01-01

    The first step that precedes hematopoietic transplantation is elimination of pathological hematopoiesis by administration of myeloablative doses of radiochemotherapy. This eliminates hematolymphopoietic cells and at the same time damages hematopoietic microenvironment in bone marrow (BM). The damage of BM tissue leads to activation of complement cascade (CC), and bioactive CC cleavage fragments modulate several steps of BM recovery after transplantation of hematopoietic stem progenitor cells (HSPCs). Accordingly, C3 cleavage fragments (soluble C3a/desArgC3a and solid phase iC3b) and generation of soluble form of C5b-C9 also known as membrane attack complex (MAC) as well as release of antimicrobial cationic peptides from stromal cells (cathelicidin or LL-37 and beta-2 defensin) promote homing of HSPCs. To support this, C3 cleavage fragments and antimicrobial cationic peptides increase homing responsiveness of transplanted HSPCs to stroma-derived factor-1 (SDF-1) gradient. Furthermore, damaged BM cells release several other chemoattractants for HSPCs such as bioactive lipids sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) and chemotactic purines (ATP and UTP). In this chapter, we will discuss the current view on homing of transplanted HSPCs into BM that in addition to SDF-1 is orchestrated by CC, antimicrobial cationic peptides, and several other prohoming factors. We also propose modulation of CC as a novel strategy to optimize/accelerate homing of HSPCs.

  17. Lamins regulate cell trafficking and lineage maturation of adult human hematopoietic cells

    PubMed Central

    Shin, Jae-Won; Spinler, Kyle R.; Swift, Joe; Chasis, Joel A.; Mohandas, Narla; Discher, Dennis E.

    2013-01-01

    Hematopoietic stem and progenitor cells, as well as nucleated erythroblasts and megakaryocytes, reside preferentially in adult marrow microenvironments whereas other blood cells readily cross the endothelial barrier into the circulation. Because the nucleus is the largest organelle in blood cells, we hypothesized that (i) cell sorting across microporous barriers is regulated by nuclear deformability as controlled by lamin-A and -B, and (ii) lamin levels directly modulate hematopoietic programs. Mass spectrometry-calibrated intracellular flow cytometry indeed reveals a lamin expression map that partitions human blood lineages between marrow and circulating compartments (P = 0.00006). B-type lamins are highly variable and predominate only in CD34+ cells, but migration through micropores and nuclear flexibility in micropipette aspiration both appear limited by lamin-A:B stoichiometry across hematopoietic lineages. Differentiation is also modulated by overexpression or knockdown of lamins as well as retinoic acid addition, which regulates lamin-A transcription. In particular, erythroid differentiation is promoted by high lamin-A and low lamin-B1 expression whereas megakaryocytes of high ploidy are inhibited by lamin suppression. Lamins thus contribute to both trafficking and differentiation. PMID:24191023

  18. Histocompatibility and Hematopoietic Transplantation in the Zebrafish

    PubMed Central

    de Jong, Jill L. O.; Zon, Leonard I.

    2012-01-01

    The zebrafish has proven to be an excellent model for human disease, particularly hematopoietic diseases, since these fish make similar types of blood cells as humans and other mammals. The genetic program that regulates the development and differentiation of hematopoietic cells is highly conserved. Hematopoietic stem cells (HSCs) are the source of all the blood cells needed by an organism during its lifetime. Identifying an HSC requires a functional assay, namely, a transplantation assay consisting of multilineage engraftment of a recipient and subsequent serial transplant recipients. In the past decade, several types of hematopoietic transplant assays have been developed in the zebrafish. An understanding of the major histocompatibility complex (MHC) genes in the zebrafish has lagged behind transplantation experiments, limiting the ability to perform unbiased competitive transplantation assays. This paper summarizes the different hematopoietic transplantation experiments performed in the zebrafish, both with and without immunologic matching, and discusses future directions for this powerful experimental model of human blood diseases. PMID:22778744

  19. Plasticity of hematopoietic stem cells.

    PubMed

    Ogawa, Makio; LaRue, Amanda C; Mehrotra, Meenal

    2015-01-01

    Almost two decades ago, a number of cell culture and preclinical transplantation studies suggested the striking concept of the tissue-reconstituting ability of hematopoietic stem cells (HSCs). While this heralded an exciting time of radically new therapies for disorders of many organs and tissues, the concept was soon mired by controversy and remained dormant. This chapter provides a brief review of evidence for HSC plasticity including our findings based on single HSC transplantation in mouse. These studies strongly support the concept that HSCs are pluripotent and may be the source for the majority, if not all, of the cell types in our body.

  20. Ott1(Rbm15) has pleiotropic roles in hematopoietic development

    PubMed Central

    Raffel, Glen D.; Mercher, Thomas; Shigematsu, Hirokazu; Williams, Ifor R.; Cullen, Dana E.; Akashi, Koichi; Bernard, Olivier A.; Gilliland, D. Gary

    2007-01-01

    OTT1(RBM15) was originally described as a 5′ translocation partner of the MAL(MKL1) gene in t(1,22)(p13;q13) infant acute mega karyocytic leukemia. OTT1 has no established physiological function, but it shares homology with the spen/Mint/SHARP family of proteins defined by three amino-terminal RNA recognition motifs and a carboxyl-terminal SPOC (Spen paralog and ortholog carboxyl-terminal) domain believed to act as a transcriptional repressor. To define the role of OTT1 in hematopoiesis and help elucidate the mechanism of t(1,22) acute megakaryocytic leukemia pathogenesis, a conditional allele of Ott1 was generated in mice. Deletion of Ott1 in adult mice caused a loss of peripheral B cells due to a block in pro/pre-B differentiation. There is myeloid and megakaryocytic expansion in spleen and bone marrow, an increase in the Lin−Sca-1+c-Kit+ compartment that includes hematopoietic stem cells, and a shift in progenitor fate toward granulocyte differentiation. These data show a requirement for Ott1 in B lymphopoiesis, and inhibitory roles in the myeloid, megakaryocytic, and progenitor compartments. The ability of Ott1 to affect hematopoietic cell fate and expansion in multiple lineages is a novel attribute for a spen family member and delineates Ott1 from other known effectors of hematopoietic development. It is plausible that dysregulation of Ott1-dependent hematopoietic developmental pathways, in particular those affecting the megakaryocyte lineage, may contribute to OTT1-MAL-mediated leukemogenesis. PMID:17376872

  1. Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality

    PubMed Central

    Alvarez, Silvia; Díaz, Marcos; Flach, Johanna; Rodriguez-Acebes, Sara; López-Contreras, Andrés J.; Martínez, Dolores; Cañamero, Marta; Fernández-Capetillo, Oscar; Isern, Joan; Passegué, Emmanuelle; Méndez, Juan

    2015-01-01

    Replicative stress during embryonic development influences ageing and predisposition to disease in adults. A protective mechanism against replicative stress is provided by the licensing of thousands of origins in G1 that are not necessarily activated in the subsequent S-phase. These ‘dormant' origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini-chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors. Mcm3-deficient erythroblasts display aberrant DNA replication patterns and fail to complete maturation, causing lethal anemia. Our results indicate that hematopoietic progenitors are particularly sensitive to replication stress, and full origin licensing ensures their correct differentiation and functionality. PMID:26456157

  2. Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality.

    PubMed

    Alvarez, Silvia; Díaz, Marcos; Flach, Johanna; Rodriguez-Acebes, Sara; López-Contreras, Andrés J; Martínez, Dolores; Cañamero, Marta; Fernández-Capetillo, Oscar; Isern, Joan; Passegué, Emmanuelle; Méndez, Juan

    2015-10-12

    Replicative stress during embryonic development influences ageing and predisposition to disease in adults. A protective mechanism against replicative stress is provided by the licensing of thousands of origins in G1 that are not necessarily activated in the subsequent S-phase. These 'dormant' origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini-chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors. Mcm3-deficient erythroblasts display aberrant DNA replication patterns and fail to complete maturation, causing lethal anemia. Our results indicate that hematopoietic progenitors are particularly sensitive to replication stress, and full origin licensing ensures their correct differentiation and functionality.

  3. Tumor archaeology: tracking leukemic evolution to its origins.

    PubMed

    Dick, John E

    2014-05-28

    Unearthing of the BRAF mutation in self-renewing hematopoietic stem cells reveals an unexpected origin for hairy cell leukemia-a mature B cell malignancy-and a potential new therapeutic target (Chung et al., this issue).

  4. Hematopoietic stem cells in co-culture with mesenchymal stromal cells - modeling the niche compartments in vitro

    PubMed Central

    Jing, Duohui; Fonseca, Ana-Violeta; Alakel, Nael; Fierro, Fernando A.; Muller, Katrin; Bornhauser, Martin; Ehninger, Gerhard; Corbeil, Denis; Ordemann, Rainer

    2010-01-01

    Background Hematopoietic stem cells located in the bone marrow interact with a specific microenvironment referred to as the stem cell niche. Data derived from ex vivo co-culture systems using mesenchymal stromal cells as a feeder cell layer suggest that cell-to-cell contact has a significant impact on the expansion, migratory potential and ‘stemness’ of hematopoietic stem cells. Here we investigated in detail the spatial relationship between hematopoietic stem cells and mesenchymal stromal cells during ex vivo expansion. Design and Methods In the co-culture system, we defined three distinct localizations of hematopoietic stem cells relative to the mesenchymal stromal cell layer: (i) those in supernatant (non-adherent cells); (ii) those adhering to the surface of mesenchymal stromal cells (phase-bright cells) and (iii) those beneath the mesenchymal stromal cells (phase-dim cells). Cell cycle, proliferation, cell division and immunophenotype of these three cell fractions were evaluated from day 1 to 7. Results Phase-bright cells contained the highest proportion of cycling progenitors during co-culture. In contrast, phase-dim cells divided much more slowly and retained a more immature phenotype compared to the other cell fractions. The phase-dim compartment was soon enriched for CD34+/CD38− cells. Migration beneath the mesenchymal stromal cell layer could be hampered by inhibiting integrin β1 or CXCR4. Conclusions Our data suggest that the mesenchymal stromal cell surface is the predominant site of proliferation of hematopoietic stem cells, whereas the compartment beneath the mesenchymal stromal cell layer seems to mimic the stem cell niche for more immature cells. The SDF-1/CXCR4 interaction and integrin-mediated cell adhesion play important roles in the distribution of hematopoietic stem cells in the co-culture system. PMID:20145267

  5. A photoclickable peptide microarray platform for facile and rapid screening of 3-D tissue microenvironments.

    PubMed

    Sharma, Sadhana; Floren, Michael; Ding, Yonghui; Stenmark, Kurt R; Tan, Wei; Bryant, Stephanie J

    2017-10-01

    Microarrays are powerful experimental tools for high-throughput screening of cellular behavior in multivariate microenvironments. Here, we present a new, facile and rapid screening method for probing cellular behavior in 3D tissue microenvironments. This method utilizes a photoclickable peptide microarray platform developed using electrospun fibrous poly(ethylene glycol) hydrogels and microarray contact printing. We investigated the utility of this platform with five different peptide motifs and ten cell types including stem, terminally differentiated, cancer or immune cells that were from either primary origin or cell lines and from different species. We validated the capabilities of this platform to screen arrays consisting of multiple peptide motifs and concentrations for selectivity to cellular adhesion and morphology. Moreover, this platform is amenable to controlled spatial presentation of peptides. We show that by leveraging the differential attachment affinities for two cell types to two different peptides, this platform can also be used to investigate cell-cell interactions through miniature co-culture peptide arrays. Our fibrous peptide microarray platform enables high-throughput screening of 3D tissue microenvironments in a facile and rapid manner to investigate cell-matrix interactions and cell-cell signaling and to identify optimal tissue microenvironments for cell-based therapies. Copyright © 2017. Published by Elsevier Ltd.

  6. Cytokine receptors and hematopoietic differentiation.

    PubMed

    Robb, L

    2007-10-15

    Colony-stimulating factors and other cytokines signal via their cognate receptors to regulate hematopoiesis. In many developmental systems, inductive signalling determines cell fate and, by analogy with this, it has been postulated that cytokines, signalling via their cognate receptors, may play an instructive role in lineage specification in hematopoiesis. An alternative to this instructive hypothesis is the stochastic or permissive hypothesis. The latter proposes that commitment to a particular hematopoietic lineage is an event that occurs independently of extrinsic signals. It predicts that the role of cytokines is to provide nonspecific survival and proliferation signals. In this review, we look at the role of cytokine receptor signalling in hematopoiesis and consider the evidence for both hypotheses. Data from experiments that genetically manipulate receptor gene expression in vitro or in vivo are reviewed. Experiments in which cytokine receptors were installed in multipotential cells showed that, in some cases, stimulation with the cognate ligand could lead to alterations in lineage output. The creation of genetically manipulated mouse strains demonstrated that cytokine receptors are required for expansion and survival of single lineages but did not reveal a role in lineage commitment. We conclude that hematopoietic differentiation involves mainly stochastic events, but that cytokine receptors also have some instructive role.

  7. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo.

    PubMed

    Fleming, Heather E; Janzen, Viktor; Lo Celso, Cristina; Guo, Jun; Leahy, Kathleen M; Kronenberg, Henry M; Scadden, David T

    2008-03-06

    Wingless (Wnt) is a potent morphogen demonstrated in multiple cell lineages to promote the expansion and maintenance of stem and progenitor cell populations. Wnt effects are highly context dependent, and varying effects of Wnt signaling on hematopoietic stem cells (HSCs) have been reported. We explored the impact of Wnt signaling in vivo, specifically in the context of the HSC niche by using an osteoblast-specific promoter driving expression of the paninhibitor of canonical Wnt signaling, Dickkopf1 (Dkk1). Here we report that Wnt signaling was markedly inhibited in HSCs and, unexpectedly given prior reports, reduction in HSC Wnt signaling resulted in reduced p21Cip1 expression, increased cell cycling, and a progressive decline in regenerative function after transplantation. This effect was microenvironment determined, but irreversible if the cells were transferred to a normal host. Wnt pathway activation in the niche is required to limit HSC proliferation and preserve the reconstituting function of endogenous hematopoietic stem cells.

  8. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo

    PubMed Central

    Fleming, Heather E; Janzen, Viktor; Celso, Cristina Lo; Guo, Jun; Leahy, Kathleen M; Kronenberg, Henry M; Scadden, David T

    2010-01-01

    Summary Wingless (Wnt) is a potent morphogen demonstrated in multiple cell lineages to promote the expansion and maintenance of stem and progenitor cell populations. Pharmacologic modification of Wnt signaling has been shown to increase hematopoietic stem cells (HSC). We explored the impact of Wnt signaling in vivo, specifically within the context of the HSC niche. Using an osteoblast-specific promoter to drive the expression of a pan-inhibitor of canonical Wnt signaling, Dickkopf1 (Dkk1), we noted changes in trabecular bone and in HSC. Wnt signaling was inhibited in HSC and the cells exhibited reduced p21Cip1 expression, increased cell cycling and a progressive decline in regenerative function after transplantation. This effect was microenvironment-determined, but irreversible if the cells were transferred to a normal host. Wnt pathway activation in the niche is required to preserve the reconstituting function of endogenous hematopoietic stem cells. PMID:18371452

  9. Modeling of Sulfide Microenvironments on Mars

    NASA Technical Reports Server (NTRS)

    Schwenzer, S. P.; Bridges, J. C.; McAdam, A.; Steer, E. D.; Conrad, P. G.; Kelley, S. P.; Wiens, R. C.; Mangold, N.; Grotzinger, J.; Eigenbrode, J. L.; Franz, H. B.; Sutter, B.

    2016-01-01

    Yellowknife Bay (YKB; sol 124-198) is the second site that the Mars Science Laboratory Rover Curiosity investigated in detail on its mission in Gale Crater. YKB represents lake bed sediments from an overall neutral pH, low salinity environment, with a mineralogical composition which includes Ca-sulfates, Fe oxide/hydroxides, Fe-sulfides, amorphous material, and trioctahedral phyllosilicates. We investigate whether sulfide alteration could be associated with ancient habitable microenvironments in the Gale mudstones. Some textural evidence for such alteration may be pre-sent in the nodules present in the mudstone.

  10. Immune suppressive mechanisms in the tumor microenvironment.

    PubMed

    Munn, David H; Bronte, Vincenzo

    2016-04-01

    Effective immunotherapy, whether by checkpoint blockade or adoptive cell therapy, is limited in most patients by a key barrier: the immunosuppressive tumor microenvironment. Suppression of tumor-specific T cells is orchestrated by the activity of a variety of stromal myeloid and lymphoid cells. These often display inducible suppressive mechanisms that are triggered by the same anti-tumor inflammatory response that the immunotherapy intends to create. Therefore, a more comprehensive understanding of how the immunosuppressive milieu develops and persists is critical in order to harness the full power of immunotherapy of cancer.

  11. Metabolic reprogramming of the tumour microenvironment.

    PubMed

    Xing, Yazhi; Zhao, Shimin; Zhou, Binhua P; Mi, Jun

    2015-10-01

    Tumour cells, stromal cells and the stroma comprise the tumour microenvironment. The metabolism of both tumour cells and several types of tumour stromal cells, such as cancer-associated fibroblasts and tumour-associated macrophages, is reprogrammed. Current studies have found that stromal cells promote tumour progression and metastasis, through not only the paracrine secretion of cytokines or chemokines, but also intermediate metabolites. Here, we summarize the latest insights into the mechanism of metabolic reprogramming in cancer cells, cancer-associated fibroblasts and tumour-associated macrophages, and their potential roles in tumour progression and metastasis. © 2015 FEBS.

  12. Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica.

    PubMed

    Greco, Raffaella; Bondanza, Attilio; Vago, Luca; Moiola, Lucia; Rossi, Paolo; Furlan, Roberto; Martino, Gianvito; Radaelli, Marta; Martinelli, Vittorio; Carbone, Maria Rosaria; Lupo Stanghellini, Maria Teresa; Assanelli, Andrea; Bernardi, Massimo; Corti, Consuelo; Peccatori, Jacopo; Bonini, Chiara; Vezzulli, Paolo; Falini, Andrea; Ciceri, Fabio; Comi, Giancarlo

    2014-03-01

    Neuromyelitis optica is a rare neurological autoimmune disorder characterized by a poor prognosis. Immunosuppression can halt disease progression, but some patients are refractory to multiple treatments, experiencing frequent relapses with accumulating disability. Here we report on durable clinical remissions after allogeneic hematopoietic stem cell transplantation in 2 patients suffering from severe forms of the disease. Immunological data evidenced disappearance of the pathogenic antibodies and regeneration of a naive immune system of donor origin. These findings correlated with evident clinical and radiological improvement in both patients, warranting extended clinical trials to investigate this promising therapeutic option.

  13. Hematopoietic cell regulation of osteoblast proliferation and differentiation.

    PubMed

    Bethel, Monique; Srour, Edward F; Kacena, Melissa A

    2011-06-01

    The last several decades have revealed numerous interactions between cells of the hematopoietic lineage and osteoblasts (OBs) of the mesenchymal lineage. For example, OBs are important players in the hematopoietic stem cell (HSC) niche and OBs are known to impact osteoclast (OC) development. Thus, although much is known regarding the impact OBs have on hematopoietic cells, less is known about the impact of hematopoietic cells on OBs. Here we will review this reciprocal relationship: the effects of hematopoietic cells on OBs. Specifically, we will examine the impact of hematopoietic cells such as HSCs, lymphocytes, and megakaryocytes, as well as the hematopoietic cell-derived OCs on OB proliferation, differentiation, and function.

  14. Hematopoietic Cell Regulation of Osteoblast Proliferation and Differentiation

    PubMed Central

    Bethel, Monique; Srour, Edward F.

    2011-01-01

    The last several decades have revealed numerous interactions between cells of the hematopoietic lineage and osteoblasts (OBs) of the mesenchymal lineage. For example, OBs are important players in the hematopoietic stem cell (HSC) niche and OBs are known to impact osteoclast (OC) development. Thus, although much is known regarding the impact OBs have on hematopoietic cells, less is known about the impact of hematopoietic cells on OBs. Here we will review this reciprocal relationship: the effects of hematopoietic cells on OBs. Specifically, we will examine the impact of hematopoietic cells such as HSCs, lymphocytes, and megakaryocytes, as well as the hematopoietic cell–derived OCs on OB proliferation, differentiation, and function. PMID:21360286

  15. Human hematopoietic tumors in nude mice.

    PubMed

    Sordillo, P P; Hansen, H; Jhanwar, S C; Beck, J; Lieberman, P; Helson, L

    1981-01-01

    Despite the difficulty in establishing human hematopoietic tumors in nude mice, four human lymphomas were successfully heterotransplanted and passaged serially in our laboratory. Additional immunosuppression with chemotherapy, whole-body radiation or splenectomy was not required for establishment of these tumors. All four of these tumors were of the non-Hodgkin's lymphoma type. In each case the tumors in the nude mice were histologically identical to the biopsy specimens from the patient in whom they were derived. Attempts to transplant tumor from 17 patients with Hodgkin's disease or 4 patients with immunoblastic lymphadenopathy were unsuccessful. Tumors from 2 patients with chronic myelogenous leukemia and 1 with hairy cell leukemia could be grown in nude mice conditioned with whole-body radiation or cytosine arabinoside, but these tumors could not be passaged to other nude mice. Cell surface markers were determined on the four serially passaged lymphomas. These surface markers were similar to the markers on the original tumors, even after long periods of mouse-to-mouse passage. In 1 patient with fevers, night sweats and mediastinal mass in whom a diagnosis had not been made after several biopsies, examination of tumor tissue that had been transplanted from the patient to the nude mouse clearly established the diagnosis of lymphoma.

  16. Comparison of hematopoietic supportive capacity between human fetal and adult bone marrow mesenchymal stem cells in vitro.

    PubMed

    Liu, Meng; Yang, Shao-Guang; Xing, Wen; Lu, Shi-Hong; Zhao, Qin-Jun; Ren, Hong-Ying; Chi, Ying; Ma, Feng-Xia; Han, Zhong-Chao

    2011-08-01

    Hematopoietic stem cells (HSC) shift from fetal liver and spleen to bone marrow at neonatal stages and this movement may be due to inductive signals from different microenvironments. Mesenchymal stem cells (MSC) are the precursors of stromal cells in bone marrow microenvironments such as osteoblasts and endothelial cells. Some researchers speculated that fetal bone marrow before birth might be not perfectly suit HSC growth. However, it is still lack of direct evidence to prove this hypothesis. This study was aimed to compare the hematopoietic supportive capacity between human fetal and adult bone marrow MSC in vitro. Adult bone marrow MSC (ABM-MSC) were isolated from three healthy donors and fetal bone marrow MSC (FBM-MSC) were isolated from three fetuses between gestations of 19 to 20 weeks. After irradiation, MSC were co-cultured with CD34(+) cells isolated from umbilical cord blood in long-term culture-initiating cell (LTC-IC) assay. The colony number of colony forming cells (CFC) was counted and the phenotypic changes of co-cultured CD34(+) cells were analyzed by flow cytometry. Cytokine expressions in both kinds of MSC were detected by reverse transcription polymerase chain reaction (RT-PCR). The results showed that ABM-MSC had a stronger hematopoietic supportive capacity than FBM-MSC. Both of them enhanced the differentiation of CD34(+) cells into myeloid lineages. Cytokines were expressed differently in ABM-MSC and FBM-MSC. It is concluded that ABM-MSC possess more potential application in some treatments than FBM-MSC, especially in hematopoietic reconstitution.

  17. Hematopoietic stem cells are pluripotent and not just "hematopoietic".

    PubMed

    Ogawa, Makio; LaRue, Amanda C; Mehrotra, Meenal

    2013-06-01

    Over a decade ago, several preclinical transplantation studies suggested the striking concept of the tissue-reconstituting ability (often referred to as HSC plasticity) of hematopoietic stem cells (HSCs). While this heralded an exciting time of radically new therapies for disorders of many organs and tissues, the concept was soon mired in controversy and remained dormant for almost a decade. This commentary provides a concise review of evidence for HSC plasticity, including more recent findings based on single HSC transplantation in mouse and clinical transplantation studies. There is strong evidence for the concept that HSCs are pluripotent and are the source for the majority, if not all, of the cell types in our body. Also discussed are some biological and experimental issues that need to be considered in the future investigation of HSC plasticity.

  18. The influence of the microenvironment on the malignant phenotype

    NASA Technical Reports Server (NTRS)

    Park, C. C.; Bissell, M. J.; Barcellos-Hoff, M. H.

    2000-01-01

    Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. As tissue becomes cancerous, there are reciprocal interactions between neoplastic cells, adjacent normal cells such as stroma and endothelium, and their microenvironments. The current dominant paradigm wherein multiple genetic lesions provide both the impetus for, and the Achilles heel of, cancer might be inadequate to understand cancer as a disease process. In the following brief review, we will use selected examples to illustrate the influence of the microenvironment in the evolution of the malignant phenotype. We will also discuss recent studies that suggest novel therapeutic interventions might be derived from focusing on microenvironment and tumor cells interactions.

  19. The influence of the microenvironment on the malignant phenotype

    NASA Technical Reports Server (NTRS)

    Park, C. C.; Bissell, M. J.; Barcellos-Hoff, M. H.

    2000-01-01

    Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. As tissue becomes cancerous, there are reciprocal interactions between neoplastic cells, adjacent normal cells such as stroma and endothelium, and their microenvironments. The current dominant paradigm wherein multiple genetic lesions provide both the impetus for, and the Achilles heel of, cancer might be inadequate to understand cancer as a disease process. In the following brief review, we will use selected examples to illustrate the influence of the microenvironment in the evolution of the malignant phenotype. We will also discuss recent studies that suggest novel therapeutic interventions might be derived from focusing on microenvironment and tumor cells interactions.

  20. Hematopoietic ontogeny and its relevance for pediatric leukemias.

    PubMed

    Udroiu, Ion; Sgura, Antonella

    2016-03-01

    Fetal and infant hematopoiesis display characteristics different from the adult one: our suggestion is that these features may help to explain the peculiar incidence rates of acute leukemias. Hematopoietic stem cells (HSCs) are fast-cycling (those in adults instead are largely quiescent) and studies in mice demonstrated that their relative contribution to myelo- and lymphopoiesis varies during development. We hypothesize that during development some of the "hits" needed for the onset of leukemia are usually occurring (being part of the normal development), so leukemogenesis needs less mutations than in adults to take place and therefore it's more probable. The switch between the relative incidence of acute myeloid and lymphoid leukemias may be related to the changes of the percentage of lymphoid-deficient and lymphoid-proficient sub-set of HSCs during development. Further investigations may clarify this hypothesis, elucidating also the roles of the different microenvironments in determining the myeloid/lymphoid predisposition of the HSCs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Parasitic Infections in Hematopoietic Stem Cell Transplantation

    PubMed Central

    Jarque, Isidro; Salavert, Miguel; Pemán, Javier

    2016-01-01

    Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients. PMID:27413527

  2. Tracking the elusive fibrocyte: Identification and characterization of collagen producing hematopoietic lineage cells during murine wound healing

    PubMed Central

    Suga, Hirotaka; Rennert, Robert C.; Rodrigues, Melanie; Sorkin, Michael; Glotzbach, Jason P.; Januszyk, Michael; Fujiwara, Toshihiro; Longaker, Michael T.; Gurtner, Geoffrey C.

    2014-01-01

    Fibrocytes are a unique population of circulating cells reported to exhibit characteristics of both hematopoietic and mesenchymal cells, and play an important role in wound healing. However putative fibrocytes have been found to lose expression of hematopoietic surface markers such as CD45 during differentiation, making it difficult to track these cells in vivo with conventional methodologies. In this study, to distinguish hematopoietic and non-hematopoietic cells without surface markers, we took advantage of the gene vav 1, which is expressed solely on hematopoietic cells but not on other cell types, and established a novel transgenic mouse, in which hematopoietic cells are irreversibly labeled with green fluorescent protein (GFP) and non-hematopoietic cells with red fluorescent protein (RFP). Use of single-cell transcriptional analysis in this mouse model revealed two discrete types of collagen I (Col I) expressing cells of hematopoietic lineage recruited into excisional skin wounds. We confirmed this finding on a protein level, with one subset of these Col I synthesizing cells being CD45+ and CD11b+, consistent with the traditional definition of a fibrocyte, while another was CD45− and Cd11b−, representing a previously unidentified population. Both cell types were found to initially peak, then reduce post-healing, consistent with a disappearance from the wound site and not a loss of identifying surface marker expression. Taken together we have unambiguously identified two cells of hematopoietic origin that are recruited to the wound site and deposit collagen, definitively confirming the existence and natural time-course of fibrocytes in cutaneous healing. PMID:24446236

  3. Source characterization of BTEX in indoor microenvironments in Hong Kong

    NASA Astrophysics Data System (ADS)

    Guo, H.; Lee, S. C.; Li, W. M.; Cao, J. J.

    Levels of benzene, toluene, ethylbenzene and the xylenes (BTEX) in different indoor microenvironments such as offices, homes, schools, shopping malls and restaurants were investigated in Hong Kong. Different indoor environments including six offices, six homes, six air-conditioned classrooms, six shopping malls and four restaurants were selected in Hong Kong for indoor and outdoor BTEX measurement. This study is aimed to determine qualitatively or semi-quantitatively sources of BTEX. Source identification is possible by determining the indoor/outdoor ( I/ O) concentration ratio. An I/ O ratio>1 was considered as an indicator for indoor sources. For BTEX in different indoor environments except for schools, some of the pollutants were dominated by outdoor sources while others mainly originated from indoor sources. In schools, however, the BTEX predominantly originated from outdoor sources. The potential sources of BTEX in indoor environments were also identified by using principal component analysis and nonparametric Kruskal-Wallis test. The number of variables was reduced to two and one new factors for indoor and outdoor data, respectively. These factors were related to certain source characteristics. It is shown that the type of land use, the use of printers, the traffic condition, the cooking style, the type of gas stove, smoking and internal decoration strongly influence the indoor concentrations of BTEX ( p<0.05). Significant difference of BTEX concentrations in the five types of indoor environments were also observed ( p<0.05).

  4. Reticle storage in microenvironments with extreme clean dry air

    NASA Astrophysics Data System (ADS)

    Gettel, Astrid; Glüer, Detlev; Honold, Alfred

    2012-11-01

    Haze formation on the patterned metal surface of reticles is a known problem for IC manufacturers that can impact device yield and increase operational costs due to the need for more frequent cleaning of the reticles. Storage of reticles in an ultraclean environment can reduce haze formation and reduce operational costs. We examined the contamination levels of a new type of reticle stocker that stores reticles in microenvironments which are continuously purged with extreme clean dry air (XCDA). Each microenvironment consists of twelve vertically stacked reticle storage slots which can be opened at any slot. The design of the microenvironment includes an XCDA supply that provides a homogeneous horizontal flow of XCDA between the reticles. Figure 1. Reduction of contamination levels inside the storage microenvironment as a function of XCDA flow rate. As shown in Fig. 1, continuous XCDA purge reduces the contaminant levels inside the microenvironment. The amount of reduction depends on the XCDA purge flow rate and the chemical species. Volatile organic substances can be reduced by more than two orders of magnitude. Humidity is reduced less because the plastic material of the storage microenvironment incorporates water in its matrix and can release moisture to the extremely dry atmosphere. Chemical filters applied to mini- or microenvironments typically reduce the contaminant levels only by 95-99% and do not reduce the humidity. To pick and place reticles, the reticle storage microenvironment must be opened. The transient contaminant levels inside the empty microenvironment show an increase at the moment when the microenvironment is opened. Under the given conditions, the microenvironment returns to equilibrium levels with a time constant of 105 seconds (see Fig. 2). Similar dynamic response was measured for IPA and acetone. Figure 2. Transient humidity when the storage microenvironment was opened for reticle handling. The impact of handling on reticles stored inside

  5. Leukemia cell microvesicles promote survival in umbilical cord blood hematopoietic stem cells.

    PubMed

    Razmkhah, Farnaz; Soleimani, Masoud; Mehrabani, Davood; Karimi, Mohammad Hossein; Kafi-Abad, Sedigheh Amini

    2015-01-01

    Microvesicles can transfer their contents, proteins and RNA, to target cells and thereby transform them. This may induce apoptosis or survival depending on cell origin and the target cell. In this study, we investigate the effect of leukemic cell microvesicles on umbilical cord blood hematopoietic stem cells to seek evidence of apoptosis or cell survival. Microvesicles were isolated from both healthy donor bone marrow samples and Jurkat cells by ultra-centrifugation and were added to hematopoietic stem cells sorted from umbilical cord blood samples by magnetic associated cell sorting (MACS) technique. After 7 days, cell count, cell viability, flow cytometry analysis for hematopoietic stem cell markers and qPCR for P53 gene expression were performed. The results showed higher cell number, higher cell viability rate and lower P53 gene expression in leukemia group in comparison with normal and control groups. Also, CD34 expression as the most important hematopoietic stem cell marker, did not change during the treatment and lineage differentiation was not observed. In conclusion, this study showed anti-apoptotic effect of leukemia cell derived microvesicles on umbilical cord blood hematopoietic stem cells.

  6. Leukemia cell microvesicles promote survival in umbilical cord blood hematopoietic stem cells

    PubMed Central

    Razmkhah, Farnaz; Soleimani, Masoud; Mehrabani, Davood; Karimi, Mohammad Hossein; Kafi-abad, Sedigheh Amini

    2015-01-01

    Microvesicles can transfer their contents, proteins and RNA, to target cells and thereby transform them. This may induce apoptosis or survival depending on cell origin and the target cell. In this study, we investigate the effect of leukemic cell microvesicles on umbilical cord blood hematopoietic stem cells to seek evidence of apoptosis or cell survival. Microvesicles were isolated from both healthy donor bone marrow samples and Jurkat cells by ultra-centrifugation and were added to hematopoietic stem cells sorted from umbilical cord blood samples by magnetic associated cell sorting (MACS) technique. After 7 days, cell count, cell viability, flow cytometry analysis for hematopoietic stem cell markers and qPCR for P53 gene expression were performed. The results showed higher cell number, higher cell viability rate and lower P53 gene expression in leukemia group in comparison with normal and control groups. Also, CD34 expression as the most important hematopoietic stem cell marker, did not change during the treatment and lineage differentiation was not observed. In conclusion, this study showed anti-apoptotic effect of leukemia cell derived microvesicles on umbilical cord blood hematopoietic stem cells. PMID:26862318

  7. How the avian model has pioneered the field of hematopoietic development.

    PubMed

    Jaffredo, Thierry; Yvernogeau, Laurent

    2014-08-01

    The chicken embryo has a long history as a key model in developmental biology. Because of its distinctive developmental characteristics, it has contributed to major breakthroughs in the field of hematopoiesis. Among these, the discovery of B lymphocytes and the three rounds of thymus colonization; the embryonic origin of hematopoietic stem cells and the traffic between different hematopoietic organs; and the existence of two distinct endothelial cell lineages one angioblastic, restricted to endothelial cell production, and another, hemangioblastic, able to produce both endothelial and hematopoietic cells, should be cited. The avian model has also contributed to substantiate the endothelial-to-hematopoietic transition associated with aortic hematopoiesis and the existence of the allantois as a hematopoietic organ. Because the immune system develops relatively late in aves, the avian embryo is used to probe the tissue-forming potential of mouse tissues through mouse-into-chicken chimeras, providing insights into early mouse development by circumventing the lethality associated with some genetic strains. Finally, the avian embryo can be used to investigate the differentiation potential of human ES cells in the context of a whole organism. The combinations of classic approaches with the development of powerful genetic tools make the avian embryo a great and versatile model.

  8. Radiation and the Microenvironment - Tumorigenesis andTherapy

    SciTech Connect

    Barcellos-Hoff, Mary Helen; Park, Catherine; Wright, Eric G.

    2005-10-01

    Radiation rapidly and persistently alters the soluble and insoluble components of the tissue microenvironment. This affects the cell phenotype, tissue composition and the physical interactions and signaling between cells. These alterations in the microenvironment can contribute to carcinogenesis and alter the tissue response to anticancer therapy. Examples of these responses and their implications are discussed with a view to therapeutic intervention.

  9. Of Microenvironments and Mammary Stem Cells

    SciTech Connect

    LaBarge, Mark A; Petersen, Ole W; Bissell, Mina J

    2007-06-01

    In most adult tissues there reside pools of stem and progenitor cells inside specialized microenvironments referred to as niches. The niche protects the stem cells from inappropriate expansion and directs their critical functions. Thus guided, stem cells are able to maintain tissue homeostasis throughout the ebb and flow of metabolic and physical demands encountered over a lifetime. Indeed, a pool of stem cells maintains mammary gland structure throughout development, and responds to the physiological demands associated with pregnancy. This review discusses how stem cells were identified in both human and mouse mammary glands; each requiring different techniques that were determined by differing biological needs and ethical constraints. These studies together create a robust portrait of mammary gland biology and identify the location of the stem cell niche, elucidate a developmental hierarchy, and suggest how the niche might be manipulated for therapeutic benefit.

  10. Targeting Pancreatic Ductal Adenocarcinoma Acidic Microenvironment

    NASA Astrophysics Data System (ADS)

    Cruz-Monserrate, Zobeida; Roland, Christina L.; Deng, Defeng; Arumugam, Thiruvengadam; Moshnikova, Anna; Andreev, Oleg A.; Reshetnyak, Yana K.; Logsdon, Craig D.

    2014-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent. Here we took advantage of a general characteristic of solid tumors, the acidic microenvironment that is generated as a by-product of metabolism, to develop a novel approach of using pH (Low) Insertion Peptides (pHLIPs) for imaging of PDAC. We show that fluorescently labeled pHLIPs can localize and specifically detect PDAC in human xenografts as well as PDAC and PanIN lesions in genetically engineered mouse models. This novel approach may improve detection, differential diagnosis and staging of PDAC.

  11. Diverse macrophages polarization in tumor microenvironment.

    PubMed

    Rhee, Inmoo

    2016-11-01

    Macrophages are traditional innate immune cells that play critical roles in the clearance of pathogens and the maintenance of tissue homeostasis. Accumulating evidence proves that macrophages affect cancer initiation and malignancy. Macrophages can be categorized into two extreme subsets, classically activated (M1) and alternatively activated (M2) macrophages based on their distinct functional abilities in response to microenvironmental stimuli. In a tumor microenvironment, tumor associated macrophages (TAMs) are considered to be of the polarized M2 phenotype that enhances tumor progression and represent a poor prognosis. Furthermore, TAMs enhance tumor angiogenesis, growth, metastasis, and immunosuppression by secreting a series of cytokines, chemokines, and proteases. The regulation of macrophage polarization is considered to be a potential future therapy for cancer management.

  12. Exploring the Tumor Microenvironment with Nanoparticles

    PubMed Central

    Miao, Lei

    2016-01-01

    Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. While enhanced permeability and retention effect (EPR) promotes nanoparticle (NP) extravasation, the abnormal tumor vasculature, high interstitial pressure and dense stroma structure limit homogeneous intratumoral distribution of NP and compromise their imaging and therapeutic effect. Moreover, heterogeneous distribution of NP in nontumor-stroma cells damages the nontumor cells, and interferes with tumor-stroma crosstalk. This can lead to inhibition of tumor progression, but can also paradoxically induce acquired resistance and facilitate tumor cell proliferation and metastasis. Overall, the tumor microenvironment plays a crucial, yet controversial role in regulating NP distribution and their biological effects. In this review, we summarize recent studies on the stroma barriers for NP extravasation, and discuss the consequential effects of NP distribution in stroma cells. We also highlight design considerations to improve NP delivery and propose potential combinatory strategies to overcome acquired resistance induced by damaged stroma cells. PMID:25895870

  13. Role of tumor microenvironment in tumorigenesis

    PubMed Central

    Wang, Maonan; Zhao, Jingzhou; Zhang, Lishen; Wei, Fang; Lian, Yu; Wu, Yingfeng; Gong, Zhaojian; Zhang, Shanshan; Zhou, Jianda; Cao, Ke; Li, Xiayu; Xiong, Wei; Li, Guiyuan; Zeng, Zhaoyang; Guo, Can

    2017-01-01

    Tumorigenesis is a complex and dynamic process, consisting of three stages: initiation, progression, and metastasis. Tumors are encircled by extracellular matrix (ECM) and stromal cells, and the physiological state of the tumor microenvironment (TME) is closely connected to every step of tumorigenesis. Evidence suggests that the vital components of the TME are fibroblasts and myofibroblasts, neuroendocrine cells, adipose cells, immune and inflammatory cells, the blood and lymphatic vascular networks, and ECM. This manuscript, based on the current studies of the TME, offers a more comprehensive overview of the primary functions of each component of the TME in cancer initiation, progression, and invasion. The manuscript also includes primary therapeutic targeting markers for each player, which may be helpful in treating tumors. PMID:28382138

  14. Manipulating the Microvasculature and Its Microenvironment

    PubMed Central

    Krishnan, Laxminarayanan; Chang, Carlos C.; Nunes, Sara S; Williams, Stuart K.; Weiss, Jeffrey A.; Hoying, James B.

    2014-01-01

    The microvasculature is a dynamic cellular system necessary for tissue health and function. Therapeutic strategies that target the microvasculature are expanding and evolving, including those promoting angiogenesis and microvascular expansion. When considering how to manipulate angiogenesis, either as part of a tissue construction approach or a therapy to improve tissue blood flow, it is important to know the microenvironmental factors that regulate and direct neovessel sprouting and growth. Much is known concerning both diffusible and matrix-bound angiogenic factors, which stimulate and guide angiogenic activity. How the other aspects of the extravascular microenvironment, including tissue biomechanics and structure, influence new vessel formation is less well known. Recent research, however, is providing new insights into these mechanisms and demonstrating that the extent and character of angiogenesis (and the resulting new microcirculation) is significantly affected. These observations and the resulting implications with respect to tissue construction and microvascular therapy are addressed. PMID:24580565

  15. Hierarchal Autophagic Divergence of Hematopoietic System*

    PubMed Central

    Cao, Yan; Zhang, Suping; Yuan, Na; Wang, Jian; Li, Xin; Xu, Fei; Lin, Weiwei; Song, Lin; Fang, Yixuan; Wang, Zhijian; Wang, Zhen; Zhang, Han; Zhang, Yi; Zhao, Wenli; Hu, Shaoyan; Zhang, Xueguang; Wang, Jianrong

    2015-01-01

    Autophagy is integral to hematopoiesis and protects against leukemogenesis. However, the fundamentals of the required molecular machinery have yet to be fully explored. Using conditional mouse models to create strategic defects in the hematopoietic hierarchy, we have shown that recovery capacities in stem cells and somatic cells differ if autophagy is impaired or flawed. An in vivo Atg7 deletion in hematopoietic stem cells completely ablates the autophagic response, leading to irreversible and ultimately lethal hematopoiesis. However, while no adverse phenotype is manifested in vivo by Atg7-deficient myeloid cells, they maintain active autophagy that is sensitive to brefeldin A, an inhibitor targeting Golgi-derived membranes destined for autophagosome formation in alternative autophagy. Removing Rab9, a key regulatory protein, in alternative autophagy, disables autophagy altogether in Atg7-deficient macrophages. Functional analysis indicates that ATG7-dependent canonical autophagy is physiologically active in both hematopoietic stem cells and in terminally differentiated hematopoietic cells; however, only terminally differentiated cells such as macrophages are rescued by alternative autophagy if canonical autophagy is ineffective. Thus, it appears that hematopoietic stem cells rely solely on ATG7-dependent canonical autophagy, whereas terminally differentiated or somatic cells are capable of alternative autophagy in the event that ATG7-mediated autophagy is dysfunctional. These findings offer new insight into the transformational trajectory of hematopoietic stem cells, which in our view renders the autophagic machinery in stem cells more vulnerable to disruption. PMID:26245898

  16. SNP Array in Hematopoietic Neoplasms: A Review

    PubMed Central

    Song, Jinming; Shao, Haipeng

    2015-01-01

    Cytogenetic analysis is essential for the diagnosis and prognosis of hematopoietic neoplasms in current clinical practice. Many hematopoietic malignancies are characterized by structural chromosomal abnormalities such as specific translocations, inversions, deletions and/or numerical abnormalities that can be identified by karyotype analysis or fluorescence in situ hybridization (FISH) studies. Single nucleotide polymorphism (SNP) arrays offer high-resolution identification of copy number variants (CNVs) and acquired copy-neutral loss of heterozygosity (LOH)/uniparental disomy (UPD) that are usually not identifiable by conventional cytogenetic analysis and FISH studies. As a result, SNP arrays have been increasingly applied to hematopoietic neoplasms to search for clinically-significant genetic abnormalities. A large numbers of CNVs and UPDs have been identified in a variety of hematopoietic neoplasms. CNVs detected by SNP array in some hematopoietic neoplasms are of prognostic significance. A few specific genes in the affected regions have been implicated in the pathogenesis and may be the targets for specific therapeutic agents in the future. In this review, we summarize the current findings of application of SNP arrays in a variety of hematopoietic malignancies with an emphasis on the clinically significant genetic variants. PMID:27600067

  17. Trabectedin and plitidepsin: drugs from the sea that strike the tumor microenvironment.

    PubMed

    Galmarini, Carlos M; D'Incalci, Maurizio; Allavena, Paola

    2014-01-27

    The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.

  18. Trabectedin and Plitidepsin: Drugs from the Sea that Strike the Tumor Microenvironment

    PubMed Central

    Galmarini, Carlos M.; D’Incalci, Maurizio; Allavena, Paola

    2014-01-01

    The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment. PMID:24473171

  19. Reconstitution of a metastatic-resistant tumor microenvironment with cancer-associated fibroblasts enables metastasis

    PubMed Central

    Murata, Takuya; Hoffman, Robert M.

    2017-01-01

    ABSTRACT The tumor microenvironment is critical for metastasis to occur. Subcutaneous xenografts of tumors in immunodeficient mice are usually encapsulated and rarely metastasize as opposed to orthotopic tumors which metastasize if the original tumor was metastatic. In the present report, we were able to reconstitute a metastatic tumor microenvironment by subcutaneously co-transplanting a human cervical cancer cell line and human cervical cancer-associated fibroblasts (CAFs), in athymic mice, which resulted in lymph node metastasis in 40% of the animals. In contrast, no metastasis occurred from the cervical cancer without CAFs. These results suggest that CAFs can overcome an anti-metastatic tumor environment and are a potential target to prevent metastasis. PMID:28103135

  20. Forcing Stem Cells to Behave: A Biophysical Perspective of the Cellular Microenvironment

    PubMed Central

    Sun, Yubing; Chen, Christopher S.; Fu, Jianping

    2014-01-01

    Physical factors in the local cellular microenvironment, including cell shape and geometry, matrix mechanics, external mechanical forces, and nanotopographical features of the extracellular matrix, can all have strong influences in regulating stem cell fate. Stem cells sense and respond to these insoluble biophysical signals through integrin-mediated adhesions and the force balance between intracellular cytoskeletal contractility and the resistant forces originated from the extracellular matrix. Importantly, these mechanotransduction processes can couple with many other potent growth factor-mediated signaling pathways to regulate stem cell fate. Different bioengineering tools and micro/nanoscale devices have been successfully developed to engineer the physical aspects of the cellular microenvironment for stem cells, and these tools and devices have proven extremely powerful to identify the extrinsic physical factors and their downstream intracellular signaling pathways that control stem cell functions. PMID:22404680

  1. Targeting SDF-1 in multiple myeloma tumor microenvironment.

    PubMed

    Bouyssou, Juliette M C; Ghobrial, Irene M; Roccaro, Aldo M

    2016-09-28

    Multiple myeloma (MM) is a type of B-cell malignancy that remains incurable to date. The bone marrow (BM) microenvironment plays a crucial role in MM progression. The chemokine SDF-1 (CXCL12) is an important actor of the BM microenvironment that has the ability to regulate numerous processes related to its malignant transformation during MM development. The activity of SDF-1 is mainly mediated by its specific receptor CXCR4, which is expressed at the surface of MM cells and various other BM cell types. Current treatments available for MM patients mainly target tumor cells but have limited effects on the BM microenvironment. In this context, SDF-1 and CXCR4 represent ideal targets for the normalization of the MM-supportive BM microenvironment. The present review focuses on the activity of SDF-1 in the MM BM microenvironment and the current efforts carried out to target the SDF-1/CXCR4 axis for treatment of MM.

  2. Cord blood hematopoietic cells from preterm infants display altered DNA methylation patterns.

    PubMed

    de Goede, Olivia M; Lavoie, Pascal M; Robinson, Wendy P

    2017-01-01

    and <31 weeks were consistent with the hematopoietic origin of these cells during ontogeny, reflecting an important role of DNAm in their regulation. Due to the limited sample size and the high coincidence of prematurity and multiple births, the relationship between cause of preterm birth and DNAm could not be evaluated. These findings highlight gene regulatory mechanisms at both cell-specific and systemic levels that may be involved in fetal immune system maturation.

  3. New insights into role of microenvironment in multiple myeloma.

    PubMed

    Tricot, Guido J

    2002-08-01

    Multiple Myeloma (MM) is a malignant disease of terminally differentiated B cells. It most likely originates in a B cell which has traversed the germinal center and has been exposed there extensively to antigens based on the high number of somatic mutations in the complementarity determining regions. The cell of origin is either a plasmablast, or more likely, a memory B-cell. Typically MM goes through different phases from indolent (MGUS, smoldering myeloma) to overt myeloma and then to a fulminant phase, characterized by extramedullary manifestations, high LDH, immature morphology and increased proliferation rate. In the indolent phase, the disease already has acquired major cytogenetic abnormalities as demonstrated by FISH and DNA flow cytometry. It has a gene pattern very similar to myeloma cells on gene array analysis. In the early stages of overt MM, the myeloma cells are completely dependent upon the micro-environment for their growth and survival. The interaction between myeloma cells and micro-environment causes bone disease, genetic instability and more importantly, drug-resistance, which is caused by upregulation of anti-apoptotic factors, resistance to apoptosis induced by FAS and TRAIL activation, and by cell adhesion-induced growth arrest. In this phase of the disease, MM is susceptible to chemotherapy, if delivered with adequate intensity. In the fulminant phase of MM, myeloma cells have acquired sufficient genetic alternations to become completely independent of the micro-environment which allows them to grow at extramedullary sites. Because of the many DNA breaks necessary for immature B cells to become mature plasma cells, B cells already have inherent genetic instability. DNA breaks are necessary for VDJ recombinations, somatic mutations and isotype switching and it is therefore not surprising that genetic alternations frequently occur at the Ig heavy chain site at 14q32, which is abnormal in three quarters of myeloma patients. Some of the

  4. Enhancing the solubility of calcium phosphate ceramics by calcium salt infiltration for the purpose of hematopoietic stem cell culturing

    NASA Astrophysics Data System (ADS)

    Zhang, Qinghao

    The hematopoietic stem cells (HSCs) have been unquestionably important to therapies that involve blood and immune system replacement. However, the in-vitro culture and the expansion of HSCs inhibit their application. This work aims to develop a composite biodegradable 3D scaffold that would simulate key aspects of the in-vivo microenvironment (niche) in which expansion of the hematopoietic stem cells takes place in human bone marrow. Hydroxyapatite (HA) has been chosen as a scaffold material because of its biocompatibility and the ability to create an osteogenic scaffold and thereby simulate trabecular bone that is known to be important to the HSC niche in bone marrow. It is hypothesized that the use of a Ca-rich HA scaffold will create a three dimensional, protective environment for HSCs and further promote their in-vitro expansion by releasing Ca ions into the culture medium. The first part of this study examined the processing of Ca-rich HA and the release of calcium ions into saline over time. The Ca-rich phase was introduced into the HA by an infiltration process and has been shown to release calcium into the culture medium over 42 days. The second part of this study examined the effect of the scaffold material on the fate of human umbilical vein endothelial cells (HUVECS), a well-known endothelial progenitor model. The results showed, for the first time, that at least some HUVEC cells have hematopoietic potential and that the scaffold promoted differentiation down the hematopoietic cell lineage. This is thought to be due to hemangioblast character in the HUVEC cells which is also shared by HSCs. Finally the effects of the scaffold on the in-vitro co-culture of an osteoblast cell line and primary human bone marrow derived HSCs was studied. The infiltrated scaffolds were shown to stimulate the HSC population to differentiate down the hematopoietic lineage and also showed greater potential to differentiate down the HSC lineage in consequent CFU assays.

  5. Natural Compounds Regulate Glycolysis in Hypoxic Tumor Microenvironment

    PubMed Central

    Gao, Jian-Li; Chen, Ying-Ge

    2015-01-01

    In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1) is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT) and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment. PMID:25685782

  6. The Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment

    PubMed Central

    Xiang, Yi; Yoshimura, Teizo; Chen, Keqiang; Gong, Wanghua; Huang, Jian; Zhou, Ye; Yao, Xiaohong; Bian, Xiuwu; Wang, Ji Ming

    2014-01-01

    Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs) initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics. PMID:25110692

  7. JAM-B regulates maintenance of hematopoietic stem cells in the bone marrow.

    PubMed

    Arcangeli, Marie-Laure; Frontera, Vincent; Bardin, Florence; Obrados, Elodie; Adams, Susanne; Chabannon, Christian; Schiff, Claudine; Mancini, Stephane J C; Adams, Ralf H; Aurrand-Lions, Michel

    2011-10-27

    In adult mammals, hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and are maintained in a quiescent and undifferentiated state through adhesive interactions with specialized microenvironmental niches. Although junctional adhesion molecule-C (JAM-C) is expressed by HSCs, its function in adult hematopoiesis remains elusive. Here, we show that HSCs adhere to JAM-B expressed by BM stromal cells in a JAM-C dependent manner. The interaction regulates the interplay between HSCs and BM stromal cells as illustrated by the decreased pool of quiescent HSCs observed in jam-b deficient mice. We further show that this is probably because of alterations of BM stromal compartments and changes in SDF-1α BM content in jam-b(-/-) mice, suggesting that JAM-B is an active player in the maintenance of the BM stromal microenvironment.

  8. Isolation and analysis of hematopoietic stem cells from the placenta.

    PubMed

    Gekas, Christos; E Rhodes, Katrin; K A Mikkola, Hanna

    2008-06-24

    Hematopoietic stem cells (HSCs) have the ability to self-renew and generate all cell types of the blood lineages throughout the lifetime of an individual. All HSCs emerge during embryonic development, after which their pool size is maintained by self-renewing cell divisions. Identifying the anatomical origin of HSCs and the critical developmental events regulating the process of HSC development has been complicated as many anatomical sites participate during fetal hematopoiesis. Recently, we identified the placenta as a major hematopoietic organ where HSCs are generated and expanded in unique microenvironmental niches (Gekas, et al 2005, Rhodes, et al 2008). Consequently, the placenta is an important source of HSCs during their emergence and initial expansion. In this article, we show dissection techniques for the isolation of murine placenta from E10.5 and E12.5 embryos, corresponding to the developmental stages of initiation of HSCs and the peak in the size of the HSC pool in the placenta, respectively. In addition, we present an optimized protocol for enzymatic and mechanical dissociation of placental tissue into single-cell suspension for use in flow cytometry or functional assays. We have found that use of collagenase for single-cell suspension of placenta gives sufficient yields of HSCs. An important factor affecting HSC yield from the placenta is the degree of mechanical dissociation prior to, and duration of, enzymatic treatment. We also provide a protocol for the preparation of fixed-frozen placental tissue sections for the visualization of developing HSCs by immunohistochemistry in their precise cellular niches. As hematopoietic specific antigens are not preserved during preparation of paraffin embedded sections, we routinely use fixed frozen sections for localizing placental HSCs and progenitors.

  9. Investigating the interaction between hematopoietic stem cells and their niche during embryonic development: optimizing the isolation of fetal and newborn stem cells from liver, spleen, and bone marrow.

    PubMed

    Cao, Huimin; Williams, Brenda; Nilsson, Susan K

    2014-01-01

    Hematopoietic stem cells (HSCs) are maintained in a particular microenvironment termed a "niche." Within the niche, a number of critical molecules and supportive cell types have been identified to play key roles in modulating adult HSC quiescence, proliferation, differentiation, and reconstitution. However, unlike in the adult bone marrow (BM), the components of stem cell niches, as well as their interactions with fetal HSC during different stages of embryonic development, are poorly understood. During embryogenesis, hematopoietic development migrates through multiple organs, each with different cellular and molecular components and hence each with a potentially unique HSC niche. As a consequence, isolating fetal HSC from each organ at the time of hematopoietic colonization is fundamental for assessing and understanding both HSC function and their interactions with specific microenvironments. Herein, we describe methodologies for harvesting cells as well as the purification of stem and progenitors from fetal and newborn liver, spleen, and BM at various developmental stages following the expansion of hematopoiesis in the fetal liver at E14.5.

  10. Regulation of Prostate Cancer Progression by the Tumor Microenvironment

    PubMed Central

    Shiao, Stephen L.; Chu, Gina Chia-Yi; Chung, Leland W. K.

    2016-01-01

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease . Experimental data has uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. PMID:26828013

  11. [Prostate cancer microenvironment: Its structure, functions and therapeutic applications].

    PubMed

    Lorion, R; Bladou, F; Spatz, A; van Kempen, L; Irani, J

    2016-06-01

    In the field of prostate cancer there is a growing tendency for more and more studies to emphasise the predominant role of the zone situated between the tumour and the host: the tumour microenvironment. The aim of this article is to describe the structure and the functions of the prostate cancer microenvironment as well as the principal treatments that are being applied to it. PubMed and ScienceDirect databases have been interrogated using the association of keywords "tumour microenvironment" and "neoplasm therapy" along with "microenvironnement tumoral" and "traitements". Of the 593 articles initially found, 50 were finally included. The tumour microenvironment principally includes host elements that are diverted from their primary functions and encourage the development of the tumour. In it we find immunity cells, support tissue as well as vascular and lymphatic neovascularization. Highlighting the major role played by this microenvironment has led to the development of specific treatments, notably antiangiogenic therapy and immunotherapy. The tumour microenvironment, the tumour and the host influence themselves mutually and create a variable situation over time. Improvement of the knowledge of the prostate cancer microenvironment gradually enables us to pass from an approach centred on the tumour to a broader approach to the whole tumoral ecosystem. This enabled the emergence of new treatments whose place in the therapeutic arsenal still need to be found. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Regulation of prostate cancer progression by the tumor microenvironment.

    PubMed

    Shiao, Stephen L; Chu, Gina Chia-Yi; Chung, Leland W K

    2016-09-28

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Ionizing radiation and hematopoietic malignancies

    PubMed Central

    Fleenor, Courtney J; Marusyk, Andriy

    2010-01-01

    Somatic evolution, which underlies tumor progression, is driven by two essential components: (1) diversification of phenotypes through heritable mutations and epigenetic changes and (2) selection for mutant clones which possess higher fitness. Exposure to ionizing radiation (IR) is highly associated with increased risk of carcinogenesis. This link is traditionally attributed to causation of oncogenic mutations through the mutagenic effects of irradiation. On the other hand, potential effects of irradiation on altering fitness and increasing selection for mutant clones are frequently ignored. Recent studies bring the effects of irradiation on fitness and selection into focus, demonstrating that IR exposure results in stable reductions in the fitness of hematopoietic stem and progenitor cell populations. These reductions of fitness are associated with alteration of the adaptive landscape, increasing the selective advantages conferred by certain oncogenic mutations. Therefore, the link between irradiation and carcinogenesis might be more complex than traditionally appreciated: while mutagenic effects of irradiation should increase the probability of occurrence of oncogenic mutations, IR can also work as a tumor promoter, increasing the selective expansion of clones bearing mutations which become advantageous in the irradiation-altered environment, such as activated mutations in Notch1 or disrupting mutations in p53. PMID:20676038

  14. Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion.

    PubMed

    Sebban, Shulamit; Farago, Marganit; Rabinovich, Shiran; Lazer, Galit; Idelchuck, Yulia; Ilan, Lena; Pikarsky, Eli; Katzav, Shulamit

    2014-10-15

    Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways.

  15. Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion

    PubMed Central

    Rabinovich, Shiran; Lazer, Galit; Idelchuck, Yulia; Ilan, Lena; Pikarsky, Eli; Katzav, Shulamit

    2014-01-01

    Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways. PMID:25313137

  16. The dominance of the microenvironment in breast and ovarian cancer

    PubMed Central

    Roskelley, Calvin D.; Bissell, Mina J.

    2013-01-01

    That cancer development is a multistep process, driven in large part by genetic change, is well established. However, it is becoming increasingly clear that, prior to its emergence, the tumorigenic phenotype must overcome the suppressive effects of the surrounding microenvironment. Because the microenvironment is tissue-specific, cancer in each organ must develop unique strategies to overcome these normal epigenetic suppressors. Surprisingly, the induction of glandularity during the earliest stages of ovarian carcinoma development produces a microenvironment that has much in common with the normal mammary gland. This phenotypic convergence may explain why similar genetic and epigenetic changes appear to play a role in breast and ovarian tumor progression. PMID:12027581

  17. Biomaterials and Emerging Anticancer Therapeutics: Engineering the Microenvironment

    PubMed Central

    Gu, Luo; Mooney, David J

    2016-01-01

    The microenvironment is increasingly recognized to play key roles in cancer, and biomaterials provide a means to engineer microenvironments both in vitro and in vivo to study and manipulate cancer. In vitro cancer models using 3D matrices recapitulate key elements of the tumor microenvironment and have revealed new aspects of cancer biology. Cancer vaccines based on some of the same biomaterials have, in parallel, allowed for the engineering of durable prophylactic and therapeutic anticancer activity in preclinical studies, and some of these vaccines have moved to clinical trials. The impact of biomaterials engineering on cancer treatment is expected to further increase in importance in the years to come. PMID:26694936

  18. Modeling the Spatiotemporal Evolution of the Melanoma Tumor Microenvironment

    NASA Astrophysics Data System (ADS)

    Signoriello, Alexandra; Bosenberg, Marcus; Shattuck, Mark; O'Hern, Corey

    The tumor microenvironment, which includes tumor cells, tumor-associated macrophages (TAM), cancer-associated fibroblasts, and endothelial cells, drives the formation and progression of melanoma tumors. Using quantitative analysis of in vivo confocal images of melanoma tumors in three spatial dimensions, we examine the physical properties of the melanoma tumor microenvironment, including the numbers of different cells types, cell size, and morphology. We also compute the nearest neighbor statistics and measure intermediate range spatial correlations between different cell types. We also calculate the step size distribution, mean-square displacement, and non-Gaussian parameter from the spatial trajectories of different cell types in the tumor microenvironment.

  19. The importance of the tissue microenvironment in hairy cell leukemia.

    PubMed

    Sivina, Mariela; Burger, Jan A

    2015-12-01

    Hairy cell leukemia (HCL) cells engage in complex cellular and molecular interactions with accessory cells, matrix proteins, and various cytokines in the bone marrow and spleen, collectively referred to as the tissue microenvironment. Chemokine receptors and adhesion molecules are critical players for homing and retention within these microenvironments. Engagement of B cell antigen receptors and CD40 on HCL cells promote survival and proliferation. In this chapter, we summarize the current knowledge about the cellular and molecular interactions between HCL cells and their supportive tissue microenvironment, and provide insight into new therapeutic approaches targeting B cell receptor signaling in HCL. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. CD47 update: a multifaceted actor in the tumour microenvironment of potential therapeutic interest.

    PubMed

    Sick, E; Jeanne, A; Schneider, C; Dedieu, S; Takeda, K; Martiny, L

    2012-12-01

    CD47 is a ubiquitous 50 kDa five-spanning membrane receptor that belongs to the immunoglobulin superfamily. This receptor, also known as integrin-associated protein, mediates cell-to-cell communication by ligation to transmembrane signal-regulatory proteins SIRPα and SIRPγ and interacts with integrins. CD47 is also implicated in cell-extracellular matrix interactions via ligation with thrombospondins. Furthermore, CD47 is involved in many and diverse cellular processes, including apoptosis, proliferation, adhesion and migration. It also plays a key role in many immune and cardiovascular responses. Thus, this multifaceted receptor might be a central actor in the tumour microenvironment. Solid tumours are composed of not only cancer cells that actively proliferate but also other cell types including immune cells and fibroblasts that make up the tumour microenvironment. Tumour cell proliferation is strongly sustained by continuous sprouting of new vessels, which also represents a gate for metastasis. Moreover, infiltration of inflammatory cells is observed in most neoplasms. Much evidence has accumulated indicating that infiltrating leukocytes promote cancer progression. Given its ubiquitous expression on all the different cell types that compose the tumour microenvironment, targeting CD47 could represent an original therapeutic strategy in the field of oncology. We present a current overview of the biological effects associated with CD47 on cancer cells and stromal cells.

  1. Tensile strength suppresses the osteogenesis of periodontal ligament cells in inflammatory microenvironments

    PubMed Central

    Sun, Chaofan; Liu, Fen; Cen, Shendan; Chen, Lijiao; Wang, Yi; Sun, Hao; Deng, Hui; Hu, Rongdang

    2017-01-01

    The present study aimed to investigate the role of orthodontic force in osteogenesis differentiation, matrix deposition and mineralization in periodontal ligament cells (PDLCs) cells in inflammatory microenvironments. The mesenchymal origin of PDLCs was confirmed by vimentin and cytokeratin staining. PDLCs were exposed to inflammatory cytokines (5 ng/ml IL-1β and 10 ng/ml TNF-α) and/or tensile strength (0.5 Hz, 12% elongation) for 12, 24 or 48 h. Cell proliferation and tensile strength-induced cytokine expression were assessed by MTT assay and ELISA, respectively. Runt-related transcription factor 2 (RUNX2) and type I collagen (COL-I) expression were analysed by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Additionally, alkaline phosphatase activity was measured, and the mineralization profile was evaluated by alizarin red S staining. PDLCs exposed to tensile strength in inflammatory microenvironments exhibited reduced proliferation and mineralization potential. Treatment with the inflammatory cytokines IL-1β and TNF-α increased RUNX2 expression levels; however, decreased COL-I expression levels, indicating that bone formation and matrix deposition involve different mechanisms in PDL tissues. Notably, RUNX2 and COL-I expression levels were decreased in PDLCs exposed to a combination of an inflammatory environment and loading strength. The decreased osteogenic potential in an inflammatory microenvironment under tensile strength suggests that orthodontic force may amplify periodontal destruction in orthodontic patients with periodontitis. PMID:28560407

  2. Tensile strength suppresses the osteogenesis of periodontal ligament cells in inflammatory microenvironments.

    PubMed

    Sun, Chaofan; Liu, Fen; Cen, Shendan; Chen, Lijiao; Wang, Yi; Sun, Hao; Deng, Hui; Hu, Rongdang

    2017-07-01

    The present study aimed to investigate the role of orthodontic force in osteogenesis differentiation, matrix deposition and mineralization in periodontal ligament cells (PDLCs) cells in inflammatory microenvironments. The mesenchymal origin of PDLCs was confirmed by vimentin and cytokeratin staining. PDLCs were exposed to inflammatory cytokines (5 ng/ml IL‑1β and 10 ng/ml TNF‑α) and/or tensile strength (0.5 Hz, 12% elongation) for 12, 24 or 48 h. Cell proliferation and tensile strength‑induced cytokine expression were assessed by MTT assay and ELISA, respectively. Runt‑related transcription factor 2 (RUNX2) and type I collagen (COL‑I) expression were analysed by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Additionally, alkaline phosphatase activity was measured, and the mineralization profile was evaluated by alizarin red S staining. PDLCs exposed to tensile strength in inflammatory microenvironments exhibited reduced proliferation and mineralization potential. Treatment with the inflammatory cytokines IL‑1β and TNF‑α increased RUNX2 expression levels; however, decreased COL‑I expression levels, indicating that bone formation and matrix deposition involve different mechanisms in PDL tissues. Notably, RUNX2 and COL‑I expression levels were decreased in PDLCs exposed to a combination of an inflammatory environment and loading strength. The decreased osteogenic potential in an inflammatory microenvironment under tensile strength suggests that orthodontic force may amplify periodontal destruction in orthodontic patients with periodontitis.

  3. The Tumor Microenvironment in Esophageal Cancer

    PubMed Central

    Lin, Eric W.; Karakasheva, Tatiana A.; Hicks, Philip D.; Bass, Adam J.; Rustgi, Anil K.

    2016-01-01

    Esophageal cancer is a deadly disease, ranking sixth among all cancers in mortality. Despite incremental advances in diagnostics and therapeutics, esophageal cancer still carries a poor prognosis, and thus there remains a need to elucidate the molecular mechanisms underlying this disease. There is accumulating evidence that a comprehensive understanding of the molecular composition of esophageal cancer requires attention to not only tumor cells but also the tumor microenvironment, which contains diverse cell populations, signaling factors, and structural molecules that interact with tumor cells and support all stages of tumorigenesis. In esophageal cancer, environmental exposures can trigger chronic inflammation, which leads to constitutive activation of pro-inflammatory signaling pathways that promote survival and proliferation. Anti-tumor immunity is attenuated by cell populations such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), as well as immune checkpoints like programmed death-1 (PD-1). Other immune cells such as tumor-associated macrophages can have other pro-tumorigenic functions, including the induction of angiogenesis and tumor cell invasion. Cancer-associated fibroblasts secrete growth factors and alter the extracellular matrix (ECM) to create a tumor niche and enhance tumor cell migration and metastasis. Further study of how these TME components relate to the different stages of tumor progression in each esophageal cancer subtype will lead to development of novel and specific TME-targeting therapeutic strategies, which offer considerable potential especially in the setting of combination therapy. PMID:26923327

  4. Targeting the Metabolic Microenvironment of Tumors

    PubMed Central

    Bailey, Kate M.; Wojtkowiak, Jonathan W.; Hashim, Arig Ibrahim; Gillies, Robert J.

    2013-01-01

    The observation of aerobic glycolysis by tumor cells in 1924 by Otto Warburg, and subsequent innovation of imaging glucose uptake by tumors in patients with PET-CT has incited a renewed interest in the altered metabolism of tumors. As tumors grow in situ, a fraction of it is further away from their blood supply, leading to decreased oxygen concentrations (hypoxia), which induces the hypoxia response pathways of HIF1α, mTOR and UPR. In normal tissues, these responses mitigate hypoxic stress and induce neo-angiogenesis. In tumors, these pathways are dysregulated and lead to decreased perfusion and exacerbation of hypoxia as a result of immature and chaotic blood vessels. Hypoxia selects for a glycolytic phenotype and resultant acidification of the tumor microenvironment, facilitated by upregulation of proton transporters. Acidification selects for enhanced metastatic potential and reduced drug efficacy through ion trapping. In this review, we provide a comprehensive summary of pre-clinical and clinical drugs under development for targeting aerobic glycolysis, acidosis, hypoxia and hypoxia-response pathways. Hypoxia and acidosis can be manipulated, providing further therapeutic benefit for cancers that feature these common phenotypes. PMID:22959024

  5. Microenvironment Tracker (MicroTrac) | Science Inventory ...

    EPA Pesticide Factsheets

    Epidemiologic studies have shown associations between air pollution concentrations measured at central-site ambient monitors and adverse health outcomes. Using central-site concentrations as exposure surrogates, however, can lead to exposure errors due to time spent in various indoor and outdoor microenvironments (ME) with pollutant concentrations that can be substantially different from central-site concentrations. These exposure errors can introduce bias and incorrect confidence intervals in health effect estimates, which diminish the power of such studies to establish correct conclusions about the exposure and health effects association. The significance of this issue was highlighted in the National Research Council (NRC) Report “Research Priorities for Airborne Particulate Matter”, which recommends that EPA address exposure error in health studies. To address this limitation, we developed MicroTrac, an automated classification model that estimates time of day and duration spent in eight ME (indoors and outdoors at home, work, school; inside vehicles; other locations) from personal global positioning system (GPS) data and geocoded boundaries of buildings (e.g., home, work, school). MicroTrac has several innovative design features: (1) using GPS signal quality to account for GPS signal loss inside certain buildings, (2) spatial buffering of building boundaries to account for the spatial inaccuracy of the GPS device, and (3) temporal buffering of GPS positi

  6. Microenvironment Tracker (MicroTrac) | Science Inventory ...

    EPA Pesticide Factsheets

    Epidemiologic studies have shown associations between air pollution concentrations measured at central-site ambient monitors and adverse health outcomes. Using central-site concentrations as exposure surrogates, however, can lead to exposure errors due to time spent in various indoor and outdoor microenvironments (ME) with pollutant concentrations that can be substantially different from central-site concentrations. These exposure errors can introduce bias and incorrect confidence intervals in health effect estimates, which diminish the power of such studies to establish correct conclusions about the exposure and health effects association. The significance of this issue was highlighted in the National Research Council (NRC) Report “Research Priorities for Airborne Particulate Matter”, which recommends that EPA address exposure error in health studies. To address this limitation, we developed MicroTrac, an automated classification model that estimates time of day and duration spent in eight ME (indoors and outdoors at home, work, school; inside vehicles; other locations) from personal global positioning system (GPS) data and geocoded boundaries of buildings (e.g., home, work, school). MicroTrac has several innovative design features: (1) using GPS signal quality to account for GPS signal loss inside certain buildings, (2) spatial buffering of building boundaries to account for the spatial inaccuracy of the GPS device, and (3) temporal buffering of GPS positi

  7. All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment

    PubMed Central

    Su, Meng; Alonso, Salvador; Jones, Jace W.; Yu, Jianshi; Kane, Maureen A.; Jones, Richard J.; Ghiaur, Gabriel

    2015-01-01

    Differentiation therapy with all-trans retinoic acid (atRA) has markedly improved outcome in acute promyelocytic leukemia (APL) but has had little clinical impact in other AML sub-types. Cell intrinsic mechanisms of resistance have been previously reported, yet the majority of AML blasts are sensitive to atRA in vitro. Even in APL, single agent atRA induces remission without cure. The microenvironment expression of cytochrome P450 (CYP)26, a retinoid-metabolizing enzyme was shown to determine normal hematopoietic stem cell fate. Accordingly, we hypothesized that the bone marrow (BM) microenvironment is responsible for difference between in vitro sensitivity and in vivo resistance of AML to atRA-induced differentiation. We observed that the pro-differentiation effects of atRA on APL and non-APL AML cells as well as on leukemia stem cells from clinical specimens were blocked by BM stroma. In addition, BM stroma produced a precipitous drop in atRA levels. Inhibition of CYP26 rescued atRA levels and AML cell sensitivity in the presence of stroma. Our data suggest that stromal CYP26 activity creates retinoid low sanctuaries in the BM that protect AML cells from systemic atRA therapy. Inhibition of CYP26 provides new opportunities to expand the clinical activity of atRA in both APL and non-APL AML. PMID:26047326

  8. All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment.

    PubMed

    Su, Meng; Alonso, Salvador; Jones, Jace W; Yu, Jianshi; Kane, Maureen A; Jones, Richard J; Ghiaur, Gabriel

    2015-01-01

    Differentiation therapy with all-trans retinoic acid (atRA) has markedly improved outcome in acute promyelocytic leukemia (APL) but has had little clinical impact in other AML sub-types. Cell intrinsic mechanisms of resistance have been previously reported, yet the majority of AML blasts are sensitive to atRA in vitro. Even in APL, single agent atRA induces remission without cure. The microenvironment expression of cytochrome P450 (CYP)26, a retinoid-metabolizing enzyme was shown to determine normal hematopoietic stem cell fate. Accordingly, we hypothesized that the bone marrow (BM) microenvironment is responsible for difference between in vitro sensitivity and in vivo resistance of AML to atRA-induced differentiation. We observed that the pro-differentiation effects of atRA on APL and non-APL AML cells as well as on leukemia stem cells from clinical specimens were blocked by BM stroma. In addition, BM stroma produced a precipitous drop in atRA levels. Inhibition of CYP26 rescued atRA levels and AML cell sensitivity in the presence of stroma. Our data suggest that stromal CYP26 activity creates retinoid low sanctuaries in the BM that protect AML cells from systemic atRA therapy. Inhibition of CYP26 provides new opportunities to expand the clinical activity of atRA in both APL and non-APL AML.

  9. Role of SDF-1 (CXCL12) in regulating hematopoietic stem and progenitor cells traffic into the liver during extramedullary hematopoiesis induced by G-CSF, AMD3100 and PHZ.

    PubMed

    Mendt, Mayela; Cardier, Jose E

    2015-12-01

    The stromal cell derived factor 1 (SDF-1/CXCL12) plays an essential role in the homing of hematopoietic stem and progenitor cells (HSPCs) to bone marrow (BM). It is not known whether SDF-1 may also regulate the homing of HSPCs to the liver during extramedullary hematopoiesis (EMH). Here, we investigated the possible role of SDF-1 in attracting HSPCs to the liver during experimental EMH induced by the hematopoietic mobilizers G-CSF, AMD3100 and phenylhydrazine (PHZ). Mice treated with G-CSF, AMD3100 and PHZ showed a significant increase in the expression of SDF-1 in the liver sinusoidal endothelial cells (LSECs) microenvironments. Liver from mice treated with the hematopoietic mobilizers showed HSPCs located adjacent to the LSEC microenvironments, expressing high levels of SDF-1. An inverse relationship was found between the hepatic SDF-1 levels and those in the BM. In vitro, LSEC monolayers induced the migration of HSPCs, and this effect was significantly reduced by AMD3100. In conclusion, our results provide the first evidence showing that SDF-1 expressed by LSEC can be a major player in the recruitment of HSPCs to the liver during EMH induced by hematopoietic mobilizers.

  10. Quantitative evaluation of the transplanted lin(-) hematopoietic cell migration kinetics.

    PubMed

    Kašėta, Vytautas; Vaitkuvienė, Aida; Liubavičiūtė, Aušra; Maciulevičienė, Rūta; Stirkė, Arūnas; Biziulevičienė, Genė

    2016-02-01

    Stem cells take part in organogenesis, cell maturation and injury repair. The migration is necessary for each of these functions to occur. The aim of this study was to investigate the kinetics of transplanted hematopoietic lin(-) cell population (which consists mainly of the stem and progenitor cells) in BALB/c mouse contact hypersensitivity model and quantify the migration to the site of inflammation in the affected foot and other healthy organs. Quantitative analysis was carried out with the real-time polymerase chain reaction method. Spleen, kidney, bone marrow, lung, liver, damaged and healthy foot tissue samples at different time points were collected for analysis. The quantitative data normalization was performed according to the comparative quantification method. The analysis of foot samples shows the significant migration of transplanted cells to the recipient mice affected foot. The quantity was more than 1000 times higher, as compared with that of the untreated foot. Due to the inflammation, the number of donor origin cells migrating to the lungs, liver, spleen and bone marrow was found to be decreased. Our data shows that transplanted cells selectively migrated into the inflammation areas of the foot edema. Also, the inflammation caused a secondary migration in ectopic spleen of hematopoietic stem cell niches and re-homing from the spleen to the bone marrow took place.

  11. De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes

    PubMed Central

    Lopes, Matheus Rodrigues; Pereira, João Kleber Novais; de Melo Campos, Paula; Machado-Neto, João Agostinho; Traina, Fabiola; Saad, Sara T. Olalla; Favaro, Patricia

    2017-01-01

    The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu. PMID:28084439

  12. De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes.

    PubMed

    Lopes, Matheus Rodrigues; Pereira, João Kleber Novais; de Melo Campos, Paula; Machado-Neto, João Agostinho; Traina, Fabiola; Saad, Sara T Olalla; Favaro, Patricia

    2017-01-13

    The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu.

  13. [Peripheral blood hematopoietic stem cell collection].

    PubMed

    Bojanić, Ines; Mazić, Sanja; Cepulić, Branka Golubić

    2009-01-01

    Summary. Peripheral blood hematopoietic stem cells (PBSC) have numerous advatages in comparison with traditionally used bone marrow. PBSC collection by leukapheresis procedure is simpler and better tolerated than bone marrow harvest. PBCS are mobilized by myelosupressive chemotherapy or/and hematopoietic growth factors. Leukapheresis product contains PBSC along with lineage commited progenitors and precursors which contribute to faster hematopoietic recovery. In "poor mobilizers" options are large-volume leukapheresis (LVL) procedure or second generation of mobilising agents (pegfilgrastim, CXCR4 receptor antagonists). Total blood volume is processed 2-3 times in standard procedure compared to more than 3 times in LVL. LVL yields significantly higher numbers of CD34+ cells. Adverse effects of leukapheresis are electrolyte disbalance (hypocalcemia) caused by citrat administration and risk of bleeding due to trobocytopenia and heparin administration. PBSC collection and product quality control are regulated by national and international standards and recommendations.

  14. Estimating the number of hematopoietic or lymphoid stem cells giving rise to clonal chromosome aberrations in blood T lymphocytes.

    PubMed

    Nakano, M; Kodama, Y; Ohtaki, K; Itoh, M; Awa, A A; Cologne, J; Kusunoki, Y; Nakamura, N

    2004-03-01

    Quantifying the proliferative capacity of long-term hematopoietic stem cells in humans is important for bone marrow transplantation and gene therapy. Obtaining appropriate data is difficult, however, because the experimental tools are limited. We hypothesized that tracking clonal descendants originating from hematopoietic stem cells would be possible if we used clonal chromosome aberrations as unique tags of individual hematopoietic stem cells in vivo. Using FISH, we screened 500 blood T lymphocytes from each of 513 atomic bomb survivors and detected 96 clones composed of at least three cells with identical aberrations. The number of clones was inversely related to their population size, which we interpreted to mean that the progenitor cells were heterogeneous in the number of progeny that they could produce. The absolute number of progenitor cells contributing to the formation of the observed clones was estimated as about two in an unexposed individual. Further, scrutiny of ten clones revealed that lymphocyte clones could originate roughly equally from hematopoietic stem cells or from mature T lymphocytes, thereby suggesting that the estimated two progenitor cells are shared as one hematopoietic stem cell and one mature T cell. Our model predicts that one out of ten people bears a non- aberrant clone comprising >10% of the total lymphocytes, which indicates that clonal expansions are common and probably are not health-threatening.

  15. Fish Oil–Rich Diet Promotes Hematopoiesis and Alters Hematopoietic Niche

    PubMed Central

    Li, Xiao-ping; Cheng, Lu; Han, Mu-tian; Zhang, Miao-miao; Shao, Qi-xiang; Xu, Hua-xi

    2015-01-01

    The self-renewal and differentiation of hematopoietic stem cells (HSCs) in bone marrow are essential to replenish all blood cell types, but how this process is influenced by diet remains largely unclear. Here we show that a diet rich in fish oils promotes self-renewal of HSCs and extramedullary hematopoiesis. Chronic intake of a fish oil–rich diet increases the abundance of HSCs, alters the hematopoietic microenvironment, and, intriguingly, induces the expression of matrix metalloproteinase 12 (MMP12) in the bone marrow. Pointing to a direct effect of fish oil on MMP12 expression, omega-3 polyunsaturated fatty acids induce the expression of MMP12 in a dose-dependent manner in bone marrow cells. Importantly, down-regulation of MMP12 activity using an MMP12-specific inhibitor attenuates diet-induced myelopoiesis in both bone marrow and spleen. Thus, a fish oil–rich diet promotes hematopoiesis in the bone marrow and spleen, in part via the activity of MMP12. Taken together, these data provide new insights into diet-mediated regulation of hematopoiesis. PMID:26061726

  16. In vivo imaging of hematopoietic stem cells in the bone marrow niche.

    PubMed

    Barrett, Oliver; Sottocornola, Roberta; Lo Celso, Cristina

    2012-01-01

    Even though hematopoietic stem cells (HSC) are amongst the first somatic stem cells exploited for therapeutic purposes, their application is still limited by the inability to expand them ex vivo without impairing their function. Moreover, it has recently emerged that several types of leukemia develop and relapse through complex interactions with bone marrow (BM) components and may directly affect the HSC and their niche. Increasing attention has therefore been dedicated to the BM microenvironment the HSC reside in, with the view that a better understanding of the molecular regulators of HSC-niche interaction in vivo will allow improving HSC mobilization, collection and transplantation and provide clues for the development of innovative leukemia treatments. This chapter focuses on a recently established technique for the visualization of transplanted hematopoietic stem and progenitor cells (HSPC) within the calvarium bone marrow of live mice (Lo Celso et al. Nature 457:92-96, 2007). Intravital microscopy is a rapidly developing field, driven by constant improvement in both detection technologies (i.e., spatial resolution, depth of penetration, spectral definition) and probe availability (i.e., increasingly sophisticated genetic and chemical reporter systems). We therefore discuss the current limitations and challenges related to intravital microscopy of the HSC niche and introduce a number of potential imaging approaches, which could be promising candidates for future development of this technique.

  17. In vivo imaging of transplanted hematopoietic stem and progenitor cells in mouse calvarium bone marrow

    PubMed Central

    Lo Celso, Cristina; Lin, Charles P; Scadden, David T

    2011-01-01

    In vivo imaging of transplanted hematopoietic stem and progenitor cells (HSPCs) was developed to investigate the relationship between HSPCs and components of their microenvironment in the bone marrow. In particular, it allows a direct observation of the behavior of hematopoietic cells during the first few days after transplantation, when the critical events in homing and early engraftment are occurring. By directly imaging these events in living animals, this method permits a detailed assessment of functions previously evaluated by crude assessments of cell counts (homing) or after prolonged periods (engraftment). This protocol offers a new means of investigating the role of cell-intrinsic and cell-extrinsic molecular regulators of hematopoiesis during the early stages of transplantation, and it is the first to allow the study of cell-cell interactions within the bone marrow in three dimensions and in real time. In this paper, we describe how to isolate, label and inject HSPCs, as well as how to perform calvarium intravital microscopy and analyze the resulting images. A typical experiment can be performed and analyzed in ~1 week. PMID:21212779

  18. In vivo imaging of transplanted hematopoietic stem and progenitor cells in mouse calvarium bone marrow.

    PubMed

    Lo Celso, Cristina; Lin, Charles P; Scadden, David T

    2011-01-01

    In vivo imaging of transplanted hematopoietic stem and progenitor cells (HSPCs) was developed to investigate the relationship between HSPCs and components of their microenvironment in the bone marrow. In particular, it allows a direct observation of the behavior of hematopoietic cells during the first few days after transplantation, when the critical events in homing and early engraftment are occurring. By directly imaging these events in living animals, this method permits a detailed assessment of functions previously evaluated by crude assessments of cell counts (homing) or after prolonged periods (engraftment). This protocol offers a new means of investigating the role of cell-intrinsic and cell-extrinsic molecular regulators of hematopoiesis during the early stages of transplantation, and it is the first to allow the study of cell-cell interactions within the bone marrow in three dimensions and in real time. In this paper, we describe how to isolate, label and inject HSPCs, as well as how to perform calvarium intravital microscopy and analyze the resulting images. A typical experiment can be performed and analyzed in ∼1 week.

  19. CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress

    PubMed Central

    Zhang, Yanyan; Dépond, Mallorie; He, Liang; Foudi, Adlen; Kwarteng, Edward Owusu; Lauret, Evelyne; Plo, Isabelle; Desterke, Christophe; Dessen, Philippe; Fujii, Nobutaka; Opolon, Paule; Herault, Olivier; Solary, Eric; Vainchenker, William; Joulin, Virginie; Louache, Fawzia; Wittner, Monika

    2016-01-01

    Hematopoietic stem cells (HSCs) undergo self-renewal to maintain hematopoietic homeostasis for lifetime, which is regulated by the bone marrow (BM) microenvironment. The chemokine receptor CXCR4 and its ligand CXCL12 are critical factors supporting quiescence and BM retention of HSCs. Here, we report an unknown function of CXCR4/CXCL12 axis in the protection of HSCs against oxidative stress. Disruption of CXCR4 receptor in mice leads to increased endogenous production of reactive oxygen species (ROS), resulting in p38 MAPK activation, increased DNA double-strand breaks and apoptosis leading to marked reduction in HSC repopulating potential. Increased ROS levels are directly responsible for exhaustion of the HSC pool and are not linked to loss of quiescence of CXCR4-deficient HSCs. Furthermore, we report that CXCL12 has a direct rescue effect on oxidative stress-induced HSC damage at the mitochondrial level. These data highlight the importance of CXCR4/CXCL12 axis in the regulation of lifespan of HSCs by limiting ROS generation and genotoxic stress. PMID:27886253

  20. Regulation of Hematopoietic Stem Cell Behavior by the Nanostructured Presentation of Extracellular Matrix Components

    PubMed Central

    Muth, Christine Anna; Steinl, Carolin; Klein, Gerd; Lee-Thedieck, Cornelia

    2013-01-01

    Hematopoietic stem cells (HSCs) are maintained in stem cell niches, which regulate stem cell fate. Extracellular matrix (ECM) molecules, which are an essential part of these niches, can actively modulate cell functions. However, only little is known on the impact of ECM ligands on HSCs in a biomimetic environment defined on the nanometer-scale level. Here, we show that human hematopoietic stem and progenitor cell (HSPC) adhesion depends on the type of ligand, i.e., the type of ECM molecule, and the lateral, nanometer-scaled distance between the ligands (while the ligand type influenced the dependency on the latter). For small fibronectin (FN)–derived peptide ligands such as RGD and LDV the critical adhesive interligand distance for HSPCs was below 45 nm. FN-derived (FN type III 7–10) and osteopontin-derived protein domains also supported cell adhesion at greater distances. We found that the expression of the ECM protein thrombospondin-2 (THBS2) in HSPCs depends on the presence of the ligand type and its nanostructured presentation. Functionally, THBS2 proved to mediate adhesion of HSPCs. In conclusion, the present study shows that HSPCs are sensitive to the nanostructure of their microenvironment and that they are able to actively modulate their environment by secreting ECM factors. PMID:23405094

  1. Dual role for Jumu in the control of hematopoietic progenitors in the Drosophila lymph gland

    PubMed Central

    Hao, Yangguang; Jin, Li Hua

    2017-01-01

    The Drosophila lymph gland is a hematopoietic organ in which the maintenance of hematopoietic progenitor cell fate relies on intrinsic factors and extensive interaction with cells within a microenvironment. The posterior signaling center (PSC) is required for maintaining the balance between progenitors and their differentiation into mature hemocytes. Moreover, some factors from the progenitors cell-autonomously control blood cell differentiation. Here, we show that Jumeau (Jumu), a member of the forkhead (Fkh) transcription factor family, controls hemocyte differentiation of lymph gland through multiple regulatory mechanisms. Jumu maintains the proper differentiation of prohemocytes by cell-autonomously regulating the expression of Col in medullary zone and by non-cell-autonomously preventing the generation of expanded PSC cells. Jumu can also cell-autonomously control the proliferation of PSC cells through positive regulation of dMyc expression. We also show that a deficiency of jumu throughout the lymph gland can induce the differentiation of lamellocytes via activating Toll signaling. DOI: http://dx.doi.org/10.7554/eLife.25094.001 PMID:28350299

  2. In vivo 4-dimensional tracking of hematopoietic stem and progenitor cells in adult mouse calvarial bone marrow.

    PubMed

    Scott, Mark K; Akinduro, Olufolake; Lo Celso, Cristina

    2014-09-04

    Through a delicate balance between quiescence and proliferation, self renewal and production of differentiated progeny, hematopoietic stem cells (HSCs) maintain the turnover of all mature blood cell lineages. The coordination of the complex signals leading to specific HSC fates relies upon the interaction between HSCs and the intricate bone marrow microenvironment, which is still poorly understood([1-2]). We describe how by combining a newly developed specimen holder for stable animal positioning with multi-step confocal and two-photon in vivo imaging techniques, it is possible to obtain high-resolution 3D stacks containing HSPCs and their surrounding niches and to monitor them over time through multi-point time-lapse imaging. High definition imaging allows detecting ex vivo labeled hematopoietic stem and progenitor cells (HSPCs) residing within the bone marrow. Moreover, multi-point time-lapse 3D imaging, obtained with faster acquisition settings, provides accurate information about HSPC movement and the reciprocal interactions between HSPCs and stroma cells. Tracking of HSPCs in relation to GFP positive osteoblastic cells is shown as an exemplary application of this method. This technique can be utilized to track any appropriately labeled hematopoietic or stromal cell of interest within the mouse calvarium bone marrow space.

  3. Endothelial progenitor cells improve the quality of transplanted hematopoietic stem cells and maintain longer term effects in mice.

    PubMed

    Qiao, Jianlin; Ding, Lan; Fu, Jinyu; Yao, Haina; Li, Xiaoli; Chen, Chao; Yang, Na; Mi, Hongling; Liu, Yun; Chu, Peipei; Xia, Yuan; Zhang, Xi; Xu, Kailin; Zeng, Lingyu

    2017-01-01

    Engraftment of hematopoietic stem cells (HSCs) is a pre-requisite for the success of hematopoietic stem cell transplantation (HSCT). Fetal blood cell (FBC)-derived endothelial progenitor cells (EPCs) are known to facilitate HSC reconstitution in the early phase. However, longer term effects on HSCs remain unclear. The purpose of this study was to evaluate the effect of EPCs on the quality of transplanted hematopoietic stem cells in mouse HSCT model. BALB/c mice were randomly divided into four groups, namely, control, total body irradiation only, HSCT, and HSCT + EPCs (with infusion of 5 × 10(5) EPCs). Mice was sacrificed on days 7, 14, 21, and 28 post-HSCT for the analysis of the bone marrow pathology by H&E staining, measurement of c-kit(+)sca-1(+), c-kit(+), apoptosis, and necrosis by flow cytometry as well as colony formation assay. Secondary transplantation involved the injection of transplanted BALB/c-derived HSCs into new TBI-treated BALB/c mice. Compared with HSCT, EPCs infusion promoted the differentiation and reduced apoptosis of transplanted HSCs, possibly through promotion of vascular repair of the bone marrow microenvironment via differentiation into the bone marrow endothelial cells. Significantly, EPCs' effect on HSCs was maintained for a long period as demonstrated using a secondary transplantation approach. These data revealed EPCs improved the quality and quantity of transplanted HSCs and maintained their effects over the longer term, suggesting a novel approach to improve HSCT efficiency and outcomes.

  4. Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation

    PubMed Central

    Etchart, Nathalie; Thomas, Daniel; Hofmann, Nicole A.; Fruehwirth, Margareta; Sinha, Subarna; Chan, Charles K.; Senarath-Yapa, Kshemendra; Seo, Eun-Young; Wearda, Taylor; Hartwig, Udo F.; Beham-Schmid, Christine; Trajanoski, Slave; Lin, Qiong; Wagner, Wolfgang; Dullin, Christian; Alves, Frauke; Andreeff, Michael; Weissman, Irving L.; Longaker, Michael T.; Schallmoser, Katharina; Majeti, Ravindra; Strunk, Dirk

    2015-01-01

    In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype, and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription, and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord, and skin cultured in humanized media. Surprisingly, only BM-derived MSCs spontaneously formed a BM cavity through a vascularized cartilage intermediate in vivo that was progressively replaced by hematopoietic tissue and bone. Only BM-derived MSCs exhibited a chondrogenic transcriptional program with hypomethylation and increased expression of RUNX3, RUNX2, BGLAP, MMP13, and ITGA10 consistent with a latent and primed skeletal developmental potential. The humanized MSC–derived microenvironment permitted homing and maintenance of long-term murine SLAM+ hematopoietic stem cells (HSCs), as well as human CD34+/CD38−/CD90+/CD45RA+ HSCs after cord blood transplantation. These studies underscore the profound differences in developmental potential between MSC sources independent of donor age, with implications for their clinical use. We also demonstrate a tractable human niche model for studying homing and engraftment of human hematopoietic cells in normal and neoplastic states. PMID:25406351

  5. In Vivo 4-Dimensional Tracking of Hematopoietic Stem and Progenitor Cells in Adult Mouse Calvarial Bone Marrow

    PubMed Central

    Scott, Mark K.; Akinduro, Olufolake; Lo Celso, Cristina

    2014-01-01

    Through a delicate balance between quiescence and proliferation, self renewal and production of differentiated progeny, hematopoietic stem cells (HSCs) maintain the turnover of all mature blood cell lineages. The coordination of the complex signals leading to specific HSC fates relies upon the interaction between HSCs and the intricate bone marrow microenvironment, which is still poorly understood[1-2]. We describe how by combining a newly developed specimen holder for stable animal positioning with multi-step confocal and two-photon in vivo imaging techniques, it is possible to obtain high-resolution 3D stacks containing HSPCs and their surrounding niches and to monitor them over time through multi-point time-lapse imaging. High definition imaging allows detecting ex vivo labeled hematopoietic stem and progenitor cells (HSPCs) residing within the bone marrow. Moreover, multi-point time-lapse 3D imaging, obtained with faster acquisition settings, provides accurate information about HSPC movement and the reciprocal interactions between HSPCs and stroma cells. Tracking of HSPCs in relation to GFP positive osteoblastic cells is shown as an exemplary application of this method. This technique can be utilized to track any appropriately labeled hematopoietic or stromal cell of interest within the mouse calvarium bone marrow space. PMID:25225854

  6. Microenvironment Tracker (MicroTrac) Model helps track air quality

    EPA Pesticide Factsheets

    MicroTrac is a model that uses global positioning system (GPS) data to estimate time of day and duration that people spend in different microenvironments (e.g., indoors and outdoors at home, work, school).

  7. Dry Eye Management: Targeting the Ocular Surface Microenvironment

    PubMed Central

    Zhang, Xiaobo; Jeyalatha M, Vimalin; Qu, Yangluowa; He, Xin; Ou, Shangkun; Bu, Jinghua; Jia, Changkai; Wang, Junqi; Wu, Han; Liu, Zuguo

    2017-01-01

    Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment. PMID:28661456

  8. Hydrogels in Healthcare: From Static to Dynamic Material Microenvironments.

    PubMed

    Kirschner, Chelsea M; Anseth, Kristi S

    2013-02-01

    Advances in hydrogel design have revolutionized the way biomaterials are applied to address biomedical needs. Hydrogels were introduced in medicine over 50 years ago and have evolved from static, bioinert materials to dynamic, bioactive microenvironments, which can be used to direct specific biological responses such as cellular ingrowth in wound healing or on-demand delivery of therapeutics. Two general classes of mechanisms, those defined by the user and those dictated by the endogenous cells and tissues, can control dynamic hydrogel microenvironments. These highly tunable materials have provided bioengineers and biological scientists with new ways to not only treat patients in the clinic but to study the fundamental cellular responses to engineered microenvironments as well. Here, we provide a brief history of hydrogels in medicine and follow with a discussion of the synthesis and implementation of dynamic hydrogel microenvironments for healthcare-related applications.

  9. Hydrogels in Healthcare: From Static to Dynamic Material Microenvironments

    PubMed Central

    Kirschner, Chelsea M.; Anseth, Kristi S.

    2013-01-01

    Advances in hydrogel design have revolutionized the way biomaterials are applied to address biomedical needs. Hydrogels were introduced in medicine over 50 years ago and have evolved from static, bioinert materials to dynamic, bioactive microenvironments, which can be used to direct specific biological responses such as cellular ingrowth in wound healing or on-demand delivery of therapeutics. Two general classes of mechanisms, those defined by the user and those dictated by the endogenous cells and tissues, can control dynamic hydrogel microenvironments. These highly tunable materials have provided bioengineers and biological scientists with new ways to not only treat patients in the clinic but to study the fundamental cellular responses to engineered microenvironments as well. Here, we provide a brief history of hydrogels in medicine and follow with a discussion of the synthesis and implementation of dynamic hydrogel microenvironments for healthcare-related applications. PMID:23929381

  10. Role of the Tumor Microenvironment in Breast Cancer.

    PubMed

    Soysal, Savas D; Tzankov, Alexandar; Muenst, Simone E

    2015-09-01

    In recent years, it has been shown that breast cancer consists not only of neoplastic cells, but also of significant alterations in the surrounding stroma or tumor microenvironment. These alterations are now recognized as a critical element for breast cancer development and progression, as well as potential therapeutic targets. Various components of the breast cancer microenvironment, such as suppressive immune cells, soluble factors and altered extracellular matrix, act together to impede effective antitumor immunity and promote breast cancer progression and metastasis. Stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways, some of which are prognostic of clinical outcome. Several new therapies targeting stromal components are in development or undergoing clinical trials. We focus herein on the composition of the breast cancer microenvironment and concomitant molecular alterations, the specific interplay between various cell types and cancer cells, and the clinical implications of these findings. © 2015 S. Karger AG, Basel.

  11. Remodeling Components of the Tumor Microenvironment to Enhance Cancer Therapy

    PubMed Central

    Gkretsi, Vasiliki; Stylianou, Andreas; Papageorgis, Panagiotis; Polydorou, Christiana; Stylianopoulos, Triantafyllos

    2015-01-01

    Solid tumor pathophysiology is characterized by an abnormal microenvironment that guides tumor progression and poses barriers to the efficacy of cancer therapies. Most common among tumor types are abnormalities in the structure of the tumor vasculature and stroma. Remodeling the tumor microenvironment with the aim to normalize any aberrant properties has the potential to improve therapy. In this review, we discuss structural abnormalities of the tumor microenvironment and summarize the therapeutic strategies that have been developed to normalize tumors as well as their potential to enhance therapy. Finally, we present different in vitro models that have been developed to analyze and better understand the effects of the tumor microenvironment on cancer cell behavior. PMID:26528429

  12. Shaping of the tumor microenvironment: Stromal cells and vessels.

    PubMed

    Blonska, Marzenna; Agarwal, Nitin K; Vega, Francisco

    2015-10-01

    Lymphomas develop and progress in a specialized tissue microenvironment such as bone marrow as well as secondary lymphoid organs such as lymph node and spleen. The lymphoma microenvironment is characterized by a heterogeneous population of stromal cells, including fibroblastic reticular cells, nurse-like cells, mesenchymal stem cells, follicular dendritic cells, and inflammatory cells such as macrophages, T- and B-cells. These cell populations interact with the lymphoma cells to promote lymphoma growth, survival and drug resistance through multiple mechanisms. Angiogenesis is also recognized as an important factor associated with lymphoma progression. In recent years, we have learned that the interaction between the malignant and non-malignant cells is bidirectional and resembles, at least in part, the pattern seen between non-neoplastic lymphoid cells and the normal microenvironment of lymphoid organs. A summary of the current knowledge of lymphoma microenvironment focusing on the cellular components will be reviewed here. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Dry Eye Management: Targeting the Ocular Surface Microenvironment.

    PubMed

    Zhang, Xiaobo; M, Vimalin Jeyalatha; Qu, Yangluowa; He, Xin; Ou, Shangkun; Bu, Jinghua; Jia, Changkai; Wang, Junqi; Wu, Han; Liu, Zuguo; Li, Wei

    2017-06-29

    Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment.

  14. Microenvironment -Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs)

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-13-1-0352 TITLE: Microenvironment-Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs) PRINCIPAL INVESTIGATOR: Dean...Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Microenvironment-Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs) 5b. GRANT NUMBER 5c...that eventually kills the patient. Although many PCa cell -intrinsic molecules and end-organ factors have been implicated in the metastatic

  15. Automated Identification and Localization of Hematopoietic Stem Cells in 3D Intravital Microscopy Data.

    PubMed

    Khorshed, Reema A; Hawkins, Edwin D; Duarte, Delfim; Scott, Mark K; Akinduro, Olufolake A; Rashidi, Narges M; Spitaler, Martin; Lo Celso, Cristina

    2015-07-14

    Measuring three-dimensional (3D) localization of hematopoietic stem cells (HSCs) within the bone marrow microenvironment using intravital microscopy is a rapidly expanding research theme. This approach holds the key to understanding the detail of HSC-niche interactions, which are critical for appropriate stem cell function. Due to the complex tissue architecture of the bone marrow and to the progressive introduction of scattering and signal loss at increasing imaging depths, there is no ready-made software to handle efficient segmentation and unbiased analysis of the data. To address this, we developed an automated image analysis tool that simplifies and standardizes the biological interpretation of 3D HSC microenvironment images. The algorithm identifies HSCs and measures their localization relative to surrounding osteoblast cells and bone collagen. We demonstrate here the effectiveness, consistency, and accuracy of the proposed approach compared to current manual analysis and its wider applicability to analyze other 3D bone marrow components. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. The Effects of Zoledronic Acid in the Bone and Vasculature Support of Hematopoietic Stem Cell Niches

    PubMed Central

    Soki, Fabiana N.; Li, Xin; Berry, Janice; Koh, Amy; Sinder, Benjamin P.; Qian, Xu; Kozloff, Kenneth M.; Taichman, Russell S.; McCauley, Laurie K.

    2013-01-01

    Hematopoietic stem cells (HSC) are maintained in a tightly regulated bone microenvironment constituted by a rich milieu of cells. Bone cells such as osteoblasts are associated with niche maintenance as regulators of the endosteal microenvironment. Bone remodeling also plays a role in HSC mobilization although it is poorly defined. The effects of zoledronic acid (ZA), a potent bisphosphonate that inhibits bone resorption, were investigated on bone marrow cell populations focusing on HSCs, and the endosteal and vascular niches in bone. ZA treatment significantly increased bone volume and HSCs in both young and adult mice (4 week and 4 month old, respectively). ZA increased vessel numbers with no overall change in vascular volume in bones of young and had no effect on vasculature in adult mice. Since both young and adult mice had increased HSCs and bone mass with differing vasculature responses, this suggests that ZA indirectly supports HSCs via the osteoblastic niche and not the vascular niche. Additionally, gene expression in Lin- cells demonstrated increased expression of self-renewal-related genes Bmi1 and Ink4a suggesting a role of ZA in the modulation of cell commitment and differentiation toward a long-term self-renewing cell. Genes that support the osteoblastic niche, BMP2 and BMP6 were also augmented in ZA treated mice. In conclusion, ZA-induced HSC expansion occurs independent of the vascular niche via indirect modulation of the osteoblastic niche. PMID:22833499

  17. [Hematopoietic stem cell transplantation in autoimmune diseases].

    PubMed

    Albarracín, Flavio; López Meiller, María José; Naswetter, Gustavo; Longoni, Héctor

    2008-01-01

    Transplantation of hematopoietic stem cells, which are capable of self renewal and reconstitution of all types of blood cells, can be a treatment for numerous potential lethal diseases, including leukemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant multiple sclerosis, lupus and systemic sclerosis. Studies in animal models show that the transfer of hematopoietic stem cells can reverse autoimmunity. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.

  18. Hematopoietic Aging Biomarkers in Peromyscus leucopus Mice.

    PubMed

    Lin, Zenghua; Kajigaya, Sachiko; Feng, Xingmin; Chen, Jichun; Young, Neal S

    2017-04-01

    We analyzed hematopoietic phenotypes in Peromyscus leucopus (PL) mice at young (2-9 months), middle (22-23 months) and old (33-46 months) ages aimed at characterizing age-associated changes in this unique rodent species. We found a significantly higher number of monocytes in old PL mice in peripheral blood, and higher proportions of CD44(+) cells in blood, spleen and bone marrow in old PL mice than in middle and young counterparts. We conclude that elevated blood monocyte counts and up-regulated hematopoietic cell CD44 expression are two useful aging biomarkers for PL mice.

  19. Hematopoietic Aging Biomarkers in Peromyscus leucopus Mice

    PubMed Central

    Lin, Zenghua; Kajigaya, Sachiko; Feng, Xingmin; Chen, Jichun; Young, Neal S

    2017-01-01

    We analyzed hematopoietic phenotypes in Peromyscus leucopus (PL) mice at young (2–9 months), middle (22–23 months) and old (33–46 months) ages aimed at characterizing age-associated changes in this unique rodent species. We found a significantly higher number of monocytes in old PL mice in peripheral blood, and higher proportions of CD44+ cells in blood, spleen and bone marrow in old PL mice than in middle and young counterparts. We conclude that elevated blood monocyte counts and up-regulated hematopoietic cell CD44 expression are two useful aging biomarkers for PL mice. PMID:28620625

  20. Canine hematopoietic tumors: diagnosis, treatment and complications

    SciTech Connect

    Weller, R.E.

    1986-02-01

    Canine hematopoietic tumors constitute a group of neoplasms that are frequently encountered in veterinary practice. Although common, they are also a diagnostically confusing group of tumors due to continued revision of their definition and classification. The confusion that arises from these changes presents the clinician with a perpetual challenge of diagnosis and therapy. Therapy of canine hematopoietic tumors has traditionally evolved from treatment of human patients with similar diseases, and in turn, these neoplasms have served as models for evaluating newer therapies for possible application in human patients. Methods of treatment have included chemotherapy, immunotherapy, radiation therapy, surgery, and hyperthermia. 9 tabs.

  1. TLR-mediated albuminuria needs TNFα-mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice

    PubMed Central

    Jain, Nidhi; Khullar, Bhavya; Oswal, Neelam; Banoth, Balaji; Joshi, Prashant; Ravindran, Balachandran; Panda, Subrat; Basak, Soumen; George, Anna; Rath, Satyajit; Sopory, Shailaja

    2016-01-01

    ABSTRACT Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs) in mice through engagement of Toll-like receptors (TLRs) is widely studied as a partial model for some forms of human nephrotic syndrome (NS). In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development. PMID:27125280

  2. The bone marrow microenvironment - Home of the leukemic blasts.

    PubMed

    Shafat, Manar S; Gnaneswaran, Bruno; Bowles, Kristian M; Rushworth, Stuart A

    2017-09-01

    Acute Myeloid Leukaemia (AML) is a genetically, biologically and clinically heterogeneous set of diseases, which are characterised by an increased growth of abnormal myeloid progenitor cells within the bone marrow (BM). Ex-vivo AML exhibits a high level of spontaneous apoptosis. Furthermore, relapse for patients achieving remission occurs from minimal residual disease harboured within the BM microenvironment. Taken together, these observations illustrate the importance of the BM microenvironment in sustaining AML. While significant progress has been made elaborating the small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of AML and its prognosis in response to treatment, less is understood about the complex microenvironment of the BM, which is known to be a key player in the pathogenesis of the disease. As we look towards future therapies, the consideration that the BM microenvironment is uniquely important as a niche for AML - coupled with the idea that leukaemic blasts are more likely to be genetically unstable and therefore evolve resistance to conventional chemotherapies - make the functions of the non-malignant cells of the BM attractive targets for therapy. In this review, we discuss the microanatomy of the BM and provide an overview of the evidence supporting the role of the BM microenvironment in creating conditions conducive to the survival and proliferation of AML blasts. Ultimately, we examine the therapeutic potential of uncoupling AML from the BM microenvironment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Accelerated aging in the tumor microenvironment

    PubMed Central

    Martinez-Outschoorn, Ubaldo E; Pavlides, Stephanos; Whitaker-Menezes, Diana; Pestell, Richard G; Howell, Anthony

    2011-01-01

    Cancer is thought to be a disease associated with aging. Interestingly, normal aging is driven by the production of ROS and mitochondrial oxidative stress, resulting in the cumulative accumulation of DNA damage. Here, we discuss how ROS signaling, NFκB- and HIF1-activation in the tumor micro-environment induces a form of “accelerated aging,” which leads to stromal inflammation and changes in cancer cell metabolism. Thus, we present a unified model where aging (ROS), inflammation (NFκB) and cancer metabolism (HIF1), act as co-conspirators to drive autophagy (“self-eating”) in the tumor stroma. Then, autophagy in the tumor stroma provides high-energy “fuel” and the necessary chemical building blocks, for accelerated tumor growth and metastasis. Stromal ROS production acts as a “mutagenic motor” and allows cancer cells to buffer—at a distance—exactly how much of a mutagenic stimulus they receive, further driving tumor cell selection and evolution. Surviving cancer cells would be selected for the ability to induce ROS more effectively in stromal fibroblasts, so they could extract more nutrients from the stroma via autophagy. If lethal cancer is a disease of “accelerated host aging” in the tumor stroma, then cancer patients may benefit from therapy with powerful antioxidants. Antioxidant therapy should block the resulting DNA damage, and halt autophagy in the tumor stroma, effectively “cutting off the fuel supply” for cancer cells. These findings have important new implications for personalized cancer medicine, as they link aging, inflammation and cancer metabolism with novel strategies for more effective cancer diagnostics and therapeutics. PMID:21654190

  4. XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer

    PubMed Central

    Morton, J. Jason; Bird, Gregory; Keysar, Stephen B.; Astling, David P.; Lyons, Traci R; Anderson, Ryan T.; Glogowska, Magdalena J.; Estes, Patricia; Eagles, Justin R.; Le, Phuong N.; Gan, Gregory; McGettigan, Brett; Fernandez, Pamela; Padilla-Just, Nuria; Varella-Garcia, Marileila; Song, John I.; Bowles, Daniel W.; Schedin, Pepper; Tan, Aik-Choon; Roop, Dennis R.; Wang, Xiao-Jing; Refaeli, Yosef; Jimeno, Antonio

    2015-01-01

    The limitations of cancer cell lines have led to the development of direct patient derived xenograft (PDX) models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg−/− (NSG) mouse on which a patient’s tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal, and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice – an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice, and provide a more accurate tumor model to guide patient treatment. PMID:25893296

  5. The human chorion contains definitive hematopoietic stem cells from the fifteenth week of gestation.

    PubMed

    Muench, Marcus O; Kapidzic, Mirhan; Gormley, Matthew; Gutierrez, Alan G; Ponder, Kathryn L; Fomin, Marina E; Beyer, Ashley I; Stolp, Haley; Qi, Zhongxia; Fisher, Susan J; Bárcena, Alicia

    2017-04-15

    We examined the contribution of the fetal membranes, amnion and chorion, to human embryonic and fetal hematopoiesis. A population of cells displaying a hematopoietic progenitor phenotype (CD34(++) CD45(low)) of fetal origin was present in the chorion at all gestational ages, associated with stromal cells or near blood vessels, but was absent in the amnion. Prior to 15 weeks of gestation, these cells lacked hematopoietic in vivo engraftment potential. Differences in the chemokine receptor and β1 integrin expression profiles of progenitors between the first and second trimesters suggest that these cells had gestationally regulated responses to homing signals and/or adhesion mechanisms that influenced their ability to colonize the stem cell niche. Definitive hematopoietic stem cells, capable of multilineage and long-term reconstitution when transplanted in immunodeficient mice, were present in the chorion from 15-24 weeks gestation, but were absent at term. The second trimester cells also engrafted secondary recipients in serial transplantation experiments. Thus, the human chorion contains functionally mature hematopoietic stem cells at mid-gestation.

  6. Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells

    PubMed Central

    Serafini, Marta; Dylla, Scott J.; Oki, Masayuki; Heremans, Yves; Tolar, Jakub; Jiang, Yuehua; Buckley, Shannon M.; Pelacho, Beatriz; Burns, Terry C.; Frommer, Sarah; Rossi, Derrick J.; Bryder, David; Panoskaltsis-Mortari, Angela; O'Shaughnessy, Matthew J.; Nelson-Holte, Molly; Fine, Gabriel C.; Weissman, Irving L.; Blazar, Bruce R.; Verfaillie, Catherine M.

    2007-01-01

    For decades, in vitro expansion of transplantable hematopoietic stem cells (HSCs) has been an elusive goal. Here, we demonstrate that multipotent adult progenitor cells (MAPCs), isolated from green fluorescent protein (GFP)-transgenic mice and expanded in vitro for >40–80 population doublings, are capable of multilineage hematopoietic engraftment of immunodeficient mice. Among MAPC-derived GFP+CD45.2+ cells in the bone marrow of engrafted mice, HSCs were present that could radioprotect and reconstitute multilineage hematopoiesis in secondary and tertiary recipients, as well as myeloid and lymphoid hematopoietic progenitor subsets and functional GFP+ MAPC-derived lymphocytes that were functional. Although hematopoietic contribution by MAPCs was comparable to control KTLS HSCs, approximately 103-fold more MAPCs were required for efficient engraftment. Because GFP+ host-derived CD45.1+ cells were not observed, fusion is not likely to account for the generation of HSCs by MAPCs. PMID:17227908

  7. Low oxygen tension favored expansion and hematopoietic reconstitution of CD34(+) CD38(-) cells expanded from human cord blood-derived CD34(+) Cells.

    PubMed

    Wang, Ziyan; Du, Zheng; Cai, Haibo; Ye, Zhaoyang; Fan, Jinli; Tan, Wen-Song

    2016-07-01

    Oxygen tension is an important factor that regulates hematopoietic stem cells (HSCs) in both in vivo hematopoietic microenvironment and ex vivo culture system. Although the effect of oxygen tension on ex vivo expansion of HSCs was extensively studied, there were no clear descriptions on physiological function and gene expression analysis of HSCs under different oxygen tensions. In this study, the effects of oxygen tension on ex vivo expansion characteristics of human umbilical cord blood (UCB)-derived CD34(+) cells are evaluated. Moreover, the physiological function of expanded CD34(+) cells was assessed by secondary expansion ability ex vivo and hematopoietic reconstitution ability in vivo. Also, genetic profiling was applied to analyze the expression of genes related to cell function. It was found that low oxygen tension favored expansion of CD34(+) CD38(-) cells. Additionally, CD34(+) cells expanded under low oxygen tension showed better secondary expansion ability and reconstitution ability than those under atmospheric oxygen concentration. Finally, the genetic profiling of CD34(+) CD38(-) cells cultured under low oxygen tension was more akin to freshly isolated cells. These results collectively demonstrate that low oxygen tension was able to better maintain both self-renewal and hematopoietic reconstitution potential and may lay an experimental basis for clinical transplantation of HSCs. Copyright © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Stage-specific roles for CXCR4 signaling in murine hematopoietic stem/progenitor cells in the process of bone marrow repopulation.

    PubMed

    Lai, Chen-Yi; Yamazaki, Satoshi; Okabe, Motohito; Suzuki, Sachie; Maeyama, Yoshihiro; Iimura, Yasuaki; Onodera, Masafumi; Kakuta, Shigeru; Iwakura, Yoichiro; Nojima, Masanori; Otsu, Makoto; Nakauchi, Hiromitsu

    2014-07-01

    Hematopoietic cell transplantation has proven beneficial for various intractable diseases, but it remains unclear how hematopoietic stem/progenitor cells (HSPCs) home to the bone marrow (BM) microenvironment, initiate hematopoietic reconstitution, and maintain life-long hematopoiesis. The use of newly elucidated molecular determinants for overall HSPC engraftment should benefit patients. Here, we report that modification of C-X-C chemokine receptor type 4 (Cxcr4) signaling in murine HSPCs does not significantly affect initial homing/lodging events, but leads to alteration in subsequent BM repopulation kinetics, with observations confirmed by both gain- and loss-of-function approaches. By using C-terminal truncated Cxcr4 as a gain-of-function effector, we demonstrated that signal augmentation likely led to favorable in vivo repopulation of primitive cell populations in BM. These improved features were correlated with enhanced seeding efficiencies in stromal cell cocultures and altered ligand-mediated phosphorylation kinetics of extracellular signal-regulated kinases observed in Cxcr4 signal-augmented HSPCs in vitro. Unexpectedly, however, sustained signal enhancement even with wild-type Cxcr4 overexpression resulted in impaired peripheral blood (PB) reconstitution, most likely by preventing release of donor hematopoietic cells from the marrow environment. We thus conclude that timely regulation of Cxcr4/CXCR4 signaling is key in providing donor HSPCs with enhanced repopulation potential following transplantation, whilst preserving the ability to release HSPC progeny into PB for improved transplantation outcomes.

  9. Vascular precursors: origin, regulation and function

    USDA-ARS?s Scientific Manuscript database

    In this miniseries, we discuss the phenotype, origin, and specialized microenvironment (niche) of distinct populations of stem and progenitor cells that exhibit vascular potential. Their usefulness and effectiveness for clinical therapies are also described. We have learned a great deal about post...

  10. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells

    PubMed Central

    2013-01-01

    Pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, are undifferentiated cells that can self-renew and potentially differentiate into all hematopoietic lineages, such as hematopoietic stem cells (HSCs), hematopoietic progenitor cells and mature hematopoietic cells in the presence of a suitable culture system. Establishment of pluripotent stem cells provides a comprehensive model to study early hematopoietic development and has emerged as a powerful research tool to explore regenerative medicine. Nowadays, HSC transplantation and hematopoietic cell transfusion have successfully cured some patients, especially in malignant hematological diseases. Owing to a shortage of donors and a limited number of the cells, hematopoietic cell induction from pluripotent stem cells has been regarded as an alternative source of HSCs and mature hematopoietic cells for intended therapeutic purposes. Pluripotent stem cells are therefore extensively utilized to facilitate better understanding in hematopoietic development by recapitulating embryonic development in vivo, in which efficient strategies can be easily designed and deployed for the generation of hematopoietic lineages in vitro. We hereby review the current progress of hematopoietic cell induction from embryonic stem/induced pluripotent stem cells. PMID:23796405

  11. Hematopoietic stem cell transplantation for sickle cell anemia.

    PubMed

    Vermylen, C; Cornu, G

    1997-11-01

    Hematopoietic stem cell transplantation is the only therapy able to cure sickle cell anemia at the present time. So far, transplantations have been undertaken in approximatively 140 sickle cell patients all over the world, with good results. The selection of patients for transplantation remains a subject of dilemma because of the unpredictable course of the disease and the lack of valuable prognostic markers. The selection criteria accepted so far concern young patients under the age of 16, with a morbid course of the disease and having a HLA-compatible sibling. In Belgium, patients going back to their country of origin were also considered for transplantation. For 100 patients who underwent transplantation in Europe, the current Kaplan-Meier estimates of overall survival, event-free survival, and disease-free survival rates are 90%, 79%, and 81%, respectively. Benefits and side effects are analyzed.

  12. Aging Hematopoietic Stem Cells Make Their History.

    PubMed

    Fast, Eva Maria; Zon, Leonard Ira

    2016-11-21

    A major hallmark of aging is a decline in tissue regeneration. In a recent issue of Cell, Bernitz and colleagues (2016) determine the divisional history of hematopoietic stem cells (HSCs) to be a key player of regenerative potential in the aging mouse. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Exosome mediated communication within the tumor microenvironment.

    PubMed

    Milane, Lara; Singh, Amit; Mattheolabakis, George; Suresh, Megha; Amiji, Mansoor M

    2015-12-10

    It is clear that exosomes (endosome derived vesicles) serve important roles in cellular communication both locally and distally and that the exosomal process is abnormal in cancer. Cancer cells are not malicious cells; they are cells that represent 'survival of the fittest' at its finest. All of the mutations, abnormalities, and phenomenal adaptations to a hostile microenvironment, such as hypoxia and nutrient depletion, represent the astute ability of cancer cells to adapt to their environment and to intracellular changes to achieve a single goal - survival. The aberrant exosomal process in cancer represents yet another adaptation that promotes survival of cancer. Cancer cells can secrete more exosomes than healthy cells, but more importantly, the content of cancer cells is distinct. An illustrative distinction is that exosomes derived from cancer cells contain more microRNA than healthy cells and unlike exosomes released from healthy cells, this microRNA can be associated with the RNA-induced silencing complex (RISC) which is required for processing mature and biologically active microRNA. Cancer derived exosomes have the ability to transfer metastatic potential to a recipient cell and cancer exosomes function in the physical process of invasion. In this review we conceptualize the aberrant exosomal process (formation, content selection, loading, trafficking, and release) in cancer as being partially attributed to cancer specific differences in the endocytotic process of receptor recycling/degradation and plasma membrane remodeling and the function of the endosome as a signaling entity. We discuss this concept and, to advance comprehension of exosomal function in cancer as mediators of communication, we detail and discuss exosome biology, formation, and communication in health and cancer; exosomal content in cancer; exosomal biomarkers in cancer; exosome mediated communication in cancer metastasis, drug resistance, and interfacing with the immune system; and

  14. Tracking the elusive fibrocyte: identification and characterization of collagen-producing hematopoietic lineage cells during murine wound healing.

    PubMed

    Suga, Hirotaka; Rennert, Robert C; Rodrigues, Melanie; Sorkin, Michael; Glotzbach, Jason P; Januszyk, Michael; Fujiwara, Toshihiro; Longaker, Michael T; Gurtner, Geoffrey C

    2014-05-01

    Fibrocytes are a unique population of circulating cells reported to exhibit characteristics of both hematopoietic and mesenchymal cells, and play an important role in wound healing. However, putative fibrocytes have been found to lose expression of hematopoietic surface markers such as CD45 during differentiation, making it difficult to track these cells in vivo with conventional methodologies. In this study, to distinguish hematopoietic and nonhematopoietic cells without surface markers, we took advantage of the gene vav 1, which is expressed solely on hematopoietic cells but not on other cell types, and established a novel transgenic mouse, in which hematopoietic cells are irreversibly labeled with green fluorescent protein and nonhematopoietic cells with red fluorescent protein. Use of single-cell transcriptional analysis in this mouse model revealed two discrete types of collagen I (Col I) expressing cells of hematopoietic lineage recruited into excisional skin wounds. We confirmed this finding on a protein level, with one subset of these Col I synthesizing cells being CD45+ and CD11b+, consistent with the traditional definition of a fibrocyte, while another was CD45- and Cd11b-, representing a previously unidentified population. Both cell types were found to initially peak, then reduce posthealing, consistent with a disappearance from the wound site and not a loss of identifying surface marker expression. Taken together, we have unambiguously identified two cells of hematopoietic origin that are recruited to the wound site and deposit collagen, definitively confirming the existence and natural time course of fibrocytes in cutaneous healing. © 2014 AlphaMed Press.

  15. Epigenetic Regulation of Hematopoietic Stem Cells

    PubMed Central

    Sharma, Shilpa; Gurudutta, Gangenahalli

    2016-01-01

    Hematopoietic stem cells are endowed with a distinct potential to bolster self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. Both hematopoietic stem cells and mature cells have the same genome, but their gene expression is controlled by an additional layer of epigenetics such as DNA methylation and post-translational histone modifications, enabling each cell-type to acquire various forms and functions. Until recently, several studies have largely focussed on the transcription factors andniche factors for the understanding of the molecular mechanisms by which hematopoietic cells replicate and differentiate. Several lines of emerging evidence suggest that epigenetic modifications eventually result in a defined chromatin structure and an “individual” gene expression pattern, which play an essential role in the regulation of hematopoietic stem cell self-renewal and differentiation. Distinct epigenetic marks decide which sets of genes may be expressed and which genes are kept silent. Epigenetic mechanisms are interdependent and ensure lifelong production of blood and bone marrow, thereby contributing to stem cell homeostasis. The epigenetic analysis of hematopoiesis raises the exciting possibility that chromatin structure is dynamic enough for regulated expression of genes. Though controlled chromatin accessibility plays an essential role in maintaining blood homeostasis; mutations in chromatin impacts on the regulation of genes critical to the development of leukemia. In this review, we explored the contribution of epigenetic machinery which has implications for the ramification of molecular details of hematopoietic self-renewal for normal development and underlying events that potentially co-operate to induce leukemia. PMID:27426084

  16. Metastasis genetics, epigenetics, and the tumor microenvironment

    USDA-ARS?s Scientific Manuscript database

    KISS1 is a member of a family of genes known as metastasis suppressors, defined by their ability to block metastasis without blocking primary tumor development and growth. KISS1 re-expression in multiple metastatic cell lines of diverse cellular origin suppresses metastasis; yet, still allows comple...

  17. Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy

    PubMed Central

    Li, Hanmin; Zhang, Lisheng

    2017-01-01

    Research on liver cancer prevention and treatment has mainly focused on the liver cancer cells themselves. Currently, liver cancers are no longer viewed as only collections of genetically altered cells but as aberrant organs with a plastic stroma, matrix, and vasculature. Improving the microenvironment of the liver to promote liver regeneration and repair by affecting immune function, inflammation and vasculature can regulate the dynamic imbalance between normal liver regeneration and repair and abnormal liver regeneration, thus improving the microenvironment of liver regeneration for the prevention and treatment of liver cancer. This review addresses the basic theory of the liver regeneration microenvironment, including the latest findings on immunity, inflammation and vasculature. Attention is given to the potential design of molecular targets in the microenvironment of hepatocellular carcinoma (HCC). In an effort to improve the liver regeneration microenvironment of HCC, researchers have extensively utilized the enhancement of immunity, anti-inflammation and the vasculature niche, which are discussed in detail in this review. In addition, the authors summarize the latest pro-fibrotic transition characteristics of the vascular niche and review potential cell therapies for liver disease. PMID:27655683

  18. Engineering cancer microenvironments for in vitro 3-D tumor models

    PubMed Central

    Asghar, Waseem; El Assal, Rami; Shafiee, Hadi; Pitteri, Sharon; Paulmurugan, Ramasamy; Demirci, Utkan

    2017-01-01

    The natural microenvironment of tumors is composed of extracellular matrix (ECM), blood vasculature, and supporting stromal cells. The physical characteristics of ECM as well as the cellular components play a vital role in controlling cancer cell proliferation, apoptosis, metabolism, and differentiation. To mimic the tumor microenvironment outside the human body for drug testing, two-dimensional (2-D) and murine tumor models are routinely used. Although these conventional approaches are employed in preclinical studies, they still present challenges. For example, murine tumor models are expensive and difficult to adopt for routine drug screening. On the other hand, 2-D in vitro models are simple to perform, but they do not recapitulate natural tumor microenvironment, because they do not capture important three-dimensional (3-D) cell–cell, cell–matrix signaling pathways, and multi-cellular heterogeneous components of the tumor microenvironment such as stromal and immune cells. The three-dimensional (3-D) in vitro tumor models aim to closely mimic cancer microenvironments and have emerged as an alternative to routinely used methods for drug screening. Herein, we review recent advances in 3-D tumor model generation and highlight directions for future applications in drug testing. PMID:28458612

  19. The First Tianjin, China Forum on Tumor Microenvironment

    PubMed Central

    Keller, Evan T.; Li, Lu-Yuan

    2010-01-01

    Although it is well recognized that the tumor microenvironment plays a key role in regulating tumor progression the mechanisms through which this occurs need to be defined. Current international research activities towards defining the role of the tumor microenvironment in cancer progression were the subject of the 1st Tianjin Forum on Tumor Microenvironment held at Nankai University in Tianjin, China, July 2 to 4, 2010. The importance of variety of processes, such as inflammation and angiogenesis, in the role of tumor progression were described for multiple tumor types including breast, prostate, and hepatic cancers as well as the process of bone metastasis. Identification of novel signaling pathways that impact both angiogenesis and bone remodeling were presented. Several themes emerged from this meeting including that (1) tumor cells modify the microenvironment to enhance their own survival and progression; (2) targeting host factors, in addition to targeting tumor cells, will have important therapeutic effects; and (3) host cells distribution within the tumor has both prognostic and therapeutic significance. Several priorities for future research were defined including use of a systems biology approach to define the role of host factors in tumor progression; defining the importance of targeting both arms of the bone remodeling process for therapy of bone metastasis and determining how different cell subsets contribute to microenvironment-mediated regulation of tumor progression. PMID:21224351

  20. Microenvironment and autophagy cross-talk: Implications in cancer therapy.

    PubMed

    Gomes, Luciana R; Vessoni, Alexandre T; Menck, Carlos F M

    2016-05-01

    There are many ongoing clinical trials to validate tumour microenvironment or autophagic pathway components as targets for anticancer therapies. Different components of the tumour microenvironment play important roles in tumour cell responses, directly affecting malignant transformation, drug resistance and metastasis. Autophagy is also related to chemotherapy responses by inducing tumour cell death or survival. Thus, the autophagy pathway may act as oncosuppressor, in addition to protecting cells from chemotherapy. The cross-talk between the microenvironment and autophagy is very complex and poorly understood. In a recent study using a three-dimensional (3D) cell culture model, the well-documented chemotherapy-mediated activation of autophagy was impaired in breast cancer cells, suggesting a context-dependent outcome for autophagy modulators, under the control of the p53 protein. A deeper understanding of this microenvironment/autophagy interplay may provide important clues for identifying differences in the tumour cell signalling network from in vitro basic research studies to the actual clinical context. In this work, we summarize the role of the microenvironment and autophagy in physiological and tumourigenic conditions, their interactions, and the challenges related to the use of drugs that target these pathways in cancer treatment protocols, emphasizing the potential use of 3D cell culture models in preclinical studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Immunological Microenvironment of Hepatocellular Carcinoma and Its Clinical Implication.

    PubMed

    Nishida, Naoshi; Kudo, Masatoshi

    2017-01-01

    Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with advanced stage of disease remains unfavorable. Several immune therapies have been applied to HCC, and their responses have not been satisfactory. The immune response to cancer is determined by the balance between the antigenicity of the tumor and the microenvironment of cancer tissues. Generally, accumulated genetic mutations are observed in HCC, which may lead to increased neoantigens on cancer cells with high antigenicity. However, cancer cells may evade the immune system because of alterations in molecules and cellular pathways involved in antigen processing and presentation. In addition, hypoxia in tissue induces several cytokines, chemokines, and immunosuppressive molecules from HCC cells and stromal cells. These cells also produce cytokines that attract regulatory T cells infiltrating tumor tissues and contribute to establishing an immunosuppressive microenvironment. Some cancers show a good response to immune checkpoint therapy. However, prolonged stabilization of disease for this treatment is reportedly 12-41% in patients with advanced cancer. Therefore, immunosuppressive forces in the microenvironment of HCC may cause resistance to immune therapy, and modification of the tumor microenvironment may restore normal anticancer immunity. In this review, we focus on the immunological microenvironment of HCC tissues and discuss how the immunosuppressive environment of HCC should be modulated to achieve a favorable response to immune therapy, such as immune checkpoint therapy, in HCC. © 2016 S. Karger AG, Basel.

  2. One microenvironment does not fit all: heterogeneity beyond cancer cells.

    PubMed

    Kim, Ik Sun; Zhang, Xiang H-F

    2016-12-01

    Human cancers exhibit formidable molecular heterogeneity, to a large extent accounting for the incomplete and transitory efficacy of current anti-cancer therapies. However, neoplastic cells alone do not manifest the disease, but conscript a battery of non-tumor cells to enable and sustain hallmark capabilities of cancer. Escaping immunosurveillance is one of such capabilities. Tumors evolve immunosuppressive microenvironment to subvert anti-tumor immunity. In this review, we will focus on tumor-associated myeloid cells, which constitute an essential part of the immune microenvironment and reciprocally interact with cancer cells to establish malignancy toward metastasis. The diversity and plasticity of these cells constitute another layer of heterogeneity, beyond the heterogeneity of cancer cells themselves. We envision that immune microenvironment co-evolves with the genetic heterogeneity of tumor. Addressing the question of how genetically distinct tumors shape and are shaped by unique immune microenvironment will provide an attractive rationale to develop novel immunotherapeutic modalities. Here, we discuss the complex nature of tumor microenvironment, with an emphasis on the cellular and functional heterogeneity among tumor-associated myeloid cells as well as immune environment heterogeneity in the context of a full spectrum of human breast cancers.

  3. Multimodal imaging of lung cancer and its microenvironment (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hariri, Lida P.; Niederst, Matthew J.; Mulvey, Hillary; Adams, David C.; Hu, Haichuan; Chico Calero, Isabel; Szabari, Margit V.; Vakoc, Benjamin J.; Hasan, Tayyaba; Bouma, Brett E.; Engelman, Jeffrey A.; Suter, Melissa J.

    2016-03-01

    Despite significant advances in targeted therapies for lung cancer, nearly all patients develop drug resistance within 6-12 months and prognosis remains poor. Developing drug resistance is a progressive process that involves tumor cells and their microenvironment. We hypothesize that microenvironment factors alter tumor growth and response to targeted therapy. We conducted in vitro studies in human EGFR-mutant lung carcinoma cells, and demonstrated that factors secreted from lung fibroblasts results in increased tumor cell survival during targeted therapy with EGFR inhibitor, gefitinib. We also demonstrated that increased environment stiffness results in increased tumor survival during gefitinib therapy. In order to test our hypothesis in vivo, we developed a multimodal optical imaging protocol for preclinical intravital imaging in mouse models to assess tumor and its microenvironment over time. We have successfully conducted multimodal imaging of dorsal skinfold chamber (DSC) window mice implanted with GFP-labeled human EGFR mutant lung carcinoma cells and visualized changes in tumor development and microenvironment facets over time. Multimodal imaging included structural OCT to assess tumor viability and necrosis, polarization-sensitive OCT to measure tissue birefringence for collagen/fibroblast detection, and Doppler OCT to assess tumor vasculature. Confocal imaging was also performed for high-resolution visualization of EGFR-mutant lung cancer cells labeled with GFP, and was coregistered with OCT. Our results demonstrated that stromal support and vascular growth are essential to tumor progression. Multimodal imaging is a useful tool to assess tumor and its microenvironment over time.

  4. Galectin-3 in bone tumor microenvironment: a beacon for individual skeletal metastasis management.

    PubMed

    Nakajima, Kosei; Kho, Dong Hyo; Yanagawa, Takashi; Zimel, Melissa; Heath, Elisabeth; Hogan, Victor; Raz, Avraham

    2016-06-01

    The skeleton is frequently a secondary growth site of disseminated cancers, often leading to painful and devastating clinical outcomes. Metastatic cancer distorts bone marrow homeostasis through tumor-derived factors, which shapes different bone tumor microenvironments depending on the tumor cells' origin. Here, we propose a novel insight on tumor-secreted Galectin-3 (Gal-3) that controls the induction of an inflammatory cascade, differentiation of osteoblasts, osteoclasts, and bone marrow cells, resulting in bone destruction and therapeutic failure. In the approaching era of personalized medicine, the current treatment modalities targeting bone metastatic environments are provided to the patient with limited consideration of the cancer cells' origin. Our new outlook suggests delivering individual tumor microenvironment treatments based on the expression level/activity/functionality of tumor-derived factors, rather than utilizing a commonly shared therapeutic umbrella. The notion of "Gal-3-associated bone remodeling" could be the first step toward a specific personalized therapy for each cancer type generating a different bone niche in patients afflicted with non-curable bone metastasis.

  5. Retinoic Acid Receptor γ Regulates B and T Lymphopoiesis via Nestin-Expressing Cells in the Bone Marrow and Thymic Microenvironments.

    PubMed

    Joseph, Chacko; Nota, Celeste; Fletcher, Jessica L; Maluenda, Ana C; Green, Alanna C; Purton, Louise E

    2016-03-01

    Vitamin A has essential but largely unexplained roles in regulating lymphopoiesis. We have previously shown that retinoic acid receptor (RAR) γ-deficient mice have hematopoietic defects, some phenotypes of which were microenvironment induced. Bone marrow (BM) microenvironment cells identified by either their expression of nestin (Nes) or osterix (Osx) have previously been shown to have roles in regulating lymphopoiesis. We therefore conditionally deleted Rarγ in Nes- or Osx-expressing microenvironment cells. Osx cell-specific deletion of Rarγ had no impact on hematopoiesis. In contrast, deletion of Rarγ in Nes-expressing cells resulted in reductions in peripheral blood B cells and CD4(+) T cells, accompanied by reductions of immature PreB cells in BM. The mice lacking Rarγ in Nes-expressing cells also had smaller thymi, with reductions in double-negative 4 T cell precursors, accompanied by reduced numbers of both TCRβ(low) immature single-positive CD8(+) cells and double-positive T cells. In the thymus, Nes expression was restricted to thymic stromal cells that expressed cerebellar degeneration-related Ag 1 and lacked expression of epithelial cell adhesion molecule. These cells expressed platelet-derived growth factor α and high transcript levels of Rars, Cxcl12, and stem cell factor (Scf). Short-term treatment of mice with all-trans retinoic acid resulted in increased PreB lymphopoiesis in BM and an increase in thymic double-negative 4 T cells, inverse to that observed upon Nes cell-specific deletion of Rarγ. Collectively, these studies show that RARγ is a regulator of B and T lymphopoiesis via Nes-expressing cells in the BM and thymic microenvironments, respectively.

  6. Osteoblasts Are the Centerpiece of the Metastatic Bone Microenvironment

    PubMed Central

    2016-01-01

    The tumor microenvironment is comprised of diverse stromal cell populations in addition to tumor cells. Increasing evidence now clearly supports the role of microenvironment stromal cells in tumor progression and metastasis, yet the regulatory mechanisms and interactions among tumor and stromal cells remain to be elucidated. Bone metastasis is the major problem in many types of human malignancies including prostate, breast and lung cancers, and the biological basis of bone metastasis let alone curative approaches are largely undetermined. Among the many types of stromal cells in bone, osteoblasts are shown to be an important player. In this regard, osteoblasts are a key target cell type in the development of bone metastasis, but there are currently no drugs or therapeutic approaches are available that specifically target osteoblasts. This review paper summarizes the current knowledge on osteoblasts in the metastatic tumor microenvironment, aiming to provide clues and directions for future research endeavor. PMID:28029019

  7. Hypoxic Tumor Microenvironment: Opportunities to Develop Targeted Therapies

    PubMed Central

    Patel, Akhil; Sant, Shilpa

    2016-01-01

    Recent few years have seen great progress in understanding tumor biology and surrounding microenvironment. Solid tumors create regions with low oxygen levels, generally termed as hypoxic regions. These hypoxic areas offer a tremendous opportunity to develop targeted therapies. Hypoxia is not a random by-product of cellular milieu due to uncontrolled tumor growth; rather it is a constantly evolving participant in overall tumor growth and fate. This article reviews current trends and recent advances in drug therapies and delivery systems targeting hypoxia in the tumor microenvironment. In the first part, we give an account of important physicochemical changes and signaling pathways activated in the hypoxic microenvironment. This is then followed by various treatment strategies including hypoxia-sensitive signaling pathways and approaches to develop hypoxia-targeted drug delivery systems. PMID:27143654

  8. Hypoxic tumor microenvironment: Opportunities to develop targeted therapies.

    PubMed

    Patel, Akhil; Sant, Shilpa

    2016-01-01

    In recent years, there has been great progress in the understanding of tumor biology and its surrounding microenvironment. Solid tumors create regions with low oxygen levels, generally termed as hypoxic regions. These hypoxic areas offer a tremendous opportunity to develop targeted therapies. Hypoxia is not a random by-product of the cellular milieu due to uncontrolled tumor growth; rather it is a constantly evolving participant in overall tumor growth and fate. This article reviews current trends and recent advances in drug therapies and delivery systems targeting hypoxia in the tumor microenvironment. In the first part, we give an account of important physicochemical changes and signaling pathways activated in the hypoxic microenvironment. This is then followed by various treatment strategies including hypoxia-sensitive signaling pathways and approaches to develop hypoxia-targeted drug delivery systems. Published by Elsevier Inc.

  9. Schwann cells: a new player in the tumor microenvironment.

    PubMed

    Bunimovich, Yuri L; Keskinov, Anton A; Shurin, Galina V; Shurin, Michael R

    2017-08-01

    Cancerous cells must cooperate with the surrounding stroma and non-malignant cells within the microenvironment to support the growth and invasion of the tumor. The nervous system is a component of every organ system of the body, and therefore, is invariably at the front line of the tumor invasion. Due to the complexity of the nervous system physiology, this review separately discusses the contributions of the central and peripheral nervous systems to the tumorigenesis and tumor progression. We further focus the discussion on the evidence that Schwann cells aid in tumor growth and invasion. Schwann cells, a largely unexplored element of the tumor microenvironment, may participate in the creation of tumor-favorable conditions through both bi-directional interaction with cancer cells and the facilitation of the immune-suppressive microenvironment through the mechanism of neural repair and immunomodulation.

  10. microRNA-mediated regulation of the tumor microenvironment

    PubMed Central

    Chou, Jonathan; Shahi, Payam; Werb, Zena

    2013-01-01

    The tumor microenvironment includes cells such as fibroblasts, immune cells, endothelial cells, as well as extracellular matrix (ECM), proteases, and cytokines. Together, these components participate in a complex crosstalk with neoplastic tumor cells that affects growth, angiogenesis, and metastasis. MicroRNAs (miRNAs) are small, non-coding RNAs involved in post-transcriptional regulation of gene expression and have recently emerged as important players involved in regulating multiple aspects of cancer biology and the tumor microenvironment. Differential miRNA expression in both the epithelial and stromal compartments of tumors compared with normal tissue suggests that miRNAs are important drivers of tumorigenesis and metastasis. This review article summarizes our current understanding of the diverse roles of miRNAs involved in tumor microenvironment regulation and underscores the importance of miRNAs within multiple cell types that contribute to the hallmarks of cancer. PMID:24036551

  11. Pi (Spleen)-deficiency syndrome in tumor microenvironment is the pivotal pathogenesis of colorectal cancer immune escape.

    PubMed

    Sun, Xue-Gang; Lin, Xiao-Chang; Diao, Jian-Xin; Yu, Zhi-Ling; Li, Kun

    2016-10-01

    Cancer immunoediting consists of three sequential phases: elimination, equilibrium, and escape. For colorectal adenoma-carcinoma sequence, the adenoma dysplastic progression may represent an equilibrium phase and the cancer stage as escape phase. Immune system eliminates transformed enterocytes by destroying them at first, sculpts them at the same time and selects the variants subsequently that are no longer recognized and insensitive to immune effectors, and finally induces immunosuppressive state within the tumor microenvironment that facilitates immune escape and tumor outgrowth. Immunosuppression and inflammation are the two crucial features of Pi (Spleen)-deficiency. Classic quotations, immune evidence and clinical observations suggest that Spleen (but not other organs) deficiency is the key pathogenesis of colorectal cancer (CRC) microenvironment. Weakness of old age, immunosuppressive cytokines from chronic inflammation, tumor-derived immunosuppressive factors and surrendered immune cells-regulatory T cells, myeloid-derived suppressor cells and tumor associated macrophages (TAMs) constitutes CRC microenvironment of Pi-deficiency. Furthermore, excess in superficiality, such as phlegm stagnation, blood stasis and toxin accumulation are induced by chronic inflammation on the basis of asthenia in origin, an immunosuppressive state. Great masters of Chinese medicine emphasize that strengthen Pi is the chief therapeutic principle for CRC which receives good therapeutic effects. So, Pi-deficiency based syndrome is the pivotal pathogenesis of tumor microenvironment. The immunosuppressive microenvironment facilitates immune escape which play an important role in the transition from adenoma to adenocarcinoma. There are some signs that strengthen Pi based treatment has potential capacity to ameliorate tumor environment. It might be a novel starting point to explore the mechanism of strengthen Pi based therapy in the prevention and treatment of CRC through regulation of

  12. The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence

    PubMed Central

    Barker, Holly E.; Paget, James T. E.; Khan, Aadil A.; Harrington, Kevin J.

    2016-01-01

    Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focussed on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes induced in the tumour microenvironment by irradiation and discuss how they may promote radioresistance and tumour recurrence. Subsequently, we highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy. PMID:26105538

  13. Immunosuppression associated with chronic inflammation in the tumor microenvironment

    PubMed Central

    Wang, Dingzhi; DuBois, Raymond N.

    2015-01-01

    Chronic inflammation contributes to cancer development via multiple mechanisms. One potential mechanism is that chronic inflammation can generate an immunosuppressive microenvironment that allows advantages for tumor formation and progression. The immunosuppressive environment in certain chronic inflammatory diseases and solid cancers is characterized by accumulation of proinflammatory mediators, infiltration of immune suppressor cells and activation of immune checkpoint pathways in effector T cells. In this review, we highlight recent advances in our understanding of how immunosuppression contributes to cancer and how proinflammatory mediators induce the immunosuppressive microenvironment via induction of immunosuppressive cells and activation of immune checkpoint pathways. PMID:26354776

  14. Hematopoietic stem cell engineering at a crossroads.

    PubMed

    Rivière, Isabelle; Dunbar, Cynthia E; Sadelain, Michel

    2012-02-02

    The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead.

  15. Hematopoietic stem cell engineering at a crossroads

    PubMed Central

    Rivière, Isabelle; Dunbar, Cynthia E.

    2012-01-01

    The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead. PMID:22096239

  16. Proinflammatory signaling regulates hematopoietic stem cell emergence

    PubMed Central

    Espín-Palazón, Raquel; Stachura, David L.; Campbell, Clyde A.; García-Moreno, Diana; Cid, Natasha Del; Kim, Albert D.; Candel, Sergio; Meseguer, José; Mulero, Victoriano; Traver, David

    2014-01-01

    Summary Hematopoietic stem cells (HSCs) underlie the production of blood and immune cells for the lifetime of an organism. In vertebrate embryos, HSCs arise from the unique transdifferentiation of hemogenic endothelium comprising the floor of the dorsal aorta during a brief developmental window. To date, this process has not been replicated in vitro from pluripotent precursors, partly because the full complement of required signaling inputs remains to be determined. Here, we show that TNFR2 via TNFα activates the Notch and NF-κB signaling pathways to establish HSC fate, indicating a requirement for inflammatory signaling in HSC generation. We determine that primitive neutrophils are the major source of TNFα, assigning a role for transient innate immune cells in establishing the HSC program. These results demonstrate that proinflammatory signaling, in the absence of infection, is utilized by the developing embryo to generate the lineal precursors of the adult hematopoietic system. PMID:25416946

  17. Epigenomics in hematopoietic transplantation: novel treatment strategies.

    PubMed

    Engel, Nicole; Rank, Andreas

    2011-10-01

    Allogeneic hematopoietic stem cell transplantation is a high risk but curative treatment option for leukemia, myelodysplasia and other hematological malignancies. After high dose radio- or chemo-therapy, recipient's hematopoiesis is replaced by a new immunosystem and residual malignant cells are eliminated by the graft-versus-leukemia reaction. The benefit of this immunological effect is limited by the most frequent complication of hematopoietic stem cell transplantation: graft-versus-host disease. In addition to their well-known anti-tumor activity, epigenetic drugs mediate immunotolerance without reducing alloreactivity or even enhance graft-versus-leukemia effect without inducing graft-versus-host disease by regulating cytokine release, increasing the circulating number of regulatory T cells and interacting with natural killer cells. We focus on the use of epigenetic drugs in the allogeneic transplantation setting in relation to their anti-tumor and immunomodulatory potential.

  18. Hematopoietic Cell Transplantation after Solid Organ Transplantation.

    PubMed

    Doney, Kristine C; Mielcarek, Marco; Stewart, F Marc; Appelbaum, Frederick R

    2015-12-01

    Solid organ transplantation (SOT) followed by hematopoietic cell transplantation (HCT) has been used to treat a single disease with multiorgan involvement or 2 separate diseases, the first requiring SOT and the second often a possible complication of SOT. Results of such serial transplants have been reported sporadically in the literature, usually as single case studies. Thirteen autologous and 27 allogeneic HCTs after SOT published previously are summarized. A more detailed review is provided for an additional 16 patients transplanted at a single institution, 8 of whom had autologous and 8 of whom had allogeneic HCT after SOT. Five of 8 autologous transplant recipients are alive a median of 4.6 years after HCT. Four of 8 allogeneic HCT recipients are alive a median of 8.7 years after HCT. In carefully selected patients, HCT after SOT is feasible and associated with a low incidence of either solid organ or hematopoietic cell rejection.

  19. DNA methylation profiling of hematopoietic stem cells.

    PubMed

    Begtrup, Amber Hogart

    2014-01-01

    DNA methylation is a key epigenetic mark that is essential for properly functioning hematopoietic stem cells. Determining where functionally relevant DNA methylation marks exist in the genome is crucial to understanding the role that methylation plays in hematopoiesis. This chapter describes a method to profile DNA methylation by selectively enriching methylated DNA sequences that are bound in vitro by methyl-binding domain (MBD) proteins. The MBD-pulldown approach selects for DNA sequences that have the potential to be "read" by the endogenous machinery involved in epigenetic regulation. Furthermore, this approach is feasible with very small quantities of DNA, and is compatible with the use of any downstream high-throughput sequencing approach. This technique offers a reliable, simple, and powerful tool for exploration of the role of DNA methylation in hematopoietic stem cells.

  20. Syngeneic Transplants with Modified Chimeric Hematopoietic Tumors.

    PubMed

    Hemann, Michael

    2015-08-03

    This protocol describes strategies to rapidly transduce tumor cells ex vivo and then transplant modified cells into immunocompetent-recipient mice. Inherent in the definition of a bona fide murine hematopoietic malignancy, unlike a myelo- or lympho-proliferative disease, is the ability to transplant tumors and give rise to a malignancy in recipient animals. This characteristic of hematopoietic disease makes these tumors a tractable model for examining the role of specific genes in tumor growth, dissemination, or therapeutic response. Additionally, because of the systemic nature of hematopoietic malignancies, transplanted tumors are frequently pathologically indistinguishable from donor malignancies-allowing one to perform decisive therapy studies on large cohorts of transplant recipients. Finally, following ex vivo manipulation, transplanted tumors can be made chimeric for the presence of defined retrovirally induced alterations. Thus, these malignancies can be made to resemble genetically heterogeneous human tumors that are in the process of acquiring new capabilities. In these experiments, fluorescent markers serve as a surrogate marker for the expression of a defined alteration, and the change in the percentage of fluorescent cells in a tumor population over time or in response to therapy can be used to gauge the impact of specific alterations on tumor behavior.

  1. Sindbis viral vectors target hematopoietic malignant cells.

    PubMed

    Suzme, R; Tseng, J-C; Levin, B; Ibrahim, S; Meruelo, D; Pellicer, A

    2012-11-01

    Sindbis viral vectors target and inhibit the growth of various solid tumors in mouse models. However, their efficacy against blood cancer has not been well established. Here, we show that Sindbis vectors infect and efficiently trigger apoptosis in mouse BW5147 malignant hematopoietic T-cells, but only at low levels in human lymphoma and leukemia cells (Jurkat, Karpas, CEM, DHL and JB). The Mr 37/67 kD laminin receptor (LAMR) has been suggested to be the receptor for Sindbis virus. However, JB cells, which are infected by Sindbis at low efficiency, express high levels of LAMR, revealing that additional factors are involved in Sindbis tropism. To test the infectivity and therapeutic efficacy of Sindbis vectors against malignant hematopoietic cells in vivo, we injected BW5147 cells intraperitoneally into (C3HXAKR) F1 hybrid mice. We found that Sindbis vectors targeted the tumors and significantly prolonged survival of tumor-bearing mice. We also tested the Sindbis vectors in a transgenic CD4-Rgr model, which spontaneously develop thymic lymphomas. However, infectivity in this model was less efficient. Taken together, these results demonstrate that Sindbis vectors have the potential to target and kill hematopoietic malignancies in mice, but further research is needed to evaluate the mechanism underlining the susceptibility of human lymphoid malignancies to Sindbis therapy.

  2. Microenvironment inflammatory infiltrate drives growth speed and outcome of hepatocellular carcinoma: a prospective clinical study.

    PubMed

    Critelli, Rosina; Milosa, Fabiola; Faillaci, Francesca; Condello, Rosario; Turola, Elena; Marzi, Luca; Lei, Barbara; Dituri, Francesco; Andreani, Silvia; Sighinolfi, Pamela; Manni, Paola; Maiorana, Antonino; Caporali, Cristian; di Benedetto, Fabrizio; Del Buono, Mariagrazia; De Maria, Nicola; Schepis, Filippo; Martinez-Chantar, Maria-Luz; Giannelli, Gianluigi; Villa, Erica

    2017-08-24

    In HCC, tumor microenvironment, heavily influenced by the underlying chronic liver disease, etiology and stage of the tissue damage, affects tumor progression and determines the high heterogeneity of the tumor. Aim of this study was to identify the circulating and tissue components of the microenvironment immune-mediated response affecting the aggressiveness and the ensuing clinical outcome. We analyzed the baseline paired HCC and the surrounding tissue biopsies from a prospective cohort of 132 patients at the first diagnosis of HCC for immunolocalization of PD-1/PD-L1, FoxP3, E-cadherin, CLEC2 and for a panel of 82 microRNA associated with regulation of angiogenesis, cell proliferation, cell signaling, immune control and autophagy. Original microarray data were also explored. Serum samples were analyzed for a panel of 19 cytokines. Data were associated with biochemical data, histopathology and survival. Patients with a more aggressive disease and shorter survival, who we named fast-growing accordingly to the tumor doubling time, at presentation had significantly higher AFP levels, TGF-β1 and Cyphra 21-1 levels. Transcriptomic analysis evidenced a significant downregulation of CLEC2 and upregulation of several metalloproteinases. A marked local upregulation of both PD-1 and PD-L1, a concomitant FoxP3-positive lymphocytic infiltrate, a loss of E-cadherin, gain of epithelial-mesenchymal transition (EMT) phenotype and extreme poor differentiation at histology were also present. Upregulated microRNA in fast-growing HCCs are associated with TGF-β signaling, angiogenesis and inflammation. Our data show that fast HCCs are characterized not only by redundant neo-angiogenesis but also by unique features of distinctively immunosuppressed microenvironment, prominent EMT, and clear-cut activation of TGFβ1 signaling in a general background of long-standing and permanent inflammatory state.

  3. The microenvironment influences the pattern of bacterial translocation in formula-fed neonates.

    PubMed

    Ford, H R; Avanoğlu, A; Boechat, P R; Melgoza, D; LumCheong, R S; Boyle, P; Garrett, M; Rowe, M I

    1996-04-01

    The authors previously demonstrated that neonatal rabbits fed conventional formula have a significantly greater incident of bacterial translocation than do neonatal rabbits fed breast milk. They hypothesized that exogenous bacteria in the formula and/or the microenvironment of the neonatal rabbit may contribute to the higher incidence of bacterial translocation. In the present study, the authors examined the incidence of bacterial translocation in neonatal rabbits fed pasteurized formula, unsterile formula, or breast milk while being housed in a clean or unsterile environment. The rabbits were divided into five groups. Groups I and II were fed pasteurized formula; groups III and IV were fed unsterile formula. In addition, groups I and III were housed in a clean environment, and groups II and IV were kept in an unsterile environment. The neonates in group V were fed breast milk and were kept in an unsterile environment. On the seventh day, the animals were killed, and the mesenteric lymph nodes, liver, and spleen were cultured for the presence of bacteria. Bacterial translocation occurred in 100% of group IV neonates. A clean environment (groups I and III) eliminated gram-negative bacterial translocation. A reduction (50%) in the overall incidence of bacterial translocation was obtained by pasteurizing the formula (group I v group III). Group II had significantly less gram-negative bacterial translocation than did group IV. None of the neonates in group V had translocation. The data show that a clean environment abrogates gram-negative bacterial translocation. Pasteurizing the formula significantly reduces the incidence of gram-negative bacterial translocation, and further reduces overall bacterial translocation in a clean environment. The authors hypothesize that control of the microenvironment can significantly influence the pattern of bacterial translocation in formula-fed neonates, and thus potentially reduce the incidence of gut-origin sepsis. Factors present

  4. Emergent Complications in the Pediatric Hematopoietic Stem Cell Transplant Patient

    PubMed Central

    Munchel, Ashley; Chen, Allen; Symons, Heather

    2014-01-01

    Hematopoietic cell transplantation is the only potentially curative option for a variety of pediatric malignant and nonmalignant disorders. Despite advances in transplantation biology and immunology as well as in posttransplant management that have contributed to improved survival and decreased transplant-related mortality, hematopoietic cell transplantation does not come without significant risk of complications. When patients who have undergone hematopoietic cell transplantation present to the emergency department, it is important to consider a variety of therapy-related complications to optimize management and outcome. In this article, we use clinical cases to highlight some of the more common emergent complications after hematopoietic cell transplantation. PMID:25411564

  5. Tributyltin alters the bone marrow microenvironment and suppresses B cell development.

    PubMed

    Baker, Amelia H; Wu, Ting Hua; Bolt, Alicia M; Gerstenfeld, Louis C; Mann, Koren K; Schlezinger, Jennifer J

    2017-04-07

    Organotins are industrial chemicals and agricultural pesticides, and they contaminate both outdoor and indoor environments. Organotins are detectable in human sera at biologically active concentrations and are immuno-and neuro-toxicants. Triphenyltin, tributyltin (TBT) and dibutyltin activate peroxisome proliferator-activated receptor γ (PPARγ) in bone marrow multipotent mesenchymal stromal cells (BM-MSC) and promote adipogenesis. TBT also has been shown to suppress osteogenesis; osteoblasts not only support bone homeostasis but also support B lymphopoiesis. In addition, developing B cells are highly sensitive to exogenous insults. Thus, we hypothesized that bone marrow B cells may be negatively affected by TBT exposure both directly, through activation of apoptosis, and indirectly, through alterations of the bone marrow microenvironment. TBT activated apoptosis in developing B cells at environmentally relevant concentrations (as low as 80 nM) in vitro, via a mechanism that is distinct from that induced by high dose (μM) TBT and that requires p53. TBT suppressed the proliferation of hematopoietic cells in an ex vivo bone marrow model. Concurrent treatment of stromal cells and B cells or pretreatment of stromal cells with TBT induced adipogenesis in the stromal cells and reduced the progression of B cells from the early pro B (Hardy fraction B) to the pre B stage (Hardy fraction D). In vivo, TBT induced adipogenesis in bone marrow, reduced "aging-sensitive" AA4+CD19+ B cells in bone marrow, and reduced splenic B cell numbers. Immunosenescence and osteoporosis are adverse health effects of aging, we postulate that TBT exposure may mimic, and possibly intensify, these pathologies.

  6. Studies of the Tumor Microenvironment in Pathogenesis of Neuroblastoma

    DTIC Science & Technology

    2013-07-01

    of Neuroblastoma PRINCIPAL INVESTIGATOR: Shahab Asgharzadeh, M D CONTRACTING ORGANIZATION: Children’s Hospital Los Angeles Los Angeles...2012 - 30 June 2013 4. TITLE AND SUBTITLE Studies of the Tumor Microenvironment in Pathogenesis of Neuroblastoma 5a. CONTRACT NUMBER 5b...NOTES 14. ABSTRACT The NBL-Tag neuroblastoma tumors were assessed for presence of macrophages and their role in promoting tumor growth

  7. Targeting the Prostate Cancer Microenvironment to Improve Therapeutic Outcomes

    DTIC Science & Technology

    2014-06-01

    malignancies. However, a subset of localized cancers resist genotoxic treatments, and most advanced cancers treated with such therapies eventually progress...NF-κB, and found the physical interaction between these molecules when cells are exposed to genotoxicity . We anticipate that targeting such a key...PCa medicine. 15. SUBJECT TERMS Prostate cancer, microenvironment, DNA damage, genotoxicity , stroma, secretion, therapy resistance, outcome. 16

  8. Microenvironment-derived factors driving metastatic plasticity in melanoma

    PubMed Central

    Kim, Isabella S.; Heilmann, Silja; Kansler, Emily R.; Zhang, Yan; Zimmer, Milena; Ratnakumar, Kajan; Bowman, Robert L.; Simon-Vermot, Theresa; Fennell, Myles; Garippa, Ralph; Lu, Liang; Lee, William; Hollmann, Travis; Xavier, Joao B.; White, Richard M.

    2017-01-01

    Cellular plasticity is a state in which cancer cells exist along a reversible phenotypic spectrum, and underlies key traits such as drug resistance and metastasis. Melanoma plasticity is linked to phenotype switching, where the microenvironment induces switches between invasive/MITFLO versus proliferative/MITFHI states. Since MITF also induces pigmentation, we hypothesize that macrometastatic success should be favoured by microenvironments that induce a MITFHI/differentiated/proliferative state. Zebrafish imaging demonstrates that after extravasation, melanoma cells become pigmented and enact a gene expression program of melanocyte differentiation. We screened for microenvironmental factors leading to phenotype switching, and find that EDN3 induces a state that is both proliferative and differentiated. CRISPR-mediated inactivation of EDN3, or its synthetic enzyme ECE2, from the microenvironment abrogates phenotype switching and increases animal survival. These results demonstrate that after metastatic dissemination, the microenvironment provides signals to promote phenotype switching and provide proof that targeting tumour cell plasticity is a viable therapeutic opportunity. PMID:28181494

  9. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

    USDA-ARS?s Scientific Manuscript database

    Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate tha...

  10. Optical Windows for Imaging the Metastatic Tumour Microenvironment in vivo

    PubMed Central

    Kitamura, Takanori; Pollard, Jeffrey W.; Vendrell, Marc

    2016-01-01

    Intravital imaging enables to study dynamic tumour–stroma interactions within primary and metastatic sites, including the lung. The combination of optical windows with specific molecular probes targeting the tumour microenvironment will provide new insights into prometastatic stromal interactions and lead to novel therapeutic strategies for metastatic diseases. PMID:27238900

  11. Microenvironments and microscale productivity of cyanobacterial desert crusts

    USGS Publications Warehouse

    Garcia-Pichel, F.; Belnap, Jayne

    1996-01-01

    We used microsensors to characterize physicochemical microenvironments and photosynthesis occurring immediately after water saturation in two desert soil crusts from southeastern Utah, which were formed by the cyanobacteria Microcoleus vaginatus Gomont, Nostoc spp., and Scytonema sp. The light fields within the crusts presented steep vertical gradients in magnitude and spectral composition. Near-surface light-trapping zones were formed due to the scattering nature of the sand particles, but strong light attenuation resulted in euphotic zones only ca. 1 mm deep, which were progressively enriched in longer wavelengths with depth. Rates of gross photosynthesis (3.4a??9.4 mmol O2A?ma??2A?ha??1) and dark respiration (0.81a??3.1 mmol Oa??2A?ma??2A?ha??1) occurring within 1 to several mm from the surface were high enough to drive the formation of marked oxygen microenvironments that ranged from oxygen supersaturation to anoxia. The photosynthetic activity also resulted in localized pH values in excess of 10, 2a??3 units above the soil pH. Differences in metabolic parameters and community structure between two types of crusts were consistent with a successional pattern, which could be partially explained on the basis of the microenvironments. We discuss the significance of high metabolic rates and the formation of microenvironments for the ecology of desert crusts, as well as the advantages and limitations of microsensor-based methods for crust investigation.

  12. The mechanical microenvironment in cancer: How physics affects tumours.

    PubMed

    Nagelkerke, Anika; Bussink, Johan; Rowan, Alan E; Span, Paul N

    2015-12-01

    The tumour microenvironment contributes greatly to the response of tumour cells. It consists of chemical gradients, for example of oxygen and nutrients. However, a physical environment is also present. Apart from chemical input, cells also receive physical signals. Tumours display unique mechanical properties: they are a lot stiffer than normal tissue. This may be either a cause or a consequence of cancer, but literature suggests it has a major impact on tumour cells as will be described in this review. The mechanical microenvironment may cause malignant transformation, possibly through activation of oncogenic pathways and inhibition of tumour suppressor genes. In addition, the mechanical microenvironment may promote tumour progression by influencing processes such as epithelial-to-mesenchymal transition, enhancing cell survival through autophagy, but also affects sensitivity of tumour cells to therapeutics. Furthermore, multiple intracellular signalling pathways prove sensitive to the mechanical properties of the microenvironment. It appears the increased stiffness is unlikely to be caused by increased stiffness of the tumour cells themselves. However, there are indications that tumours display a higher cell density, making them more rigid. In addition, increased matrix deposition in the tumour, as well as increased interstitial fluid pressure may account for the increased stiffness of tumours. Overall, tumour mechanics are significantly different from normal tissue. Therefore, this feature should be further explored for use in cancer prevention, detection and treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Modulation of tumor microenvironment by chemopreventive natural products.

    PubMed

    Park, Sin-Aye; Surh, Young-Joon

    2017-08-01

    The tumor microenvironment provides a niche in which cancer cells and their surrounding stromal cells reside and in which their interactions occur. The cross talk between cancer and stromal cells in the tumor microenvironment promotes many biological processes to support cancer cell growth, invasion, angiogenesis, and metastasis. Recently, not only cancer cells but also multiple types of surrounding stromal cells, including endothelial cells, immune cells, and fibroblasts in the tumor microenvironment, have been recognized to be attractive targets for reducing resistance to anticancer therapy and tumor recurrence. Many natural products present in fruits, vegetables, herbs, spices, and some marine organisms have been reported to inhibit, delay, or reverse multistage carcinogenesis and to inhibit the proliferation of cancerous cells and the self-renewal capacity of preexisting cancer stem-like cells. Some of these naturally occurring chemopreventive and anticarcinogenic substances can modulate the signal transduction involved in maintaining the activities/functions of stromal cells and their interactions with cancer cells within the tumor microenvironment. © 2017 New York Academy of Sciences.

  14. Screening the Cellular Microenvironment: A Role for Microfluidics

    PubMed Central

    Warrick, Jay W.; Murphy, William L.; Beebe, David J.

    2010-01-01

    The cellular microenvironment is an increasingly discussed topic in cell biology as it has been implicated in the progression of cancer and the maintenance of stem cells. The microenvironment of a cell is an organized combination of extracellular matrix (ECM), cells, and interstitial fluid that influence cellular phenotype through physical, mechanical, and biochemical mechanisms. Screening can be used to map combinations of cells and microenvironments to phenotypic outcomes in a way that can help develop more predictive in vitro models and to better understand phenotypic mechanisms from a systems biology perspective. This paper examines microenvironmental screening in terms of outcomes and benefits, key elements of the screening process, challenges for implementation, and a possible role for microfluidics as the screening platform. To assess microfluidics for use in microenvironmental screening, examples and categories of micro-scale and microfluidic technology are highlighted. Microfluidic technology shows promise for simultaneous control of multiple parameters of the microenvironment and can provide a base for scaling advanced cell-based experiments into automated high-throughput formats. PMID:20190880

  15. Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment

    PubMed Central

    Kim, Jaehong; Bae, Jong-Sup

    2016-01-01

    Distinct tumor microenvironment forms in each progression step of cancer and has diverse capacities to induce both adverse and beneficial consequences for tumorigenesis. It is now known that immune cells can be activated to favor tumor growth and progression, most probably influenced by the tumor microenvironment. Tumor-associated macrophages and tumor-associated neutrophils can exert protumoral functions, enhancing tumor cell invasion and metastasis, angiogenesis, and extracellular matrix remodeling, while inhibiting the antitumoral immune surveillance. Considering that neutrophils in inflammatory environments recruit macrophages and that recruited macrophages affect neutrophil functions, there may be various degrees of interaction between tumor-associated macrophages and tumor-associated neutrophils. Platelets also play an important role in the recruitment and regulation of monocytic and granulocytic cells in the tumor tissues, suggesting that platelet function may be essential for generation of tumor-associated macrophages and tumor-associated neutrophils. In this review, we will explore the biology of tumor-associated macrophages and tumor-associated neutrophils and their possible interactions in the tumor microenvironment. Special attention will be given to the recruitment and activation of these tumor-associated cells and to the roles they play in maintenance of the tumor microenvironment and progression of tumors. PMID:26966341

  16. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia.

    PubMed

    Burger, Jan A

    2011-01-01

    Intrinsic factors such as genetic lesions, anti-apoptotic proteins, and aberrant signaling networks within leukemia cells have long been the main focus of chronic lymphocytic leukemia (CLL) research. However, over the past decade, it became increasingly clear that external signals from the leukemia microenvironment make pivotal contributions to disease progression in CLL and other B-cell malignancies. Consequently, increasing emphasis is now placed on exploring and targeting the CLL microenvironment. This review highlights critical cellular and molecular pathways of CLL-microenvironment cross-talk. In vitro and in vivo models for studying the CLL microenvironment are discussed, along with their use in searching for therapeutic targets and in drug testing. Clinically, CXCR4 antagonists and small-molecule antagonists of B cell receptor (BCR)-associated kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], and PI3Kδ) are the most advanced drugs for targeting specific interactions between CLL cells and the miocroenvironment. Preclinical and first clinical evidence suggests that high-risk CLL patients can particularly benefit from these alternative agents. These findings indicate that interplay between leukemia-inherent and environmental factors, nature and nurture determines disease progression in CLL.

  17. Operation of the computer model for microenvironment atomic oxygen exposure

    NASA Technical Reports Server (NTRS)

    Bourassa, R. J.; Gillis, J. R.; Gruenbaum, P. E.

    1995-01-01

    A computer model for microenvironment atomic oxygen exposure has been developed to extend atomic oxygen modeling capability to include shadowing and reflections. The model uses average exposure conditions established by the direct exposure model and extends the application of these conditions to treat surfaces of arbitrary shape and orientation.

  18. Parallel Aspects of the Microenvironment in Cancer and Autoimmune Disease

    PubMed Central

    Rahat, Michal A.

    2016-01-01

    Cancer and autoimmune diseases are fundamentally different pathological conditions. In cancer, the immune response is suppressed and unable to eradicate the transformed self-cells, while in autoimmune diseases it is hyperactivated against a self-antigen, leading to tissue injury. Yet, mechanistically, similarities in the triggering of the immune responses can be observed. In this review, we highlight some parallel aspects of the microenvironment in cancer and autoimmune diseases, especially hypoxia, and the role of macrophages, neutrophils, and their interaction. Macrophages, owing to their plastic mode of activation, can generate a pro- or antitumoral microenvironment. Similarly, in autoimmune diseases, macrophages tip the Th1/Th2 balance via various effector cytokines. The contribution of neutrophils, an additional plastic innate immune cell population, to the microenvironment and disease progression is recently gaining more prominence in both cancer and autoimmune diseases, as they can secrete cytokines, chemokines, and reactive oxygen species (ROS), as well as acquire an enhanced ability to produce neutrophil extracellular traps (NETs) that are now considered important initiators of autoimmune diseases. Understanding the contribution of macrophages and neutrophils to the cancerous or autoimmune microenvironment, as well as the role their interaction and cooperation play, may help identify new targets and improve therapeutic strategies. PMID:26997761

  19. Confined Sandwichlike Microenvironments Tune Myogenic Differentiation.

    PubMed

    Ballester-Beltrán, José; Trujillo, Sara; Alakpa, Enateri V; Compañ, Vicente; Gavara, Rafael; Meek, Dominic; West, Christopher C; Péault, Bruno; Dalby, Matthew J; Salmerón-Sánchez, Manuel

    2017-08-14

    Sandwichlike (SW) cultures are engineered as a multilayer technology to simultaneously stimulate dorsal and ventral cell receptors, seeking to mimic cell adhesion in three-dimensional (3D) environments in a reductionist manner. The effect of this environment on cell differentiation was investigated for several cell types cultured in standard growth media, which promotes proliferation on two-dimensional (2D) surfaces and avoids any preferential differentiation. First, murine C2C12 myoblasts showed specific myogenic differentiation. Human mesenchymal stem cells (hMSCs) of adipose and bone marrow origin, which can differentiate toward a wider variety of lineages, showed again myodifferentiation. Overall, this study shows myogenic differentiation in normal growth media for several cell types under SW conditions, avoiding the use of growth factors and cytokines, i.e., solely by culturing cells within the SW environment. Mechanistically, it provides further insights into the balance between integrin adhesion to the dorsal substrate and the confinement imposed by the SW system.

  20. Improving drug delivery to solid tumors: priming the tumor microenvironment.

    PubMed

    Khawar, Iftikhar Ali; Kim, Jung Ho; Kuh, Hyo-Jeong

    2015-03-10

    Malignant transformation and growth of the tumor mass tend to induce changes in the surrounding microenvironment. Abnormality of the tumor microenvironment provides a driving force leading not only to tumor progression, including invasion and metastasis, but also to acquisition of drug resistance, including pharmacokinetic (drug delivery-related) and pharmacodynamic (sensitivity-related) resistance. Drug delivery systems exploiting the enhanced permeability and retention (EPR) effect and active targeting moieties were expected to be able to cope with delivery-related drug resistance. However, recent evidence supports a considerable barrier role of tumors via various mechanisms, which results in imperfect or inefficient EPR and/or targeting effect. The components of the tumor microenvironment such as abnormal tumor vascular system, deregulated composition of the extracellular matrix, and interstitial hypertension (elevated interstitial fluid pressure) collectively or cooperatively hinder the drug distribution, which is prerequisite to the efficacy of nanoparticles and small-molecule drugs used in cancer medicine. Hence, the abnormal tumor microenvironment has recently been suggested to be a promising target for the improvement of drug delivery to improve therapeutic efficacy. Strategies to modulate the abnormal tumor microenvironment, referred to here as "solid tumor priming" (vascular normalization and/or solid stress alleviation leading to improvement in blood perfusion and convective molecular movement), have shown promising results in the enhancement of drug delivery and anticancer efficacy. These strategies may provide a novel avenue for the development of new chemotherapeutics and combination chemotherapeutic regimens as well as reassessment of previously ineffective agents. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. The LMO2 oncogene regulates DNA replication in hematopoietic cells

    PubMed Central

    Sincennes, Marie-Claude; Humbert, Magali; Grondin, Benoît; Lisi, Véronique; Veiga, Diogo F. T.; Haman, André; Cazaux, Christophe; Mashtalir, Nazar; Affar, EL Bachir; Verreault, Alain; Hoang, Trang

    2016-01-01

    Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression. PMID:26764384

  2. The LMO2 oncogene regulates DNA replication in hematopoietic cells.

    PubMed

    Sincennes, Marie-Claude; Humbert, Magali; Grondin, Benoît; Lisi, Véronique; Veiga, Diogo F T; Haman, André; Cazaux, Christophe; Mashtalir, Nazar; Affar, El Bachir; Verreault, Alain; Hoang, Trang

    2016-02-02

    Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.

  3. Osteoblasts and Bone Marrow Mesenchymal Stromal Cells Control Hematopoietic Stem Cell Migration and Proliferation in 3D In Vitro Model

    PubMed Central

    de Barros, Ana Paula D. N.; Takiya, Christina M.; Garzoni, Luciana R.; Leal-Ferreira, Mona Lisa; Dutra, Hélio S.; Chiarini, Luciana B.; Meirelles, Maria Nazareth; Borojevic, Radovan; Rossi, Maria Isabel D.

    2010-01-01

    Background Migration, proliferation, and differentiation of hematopoietic stem cells (HSCs) are dependent upon a complex three-dimensional (3D) bone marrow microenvironment. Although osteoblasts control the HSC pool, the subendosteal niche is complex and its cellular composition and the role of each cell population in HSC fate have not been established. In vivo models are complex and involve subtle species-specific differences, while bidimensional cultures do not reflect the 3D tissue organization. The aim of this study was to investigate in vitro the role of human bone marrow–derived mesenchymal stromal cells (BMSC) and active osteoblasts in control of migration, lodgment, and proliferation of HSCs. Methodology/Principal Findings A complex mixed multicellular spheroid in vitro model was developed with human BMSC, undifferentiated or induced for one week into osteoblasts. A clear limit between the two stromal cells was established, and deposition of extracellular matrix proteins fibronectin, collagens I and IV, laminin, and osteopontin was similar to the observed in vivo. Noninduced BMSC cultured as spheroid expressed higher levels of mRNA for the chemokine CXCL12, and the growth factors Wnt5a and Kit ligand. Cord blood and bone marrow CD34+ cells moved in and out the spheroids, and some lodged at the interface of the two stromal cells. Myeloid colony-forming cells were maintained after seven days of coculture with mixed spheroids, and the frequency of cycling CD34+ cells was decreased. Conclusions/Significance Undifferentiated and one-week osteo-induced BMSC self-assembled in a 3D spheroid and formed a microenvironment that is informative for hematopoietic progenitor cells, allowing their lodgment and controlling their proliferation. PMID:20161704

  4. Malnutrition suppresses cell cycle progression of hematopoietic progenitor cells in mice via cyclin D1 down-regulation.

    PubMed

    Nakajima, Karina; Crisma, Amanda R; Silva, Graziela B; Rogero, Marcelo M; Fock, Ricardo A; Borelli, Primavera

    2014-01-01

    Protein malnutrition (PM) often is associated with changes in bone marrow (BM) microenvironment leading to an impaired hematopoiesis; however, the mechanism involved is poorly understood. The aim of this study was to compare the cell cycle progression of hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) and evaluate the cell cycle signaling in malnourished mice to assess the mechanism of cell cycle arrest. C57Bl/6J mice were randomly assigned in control and malnourished groups receiving normoproteic and hypoproteic diets (12% and 2% protein, respectively) over a 5-wk period. Nutritional and hematologic parameters were assessed and BM immunophenotypic analysis was performed. Cell cycle of HPC (Lin(-)) and HSC (Lin(-)Sca-1(+)c-Kit(+)) were evaluated after 6 h of in vivo 5-bromo-2'-deoxyuridine (BrDU) incorporation. Cell cycle regulatory protein expression of HPC was assessed by Western blot. Malnourished mice showed lower levels of serum protein, albumin, glucose, insulin-like growth factor-1, insulin, and higher levels of serum corticosterone. PM also caused a reduction of BM myeloid compartment resulting in anemia and leukopenia. After 6 h of BrDU incorporation, malnourished mice showed G0-G1 arrest of HPC without changes of HSC proliferation kinetics. HPC of malnourished mice showed reduced expression of proteins that induce cell cycle (cyclin D1, cyclin E, pRb, PCNA, Cdc25a, Cdk2, and Cdk4) and increased expression of inhibitory proteins (p21 and p27) with no significant difference in p53 expression. PM suppressed cell cycle progression mainly of HPC. This occurred via cyclin D1 down-regulation and p21/p27 overexpression attesting that BM microenvironment commitment observed in PM is affecting cell interactions compromising cell proliferation. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Aberrant PGE₂ metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells.

    PubMed

    Eruslanov, Evgeniy; Daurkin, Irina; Vieweg, Johannes; Daaka, Yehia; Kusmartsev, Sergei

    2011-07-01

    Bladder cancer is associated with enhanced inflammation and characterized by deregulated prostanoid metabolism. Here we examined prostaglandin E₂ (PGE₂) metabolism and myeloid cell subsets that infiltrate tumor tissue using two xenograft models of human bladder cancer. Human bladder tumor xenografts implanted into athymic nude mice become highly infiltrated with host CD11b myeloid cells of bone marrow origin. Fast growing SW780 bladder tumor xenografts were infiltrated with heterogeneous CD11b myeloid cell subsets including tumor-associated macrophages and myeloid-derived suppressor cells. In contrast, majority of myeloid cells in tumor tissue from slow growing bladder cancer Urothel 11 displayed more immature, homogenous phenotype and comprised mostly MHC II class-negative myeloid-derived suppressor cells. We demonstrate that human bladder tumors secrete substantial amounts of PGE₂. Normal bone marrow myeloid cell progenitors cultured in the presence of a bladder tumor-conditioned medium, which is enriched for PGE₂, failed to differentiate into mature APCs and acquired phenotype of the myeloid-derived suppressor cells or inflammatory macrophages with up-regulated chemokine receptor CXCR4. Collectively our data demonstrate that enhanced cancer-related inflammation and deregulated PGE₂ metabolism in tumor microenvironment promote immunosuppressive pro-tumoral phenotype of myeloid cells in bladder cancer. These data also suggest that not only local tumor microenvironment but other factors such as stage of cancer disease and pace of tumor growth could markedly influence the phenotype, differentiation and immune function of myeloid cells in tumor tissue.

  6. Glycoprotein asporin as a novel player in tumour microenvironment and cancer progression.

    PubMed

    Simkova, Dana; Kharaishvili, Gvantsa; Slabakova, Eva; Murray, Paul G; Bouchal, Jan

    2016-12-01

    Small leucine rich proteoglycans (SLRPs), major non-collagen components of the extracellular matrix (ECM), have multiple biological roles with diverse effects. Asporin, a member of the SLRPs class I, competes with other molecules in binding to collagen and affects its mineralization. Its role in cancer is only now being elucidated. The PubMed online database was used to search relevant reviews and original articles. Furthermore, altered asporin expression was analysed in publicly available genome-wide expression data at the Gene Expression Omnibus database. Polymorphisms in the N-terminal polyaspartate domain, which binds calcium, are associated with osteoarthritis and prostate cancer. Asporin also promotes the progression of scirrhous gastric cancer where it is required for coordinated invasion by cancer associated fibroblasts and cancer cells. Besides the enhanced expression of asporin observed in multiple cancer types, such as breast, prostate, gastric, pancreas and colon cancer, tumour suppressive effects of asporin were described in triple-negative breast cancer. We also discuss a number of factors modulating asporin expression in different cell types relevant for alterations toing the tumour microenvironment. The apparent contradicting tumour promoting and suppressive effects of asporin require further investigation. Deciphering the role of asporin and other SLRPs in tumour-stroma interactions is needed for a better understanding of cancer progression and potentially also for novel tumour microenvironment based therapies.

  7. How Do Mesenchymal Stem Cells Influence or Are Influenced by Microenvironment through Extracellular Vesicles Communication?

    PubMed Central

    Dostert, Gabriel; Mesure, Benjamin; Menu, Patrick; Velot, Émilie

    2017-01-01

    Mesenchymal stem cells (MSCs) are widely used in cell therapy and tissue engineering thanks to their self-renewal, their multipotency, and their immunomodulatory properties that make them an attractive tool for regenerative medicine. A large part of MSCs positive effects is due to their secretion products which participate in creating a favorable microenvironment and closely relate these cells to other cell types. Extracellular vesicles (EVs) belong to cellular secretions. They are produced by cells continuously or after stimulation (e.g., calcium flux, cellular stress) and act in tissue homeostasis and intercellular communication. The understanding of the role of EVs is growing, more particularly their impact on cell migration, differentiation, or immunomodulation. EVs derived from MSCs show these interesting properties that may be considered in therapeutics, although they can have adverse effects by facilitating cancer propagation. Moreover, MSC behavior may also be influenced (proliferation, differentiation) by EVs derived from other donor cells. The aim of this mini review is to summarize the two-way communication between MSCs and other cell types, and how they can affect each other with their microenvironment through EVs. On the one hand, the manuscript presents the influence of MSC-derived EVs on diverse recipient cells and on the other hand, the effects of EVs derived from various donor cells on MSCs. The discrepancies between cancer cells and MSCs communication according to the sources of MSCs but also the tumor origins are also mentioned. PMID:28224125

  8. Omentum and bone marrow: how adipocyte-rich organs create tumour microenvironments conducive for metastatic progression

    PubMed Central

    Gusky, H. Chkourko; Diedrich, J.; MacDougald, O. A.; Podgorski, I.

    2016-01-01

    Summary A number of clinical studies have linked adiposity with increased cancer incidence, progression and metastasis, and adipose tissue is now being credited with both systemic and local effects on tumour development and survival. Adipocytes, a major component of benign adipose tissue, represent a significant source of lipids, cytokines and adipokines, and their presence in the tumour microenvironment substantially affects cellular trafficking, signalling and metabolism. Cancers that have a high predisposition to metastasize to the adipocyte-rich host organs are likely to be particularly affected by the presence of adipocytes. Although our understanding of how adipocytes influence tumour progression has grown significantly over the last several years, the mechanisms by which adipocytes regulate the meta-static niche are not well-understood. In this review, we focus on the omentum, a visceral white adipose tissue depot, and the bone, a depot for marrow adipose tissue, as two distinct adipocyte-rich organs that share common characteristic: they are both sites of significant metastatic growth. We highlight major differences in origin and function of each of these adipose depots and reveal potential common characteristics that make them environments that are attractive and conducive to secondary tumour growth. Special attention is given to how omental and marrow adipocytes modulate the tumour microenvironment by promoting angiogenesis, affecting immune cells and altering metabolism to support growth and survival of metastatic cancer cells. PMID:27432523

  9. Effect of the Microenvironment on Mesenchymal Stem Cell Paracrine Signaling: Opportunities to Engineer the Therapeutic Effect.

    PubMed

    Kusuma, Gina D; Carthew, James; Lim, Rebecca; Frith, Jessica E

    2017-05-01

    Cues from the extracellular environment, including physical stimuli, are well known to affect mesenchymal stem cell (MSC) properties in terms of proliferation and differentiation. Many therapeutic strategies are now targeting this knowledge to increase the efficacy of cell therapies, typically employed to repair tissue functions in the event of injury, either by direct engraftment into the target tissue or differentiation into mature tissues. However, it is now envisioned that harnessing the repertoire of factors secreted by MSCs (termed the secretome) may provide an alternate to these cell therapies. Of current interest are both direct protein secretions and two major subpopulations of bioactive extracellular vesicles (EVs), namely exosomes and microvesicles. EVs released by MSCs are reflective of their cells of origin, able to impact upon the activities of other cells in the local microenvironment, making the rational design of MSC paracrine activities an encouraging strategy to reproducibly modulate cell therapies. The precise mechanisms by which the secretome is modulated by the microenvironment, however, remain elusive. Controlling MSC growth conditions with oxygen tension, growth factor composition, and mechanical properties may serve to directly influence paracrine activity. Our growing understanding implicates components of the mechanotransduction machinery in translating both mechanical and chemical cues from the environment into alterations in gene regulation and varied paracrine activity. As technologies are developed to manufacture MSCs, advances in bioengineering and novel insight of how the extracellular environment affects MSC paracrine activity will play a pivotal role in the generation of widespread, successful, clinical MSC therapies.

  10. Recapitulation of complex transport and action of drugs at the tumor microenvironment using tumor-microenvironment-on-chip.

    PubMed

    Han, Bumsoo; Qu, Chunjing; Park, Kinam; Konieczny, Stephen F; Korc, Murray

    2016-09-28

    Targeted delivery aims to selectively distribute drugs to targeted tumor tissues but not to healthy tissues. This can address many clinical challenges by maximizing the efficacy but minimizing the toxicity of anti-cancer drugs. However, a complex tumor microenvironment poses various barriers hindering the transport of drugs and drug delivery systems. New tumor models that allow for the systematic study of these complex environments are highly desired to provide reliable test beds to develop drug delivery systems for targeted delivery. Recently, research efforts have yielded new in vitro tumor models, the so called tumor-microenvironment-on-chip, that recapitulate certain characteristics of the tumor microenvironment. These new models show benefits over other conventional tumor models, and have the potential to accelerate drug discovery and enable precision medicine. However, further research is warranted to overcome their limitations and to properly interpret the data obtained from these models. In this article, key features of the in vivo tumor microenvironment that are relevant to drug transport processes for targeted delivery were discussed, and the current status and challenges for developing in vitro transport model systems were reviewed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Confined Sandwichlike Microenvironments Tune Myogenic Differentiation

    PubMed Central

    2017-01-01

    Sandwichlike (SW) cultures are engineered as a multilayer technology to simultaneously stimulate dorsal and ventral cell receptors, seeking to mimic cell adhesion in three-dimensional (3D) environments in a reductionist manner. The effect of this environment on cell differentiation was investigated for several cell types cultured in standard growth media, which promotes proliferation on two-dimensional (2D) surfaces and avoids any preferential differentiation. First, murine C2C12 myoblasts showed specific myogenic differentiation. Human mesenchymal stem cells (hMSCs) of adipose and bone marrow origin, which can differentiate toward a wider variety of lineages, showed again myodifferentiation. Overall, this study shows myogenic differentiation in normal growth media for several cell types under SW conditions, avoiding the use of growth factors and cytokines, i.e., solely by culturing cells within the SW environment. Mechanistically, it provides further insights into the balance between integrin adhesion to the dorsal substrate and the confinement imposed by the SW system. PMID:28824958

  12. The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy

    DTIC Science & Technology

    2016-07-01

    dynamic process that involves critical interactions between tumor cells and the microenvironment . Hypoxia is a potent microenvironmental factor...AWARD NUMBER: W81XWH-15-1-0097 TITLE: The Role of Hypoxia in the Tumor Microenvironment : Implications for Ovarian Cancer Therapy PRINCIPAL... Microenvironment : Implications for Ovarian Cancer Therapy Ovarian Cancer Therapy 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6

  13. Hematopoietic Stem and Progenitor Cell Migration After Hypofractionated Radiation Therapy in a Murine Model

    SciTech Connect

    Kane, Jonathan; Krueger, Sarah A.; Dilworth, Joshua T.; Torma, John T.; Wilson, George D.; Marples, Brian; Madlambayan, Gerard J.

    2013-12-01

    Purpose: To characterize the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs) within tumor microenvironment after radiation therapy (RT) in a murine, heterotopic tumor model. Methods and Materials: Lewis lung carcinoma tumors were established in C57BL/6 mice and irradiated with 30 Gy given as 2 fractions over 2 days. Tumors were imaged with positron emission tomography/computed tomography (PET/CT) and measured daily with digital calipers. The HSPC and myelomonocytic cell content was assessed via immunofluorescent staining and flow cytometry. Functionality of tumor-associated HSPCs was verified in vitro using colony-forming cell assays and in vivo by rescuing lethally irradiated C57BL/6 recipients. Results: Irradiation significantly reduced tumor volumes and tumor regrowth rates compared with nonirradiated controls. The number of CD133{sup +} HSPCs present in irradiated tumors was higher than in nonirradiated tumors during all stages of regrowth. CD11b{sup +} counts were similar. PET/CT imaging and growth rate analysis based on standardized uptake value indicated that HSPC recruitment directly correlated to the extent of regrowth and intratumor cell activity after irradiation. The BM-derived tumor-associated HSPCs successfully formed hematopoietic colonies and engrafted irradiated mice. Finally, targeted treatment with a small animal radiation research platform demonstrated localized HSPC recruitment to defined tumor subsites exposed to radiation. Conclusions: Hypofractionated irradiation resulted in a pronounced and targeted recruitment of BM-derived HSPCs, possibly as a mechanism to promote tumor regrowth. These data indicate for the first time that radiation therapy regulates HSPC content within regrowing tumors.

  14. Transplanted hematopoietic cells seed in clusters in recipient bone marrow in vivo.

    PubMed

    Askenasy, Nadir; Zorina, Tatiana; Farkas, Daniel L; Shalit, Itamar

    2002-01-01

    The process of hematopoietic stem and progenitor cell (HSPC) seeding in recipient bone marrow (BM) early after transplantation is not fully characterized. In vivo tracking of HSPCs, labeled with PKH dyes, through an optical window surgically implanted on the mouse femur revealed that transplanted cells cluster in the recipient BM. Within the first day after intravenous injection, 86 +/- 6% of the cells seeded in clusters (p < 0.001 versus scattered cells) in the endosteal surfaces of the epiphyses. The primary clusters were formed by concomitant seeding of 6-10 cells over an area of approximately 70 microm, and secondarily injected cells did not join the already existing clusters but formed new clusters. Major antigen-disparate HSPCs participated in formation of the primary clusters, and T lymphocytes were also incorporated. After 4 to 5 days, some cellular clusters were observed in the more central regions of the BM, where the brightness of PKH fluorescence decreased, indicating cellular division. These later clusters were classified as secondary, assuming that the mechanisms of migration in the BM might be different from those of primary seeding. Some clusters remained in the periphery of the BM and retained bright fluorescence, indicating cellular quiescence. The number of brightly fluorescent cells in the clusters decreased exponentially to two to three cells after 24 days (p < 0.001). The data suggest that the hematopoietic niche is a functional unit of the BM stromal microenvironment that hosts seeding of a number of transplanted cells, which form a cluster. This may be the site where auxiliary non-HSPC cells, such as T lymphocytes, act in support of HSPC engraftment.

  15. Lentiviral-mediated RNAi inhibition of Sbds in murine hematopoietic progenitors impairs their hematopoietic potential

    PubMed Central

    Rawls, Amy S.; Gregory, Alyssa D.; Woloszynek, Jill R.; Liu, Fulu

    2007-01-01

    Shwachman-Diamond syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, multilineage hematopoietic dysfunction, and metaphyseal chondrodysplasia. Bone marrow dysfunction is present in nearly all patients with SDS, with neutropenia being the most common abnormality. The majority of patients with SDS have mutations in the Shwachman Bodian Diamond syndrome (SBDS) gene. We have developed a strategy to examine the consequences of lentiviral-mediated RNA interference (RNAi) of Sbds on hematopoiesis. Here, we report that both Sbds RNA and protein expression can be efficiently inhibited in primary murine hematopoietic cells using lentiviral-mediated RNAi. Inhibition of Sbds results in a defect in granulocytic differentiation in vitro and impairs myeloid progenitor generation in vivo. In addition, short-term hematopoietic engraftment was impaired, which is due in part to reduced homing of hematopoietic progenitors to the bone marrow. Finally, we show that inhibition of Sbds is associated with a decrease in circulating B lymphocytes, despite evidence of normal B lymphopoiesis. These data provide the first evidence that loss of Sbds is sufficient to induce abnormalities in hematopoiesis. PMID:17638857

  16. ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification

    PubMed Central

    Taoudi, Samir; Bee, Thomas; Hilton, Adrienne; Knezevic, Kathy; Scott, Julie; Willson, Tracy A.; Collin, Caitlin; Thomas, Tim; Voss, Anne K.; Kile, Benjamin T.; Alexander, Warren S.; Pimanda, John E.; Hilton, Douglas J.

    2011-01-01

    Although many genes are known to be critical for early hematopoiesis in the embryo, it remains unclear whether distinct regulatory pathways exist to control hematopoietic specification versus hematopoietic stem cell (HSC) emergence and function. Due to their interaction with key regulators of hematopoietic commitment, particular interest has focused on the role of the ETS family of transcription factors; of these, ERG is predicted to play an important role in the initiation of hematopoiesis, yet we do not know if or when ERG is required. Using in vitro and in vivo models of hematopoiesis and HSC development, we provide strong evidence that ERG is at the center of a distinct regulatory program that is not required for hematopoietic specification or differentiation but is critical for HSC maintenance during embryonic development. We show that, from the fetal period, ERG acts as a direct upstream regulator of Gata2 and Runx1 gene activity. Without ERG, physiological HSC maintenance fails, leading to the rapid exhaustion of definitive hematopoiesis. PMID:21245161

  17. Angiogenin Defines Heterogeneity at the Core of the Hematopoietic Niche.

    PubMed

    Di Scala, Marianna; Hidalgo, Andrés

    2016-09-01

    Successful hematopoietic regeneration demands preservation of stemness while enabling expansion and differentiation into blood lineages. Now, Silberstein et al. (2016) and Goncalves et al. (2016) identify a ribonuclease secreted by proximal niche cells that simultaneously drives quiescence of HSCs and proliferation of myeloid progenitors and dramatically enhances hematopoietic recovery after HSC transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Effects of Hematopoietic Stem Cell Age on CML Disease Progression

    DTIC Science & Technology

    2006-03-01

    leukemias . In contrast, recipients of old, transduced bone marrow developed leukemia with infrequent lymphoid involvement. Ongoing studies are aimed at...identifying the leukemia stem cells in the young and old bone marrow. 15. SUBJECT TERMS Hematopoietic Stem Cells, Chronic Myeloid Leukemia ...8 4 INTRODUCTION Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy characterized by myeloid hyperplasia

  19. Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function.

    PubMed

    Mgbemena, Victoria E; Signer, Robert A J; Wijayatunge, Ranjula; Laxson, Travis; Morrison, Sean J; Ross, Theodora S

    2017-01-24

    BRCA1 is a well-known DNA repair pathway component and a tissue-specific tumor suppressor. However, its role in hematopoiesis is uncertain. Here, we report that a cohort of patients heterozygous for BRCA1 mutations experienced more hematopoietic toxicity from chemotherapy than those with BRCA2 mutations. To test whether this reflects a requirement for BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system (Vav1-iCre;Brca1(F22-24/F22-24)) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs). Although mice homozygous for a huBRCA1 knockin allele (Brca1(BRCA1/BRCA1)) were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1(F22-24/5382insC)) had severe hematopoietic defects marked by a complete loss of hematopoietic stem and progenitor cells. Our data show that Brca1 is necessary for HSC maintenance and normal hematopoiesis and that distinct mutations lead to different degrees of hematopoietic dysfunction.

  20. [Aspergillus galactomannan detection in allogenic hematopoietic cell transplantation].

    PubMed

    Rovira Tarrats, Montserrat; Puig de la Bellacasa, Jorge

    2003-09-01

    Invasive aspergillosis has become the leading cause of death after allogeneic hematopoietic stem cell transplantation. This is partially due to the lack of a prompt diagnosis. Recently the detection of Aspergillus galactomannan antigen by means an ELISA technique in serum has been described. The objective of this study was to validate its usefulness in the allogeneic hematopoietic stem cell transplantation setting.

  1. Regulation of hematopoietic and leukemic stem cells by the immune system.

    PubMed

    Riether, C; Schürch, C M; Ochsenbein, A F

    2015-02-01

    Hematopoietic stem cells (HSCs) are rare, multipotent cells that generate via progenitor and precursor cells of all blood lineages. Similar to normal hematopoiesis, leukemia is also hierarchically organized and a subpopulation of leukemic cells, the leukemic stem cells (LSCs), is responsible for disease initiation and maintenance and gives rise to more differentiated malignant cells. Although genetically abnormal, LSCs share many characteristics with normal HSCs, including quiescence, multipotency and self-renewal. Normal HSCs reside in a specialized microenvironment in the bone marrow (BM), the so-called HSC niche that crucially regulates HSC survival and function. Many cell types including osteoblastic, perivascular, endothelial and mesenchymal cells contribute to the HSC niche. In addition, the BM functions as primary and secondary lymphoid organ and hosts various mature immune cell types, including T and B cells, dendritic cells and macrophages that contribute to the HSC niche. Signals derived from the HSC niche are necessary to regulate demand-adapted responses of HSCs and progenitor cells after BM stress or during infection. LSCs occupy similar niches and depend on signals from the BM microenvironment. However, in addition to the cell types that constitute the HSC niche during homeostasis, in leukemia the BM is infiltrated by activated leukemia-specific immune cells. Leukemic cells express different antigens that are able to activate CD4(+) and CD8(+) T cells. It is well documented that activated T cells can contribute to the control of leukemic cells and it was hoped that these cells may be able to target and eliminate the therapy-resistant LSCs. However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined. Paradoxically, many immune mechanisms that evolved to activate emergency hematopoiesis during infection may actually contribute to the expansion and differentiation of LSCs, promoting leukemia progression. In this review, we

  2. Hematopoietic Stem Cells Transplantation Can Normalize Thyroid Function in a Cystinosis Mouse Model

    PubMed Central

    Janssens, V.; Van Der Smissen, P.; Rocca, C. J.; Liao, X. H.; Refetoff, S.; Pierreux, C. E.; Cherqui, S.

    2016-01-01

    Hypothyroidism is the most frequent and earliest endocrine complication in cystinosis, a multisystemic lysosomal storage disease caused by defective transmembrane cystine transporter, cystinosin (CTNS gene). We recently demonstrated in Ctns−/− mice that altered thyroglobulin biosynthesis associated with endoplasmic reticulum stress, combined with defective lysosomal processing, caused hypothyroidism. In Ctns−/− kidney, hematopoietic stem cell (HSC) transplantation provides long-term functional and structural protection. Tissue repair involves transfer of cystinosin-bearing lysosomes from HSCs differentiated as F4/80 macrophages into deficient kidney tubular cells, via tunneling nanotubes that cross basement laminae. Here we evaluated the benefit of HSC transplantation for cystinotic thyroid and investigated the underlying mechanisms. HSC engraftment in Ctns−/− thyroid drastically decreased cystine accumulation, normalized the TSH level, and corrected the structure of a large fraction of thyrocytes. In the thyroid microenvironment, HSCs differentiated into a distinct, mixed macrophage/dendritic cell lineage expressing CD45 and major histocompatibility complex II but low CD11b and F4/80. Grafted HSCs closely apposed to follicles and produced tunneling nanotube-like extensions that crossed follicular basement laminae. HSCs themselves further squeezed into follicles, allowing extensive contact with thyrocytes, but did not transdifferentiate into Nkx2.1-expressing cells. Our observations revealed significant differences of basement lamina porosity between the thyroid and kidney and/or intrinsic macrophage invasive properties once in the thyroid microenvironment. The contrast between extensive thyrocyte protection and low HSC abundance at steady state suggests multiple sequential encounters and/or remanent impact. This is the first report demonstrating the potential of HSC transplantation to correct thyroid disease and supports a major multisystemic benefit

  3. [Research Progress on Gene Expression Abnormality of Hematopoietic Stem/Progenitor Cells in Myelodysplastic Syndromes].

    PubMed

    Zhang, Jing; Ma, Yan; Xu, Xiao-Ping

    2015-10-01

    Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal disease involving one or more series of hematopoietic cells. Its pathogenesis is still unclear. No effective targeted drug is available to prevent this disease progression. MDS originates in hematopoietic stem cells. Recent researches found that the complex abnormal gene expression occurred in bone marrow CD34⁺ cells plays a key role in development of MDS. Some of these genes are closely related with the patient's prognosis and survival, such as DLK1, ribosomal transcripts gene, Toll-like receptors gene, EPA-1 and interferon-stimulated genes. Due to heterogeneity of this disease, abnormal gene expression profiles in bone marrow CD34⁺ cells are closely associated with particular FAB or cytogenetic subtypes. To elucidate the pathogenesis of MDS and investigate its therapeutic target, this article reviews progress of researches on abnormal gene expression profiles of hematopoietic stem/progenitor cells in low-risk, high-risk patients and MDS patients who carry common cytogenetic abnormalities.

  4. Influence of coping style on symptom interference among adult recipients of hematopoietic stem cell transplantation.

    PubMed

    Schoulte, Joleen C; Lohnberg, Jessica A; Tallman, Benjamin; Altmaier, Elizabeth M

    2011-09-01

    To investigate the influence of coping style on interference caused by a variety of common post-treatment symptoms after hematopoietic stem cell transplantation. Longitudinal; secondary analysis of data from the original study that examined health-related quality-of-life variables (e.g., depression, well-being) in adult patients treated with conventional bone marrow transplantation or depleted T-cell bone marrow transplantation. Fifteen university medical centers in the United States. 105 adult recipients of hematopoietic stem cell transplantation. Patients were assessed via telephone-based interviews for coping style at baseline and for symptom interference in daily living six months post-treatment. Coping style and symptom interference. Neither age nor gender predicted symptom interference, with the exception of chronic graft-versus-host disease, where older patients experienced more interference at six months, and breathing symptoms, for which women experienced more interference than men at six months. Avoidant coping style at baseline predicted increased interference from symptoms, but emotion-focused and instrumental coping styles did not predict decreased interference. A generalized avoidant coping style before treatment increased interference from common cancer symptoms six months after hematopoietic stem cell transplantation. An intervention to teach alternate coping strategies should be implemented prior to treatment and tested for prevention of symptom-related life interference.

  5. ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver

    PubMed Central

    Zhao, Yunze; Zhou, Jie; Liu, Dan; Dong, Fang; Cheng, Hui; Wang, Weili; Pang, Yakun; Wang, Yajie; Mu, Xiaohuan; Ni, Yanli; Li, Zhuan; Xu, Huiyu; Hao, Sha; Wang, Xiaochen; Ma, Shihui; Wang, Qian-fei; Xiao, Guozhi; Yuan, Weiping; Liu, Bing

    2015-01-01

    The fetal liver (FL) serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in FL remain poorly understood. In this study, we demonstrate that deletion of activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in FL. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros region was not affected. The migration activity of ATF4−/− HSCs was moderately reduced. Interestingly, the HSC-supporting ability of both endothelial and stromal cells in FL was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed downregulated expression of a panel of cytokines in ATF4−/− stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor A (VEGFA). Addition of Angptl3, but not VEGFA, partially rescued the repopulating defect of ATF4−/− HSCs in the culture. Furthermore, chromatin immunoprecipitation assay in conjunction with silencing RNA-mediated silencing and complementary DNA overexpression showed transcriptional control of Angptl3 by ATF4. To summarize, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing FL, and it acts through upregulating transcription of cytokines such as Angptl3 in the microenvironment. PMID:26384355

  6. A Prospective Study of Bone Marrow Hematopoietic and Mesenchymal Stem Cells in Type 1 Gaucher Disease Patients

    PubMed Central

    Lecourt, Séverine; Mouly, Enguerran; Freida, Delphine; Cras, Audrey; Ceccaldi, Raphaël; Heraoui, Djazia; Chomienne, Christine; Marolleau, Jean-Pierre; Arnulf, Bertrand; Porcher, Raphael; Caillaud, Catherine; Vanneaux, Valérie; Belmatoug, Nadia; Larghero, Jérôme

    2013-01-01

    Gaucher disease (GD) is an autosomal recessive disorder characterized by lysosomal glucocerebrosidase (GBA) deficiency leading to hematological and skeletal manifestations. Mechanisms underlying these symptoms have not yet been elucidated. In vivo, bone marrow (BM) mesenchymal stem cells (MSCs) have important role in the regulation of bone mass and in the support of hematopoiesis, thus representing potential candidate that could contribute to the disease. GBA deficiency may also directly impair hematopoietic stem/progenitors cells (HSPCs) intrinsic function and induce hematological defect. In order to evaluate the role of BM stem cells in GD pathophysiology, we prospectively analyzed BM-MSCs and HSPCs properties in a series of 10 patients with type 1 GD. GBA activity was decreased in all tested cell subtypes. GD-MSCs had an impaired growth potential, morphological and cell cycle abnormalities, decreased capacities to differentiate into osteoblasts. Moreover, GD-MSCs secreted soluble factors that stimulated osteoclasts resorbing activities. In vitro and in vivo primitive and mature hematopoiesis were similar between patients and controls. However, GD-MSCs had a lower hematopoietic supportive capacity than those from healthy donors. These data suggest that BM microenvironment is altered in GD and that MSCs are key components of the manifestations observed in GD. PMID:23935976

  7. α-Tocopherol induces hematopoietic stem/progenitor cell expansion and ERK1/2-mediated differentiation.

    PubMed

    Nogueira-Pedro, Amanda; Barbosa, Christiano M V; Segreto, Helena Regina Comodo; Lungato, Lisandro; D'Almeida, Vania; Moraes, Andrea Aparecida F S; Miranda, Antonio; Paredes-Gamero, Edgar Julian; Ferreira, Alice Teixeira

    2011-12-01

    Tocopherols promote or inhibit growth in different cell types. In the hematopoietic system, the radioprotective property of tocopherols is thought to act through the expansion of primitive hematopoietic cells. However, the mechanisms activated by tocopherols and which HPs are affected remain poorly understood. To better address these questions, mice were treated with α-tocopherol, and its effects were investigated in the BM microenvironment. α-Tocopherol induced increased proliferation in HSC/HP cells, leading to BM hyperplasia. In addition, differentiation to the granulocytic/monocytic lineage was enhanced by α-tocopherol treatment. α-Tocopherol treatment resulted in decreased basal phosphorylation of ERK1/2, PKC, and STAT-5 in HSC/HP cells. In contrast, α-tocopherol enhanced ERK1/2 activation in response to IL-3 stimulation in HSC/HP cells without altering the expression of IL-3Rs. Moreover, α-tocopherol-induced differentiation and ERK1/2 activation were abolished in mice pretreated with a MEK inhibitor (PD98059); however, pretreatment with PD98059 did not reduce the α-tocopherol-mediated increase in HSC/HP cells but instead, further enhanced their proliferation. Therefore, α-tocopherol induces expansion of HSC/HP cells by a nonidentified intracellular pathway and granulocytic/monocytic differentiation through ERK1/2 activation.

  8. Reactive Oxygen Species Limit the Ability of Bone Marrow Stromal Cells to Support Hematopoietic Reconstitution in Aging Mice

    PubMed Central

    Khatri, Rahul; Krishnan, Shyam; Roy, Sushmita; Chattopadhyay, Saborni; Kumar, Vikash

    2016-01-01

    Aging of organ and abnormal tissue regeneration are recurrent problems in physiological and pathophysiological conditions. This is most crucial in case of high-turnover tissues, like bone marrow (BM). Using reciprocal transplantation experiments in mouse, we have shown that self-renewal potential of hematopoietic stem and progenitor cells (HSPCs) and BM cellularity are markedly influenced with the age of the recipient mice rather than donor mice. Moreover, accumulation of excessive reactive oxygen species (ROS) in BM stromal cells compared to HSPC compartment, in time-dependent manner, suggests that oxidative stress is involved in suppression of BM cellularity by affecting microenvironment in aged mice. Treatment of these mice with a polyphenolic antioxidant curcumin is found to partially quench ROS, thereby rescues stromal cells from oxidative stress-dependent cellular injury. This rejuvenation of stromal cells significantly improves hematopoietic reconstitution in 18-month-old mice compared to age control mice. In conclusion, this study implicates the role of ROS in perturbation of stromal cell function upon aging, which in turn affects BM's reconstitution ability in aged mice. Thus, a rejuvenation therapy using curcumin, before HSPC transplantation, is found to be an efficient strategy for successful marrow reconstitution in older mice. PMID:27140293

  9. ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver.

    PubMed

    Zhao, Yunze; Zhou, Jie; Liu, Dan; Dong, Fang; Cheng, Hui; Wang, Weili; Pang, Yakun; Wang, Yajie; Mu, Xiaohuan; Ni, Yanli; Li, Zhuan; Xu, Huiyu; Hao, Sha; Wang, Xiaochen; Ma, Shihui; Wang, Qian-fei; Xiao, Guozhi; Yuan, Weiping; Liu, Bing; Cheng, Tao

    2015-11-19

    The fetal liver (FL) serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in FL remain poorly understood. In this study, we demonstrate that deletion of activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in FL. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros region was not affected. The migration activity of ATF4(-/-) HSCs was moderately reduced. Interestingly, the HSC-supporting ability of both endothelial and stromal cells in FL was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed downregulated expression of a panel of cytokines in ATF4(-/-) stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor A (VEGFA). Addition of Angptl3, but not VEGFA, partially rescued the repopulating defect of ATF4(-/-) HSCs in the culture. Furthermore, chromatin immunoprecipitation assay in conjunction with silencing RNA-mediated silencing and complementary DNA overexpression showed transcriptional control of Angptl3 by ATF4. To summarize, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing FL, and it acts through upregulating transcription of cytokines such as Angptl3 in the microenvironment.

  10. Reactive Oxygen Species Limit the Ability of Bone Marrow Stromal Cells to Support Hematopoietic Reconstitution in Aging Mice.

    PubMed

    Khatri, Rahul; Krishnan, Shyam; Roy, Sushmita; Chattopadhyay, Saborni; Kumar, Vikash; Mukhopadhyay, Asok

    2016-06-15

    Aging of organ and abnormal tissue regeneration are recurrent problems in physiological and pathophysiological conditions. This is most crucial in case of high-turnover tissues, like bone marrow (BM). Using reciprocal transplantation experiments in mouse, we have shown that self-renewal potential of hematopoietic stem and progenitor cells (HSPCs) and BM cellularity are markedly influenced with the age of the recipient mice rather than donor mice. Moreover, accumulation of excessive reactive oxygen species (ROS) in BM stromal cells compared to HSPC compartment, in time-dependent manner, suggests that oxidative stress is involved in suppression of BM cellularity by affecting microenvironment in aged mice. Treatment of these mice with a polyphenolic antioxidant curcumin is found to partially quench ROS, thereby rescues stromal cells from oxidative stress-dependent cellular injury. This rejuvenation of stromal cells significantly improves hematopoietic reconstitution in 18-month-old mice compared to age control mice. In conclusion, this study implicates the role of ROS in perturbation of stromal cell function upon aging, which in turn affects BM's reconstitution ability in aged mice. Thus, a rejuvenation therapy using curcumin, before HSPC transplantation, is found to be an efficient strategy for successful marrow reconstitution in older mice.

  11. Early osteoinductive human bone marrow mesenchymal stromal/stem cells support an enhanced hematopoietic cell expansion with altered chemotaxis- and adhesion-related gene expression profiles.

    PubMed

    Sugino, Noriko; Miura, Yasuo; Yao, Hisayuki; Iwasa, Masaki; Fujishiro, Aya; Fujii, Sumie; Hirai, Hideyo; Takaori-Kondo, Akifumi; Ichinohe, Tatsuo; Maekawa, Taira

    2016-01-22

    Bone marrow (BM) microenvironment has a crucial role in supporting hematopoiesis. Here, by using a microarray analysis, we demonstrate that human BM mesenchymal stromal/stem cells (MSCs) in an early osteoinductive stage (e-MSCs) are characterized by unique hematopoiesis-associated gene expression with an enhanced hematopoiesis-supportive ability. In comparison to BM-MSCs without osteoinductive treatment, gene expression in e-MSCs was significantly altered in terms of their cell adhesion- and chemotaxis-related profiles, as identified with Gene Ontology and Gene Set Enrichment Analysis. Noteworthy, expression of the hematopoiesis-associated molecules CXCL12 and vascular cell adhesion molecule 1 was remarkably decreased in e-MSCs. e-MSCs supported an enhanced expansion of CD34(+) hematopoietic stem and progenitor cells, and generation of myeloid lineage cells in vitro. In addition, short-term osteoinductive treatment favored in vivo hematopoietic recovery in lethally irradiated mice that underwent BM transplantation. e-MSCs exhibited the absence of decreased stemness-associated gene expression, increased osteogenesis-associated gene expression, and apparent mineralization, thus maintaining the ability to differentiate into adipogenic cells. Our findings demonstrate the unique biological characteristics of e-MSCs as hematopoiesis-regulatory stromal cells at differentiation stage between MSCs and osteoprogenitor cells and have significant implications in developing new strategy for using pharmacological osteoinductive treatment to support hematopoiesis in hematopoietic stem and progenitor cell transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Mobilization of hematopoietic stem cells into the peripheral blood.

    PubMed

    Damon, Lloyd E; Damon, Lauren E

    2009-12-01

    Hematopoietic stem cells can be mobilized out of the bone marrow into the blood for the reconstitution of hematopoiesis following high-dose therapy. Methods to improve mobilization efficiency and yields are rapidly emerging. Traditional methods include chemotherapy with or without myeloid growth factors. Plerixafor, a novel agent that disrupts the CXCR4-CXCL12 bond, the primary hematopoietic stem cell anchor in the bone marrow, has recently been US FDA-approved for mobilizing hematopoietic stem cells in patients with non-Hodgkin lymphoma and multiple myeloma. Plerixafor and myeloid growth factors as single agents appear safe to use in family or volunteer hematopoietic stem cells donors. Plerixafor mobilizes leukemic stem cells and is not approved for use in patients with acute leukemia. Patients failing to mobilize adequate hematopoietic stem cells with myeloid growth factors can often be successfully mobilized with chemotherapy plus myeloid growth factors or with plerixafor and granulocyte colony-stimulating factor.

  13. Human Term Placenta as a Source of Hematopoietic Cells

    PubMed Central

    Serikov, Vladimir; Hounshell, Catherine; Larkin, Sandra; Green, William; Ikeda, Hirokazu; Walters, Mark C.

    2012-01-01

    The main barrier to a broader clinical application of umbilical cord blood (UCB) transplantation is its limiting cellular content. Thus, the discovery of hematopoietic progenitor cells in murine placental tissue led us investigate whether the human placenta contains hematopoietic cells, sites of hematopoiesis, and to develop a procedure of processing and storing placental hematopoietic cells for transplantation. Here we show that the human placenta contains large numbers of CD34-expressing hematopoietic cells, with the potential to provide a cellular yield several-fold greater than that of a typical UCB harvest. Cells from fresh or cryopreserved placental tissue generated erythroid and myeloid colonies in culture, and also produced lymphoid cells after transplantation in immunodeficient mice. These results suggest that human placenta could become an important new source of hematopoietic cells for allogeneic transplantation. PMID:19429852

  14. Hematopoietic stem cell transplantation for osteopetrosis.

    PubMed

    Steward, Colin G

    2010-02-01

    Osteopetrosis is the generic name for a group of diseases caused by deficient formation or function of osteoclasts, inherited in either autosomal recessive or dominant fashion. Osteopetrosis varies in severity from a disease that may kill infants to an incidental radiological finding in adults. It is increasingly clear that prognosis is governed by which gene is affected, making detailed elucidation of the cause of the disease a critical component of optimal care, including the decision on whether hematopoietic stem cell transplantation is appropriate. This article reviews the characteristics and management of osteopetrosis.

  15. Hematopoietic Stem Cell Expansion and Gene Therapy

    PubMed Central

    Watts, Korashon Lynn; Adair, Jennifer; Kiem, Hans-Peter

    2012-01-01

    Hematopoietic stem cell (HSC) gene therapy remains a highly attractive treatment option for many disorders including hematologic conditions, immunodeficiencies including HIV/AIDS, and other genetic disorders like lysosomal storage diseases, among others. In this review, we discuss the successes, side effects, and limitations of current gene therapy protocols. In addition, we describe the opportunities presented by implementing ex vivo expansion of gene-modified HSCs, as well as summarize the most promising ex vivo expansion techniques currently available. We conclude by discussing how some of the current limitations of HSC gene therapy could be overcome by combining novel HSC expansion strategies with gene therapy. PMID:21999373

  16. Human fetal hepatic progenitor cells are distinct from, but closely related to, hematopoietic stem/progenitor cells.

    PubMed

    Chen, Qingfeng; Khoury, Maroun; Limmon, Gino; Choolani, Mahesh; Chan, Jerry K Y; Chen, Jianzhu

    2013-06-01

    Much controversy surrounds the identity and origin of human hepatic stem and progenitor cells in part because of a lack of small animal models in which the developmental potential of isolated candidate cell populations can be functionally evaluated. We show here that adoptive transfer of CD34(+) cells from human fetal liver into sublethally irradiated NOD-SCID Il2rg(-/-) (NSG) mice leads to an efficient development of not only human hematopoietic cells but also human hepatocyte-like cells in the liver of the recipient mice. Using this simple in vivo assay in combination with cell fractionation, we show that CD34(+) fetal liver cells can be separated into three distinct subpopulations: CD34(hi) CD133(hi), CD34(lo) CD133(lo), and CD34(hi) CD133(neg). The CD34(hi) CD133(hi) population contains hematopoietic stem/progenitor cells (HSPCs) as they give rise to T cells, B cells, NK cells, dendritic cells, and monocytes/macrophages in NSG mice and colony-forming unit (CFU)-GEMM cells in vitro. The CD34(lo) CD133(lo) population does not give rise to hematopoietic cells, but reproducibly generates hepatocyte-like cells in NSG mice and in vitro. The CD34(hi) CD133(neg) population only gives rise to CFU-GM and burst-forming unit-erythroid in vitro. Furthermore, we show that the CD34(lo) CD133(lo) cells express hematopoietic, hepatic, and mesenchymal markers, including CD34, CD133, CD117, epithelial cell adhesion molecule, CD73, albumin, α-fetal protein, and vimentin and transcriptionally are more closely related to HSPCs than to mature hepatocytes. These results show that CD34(lo) CD133(lo) fetal liver cells possess the hepatic progenitor cell properties and that human hepatic and hematopoietic progenitor cells are distinct, although they may originate from the same precursors in the fetal liver.

  17. Transcriptome comparison of distinct osteolineage subsets in the hematopoietic stem cell niche using a triple fluorescent transgenic mouse model

    PubMed Central

    Yu, Vionnie W.C.; Lymperi, Stefania; Ferraro, Francesca; Scadden, David T.

    2015-01-01

    The bone marrow niche is recognized as a central player in maintaining and regulating the behavior of hematopoietic stem and progenitor cells. Specific gain-of and loss-of function experiments perturbing a range of osteolineage cells or their secreted proteins had been shown to affect stem cell maintenance (Calvi et al, 2003 [1]; Stier et al., 2005 [2]; Zhang et al., 2003 [3]; Nilsson et al., 2005 [4]; Greenbaum et al., 2013 [5]) and engraftment (Adam et al., 2006, 2009 [6], [7]). We used specific in vivo cell deletion approaches to dissect the niche cell-parenchymal cell dependency in a complex bone marrow microenvironment. Endogenous deletion of osteocalcin-expressing (Ocn+) cells led to a loss of T immune cells (Yu et al., 2015 [8]. Ocn+ cells express the Notch ligand DLL4 to communicate with T-competent progenitors, and thereby ensuring T precursor production and expression of chemotactic molecules on their cell surface for subsequent thymic seeding. In contrast, depletion of osterix-expressing (Osx+) osteoprogenitors led to reduced B immune cells. These distinct hematopoietic phenotypes suggest specific pairing of mesenchymal niche cells and parenchymal hematopoietic cells in the bone marrow to create unique functional units to support hematopoiesis. Here, we present the global gene expression profiles of these osteolineage subtypes utilizing a triple fluorescent transgenic mouse model (OsxCre+;Rosa-mCh+;Ocn:Topaz+) that labels Osx+ cells red, Ocn+ cells green, and Osx+ Ocn+ cells yellow. This system allows isolation of distinct osteolineage subsets within the same animal by flow cytometry. Array data that have been described in our study [8] are also publically available from NCBI Gene Expression Omnibus (GEO) with the accession number GSE66042. Differences in gene expression may correlate with functional difference in supporting hematopoiesis. PMID:26484277

  18. Acellular Bone Marrow Extracts Significantly Enhance Engraftment Levels of Human Hematopoietic Stem Cells in Mouse Xeno-Transplantation Models

    PubMed Central

    Zibara, Kazem; Hamdan, Rima; Dib, Leila; Sindet-Pedersen, Steen; Kharfan-Dabaja, Mohamed; Bazarbachi, Ali; El-Sabban, Marwan

    2012-01-01

    Hematopoietic stem cells (HSC) derived from cord blood (CB), bone marrow (BM), or mobilized peripheral blood (PBSC) can differentiate into multiple lineages such as lymphoid, myeloid, erythroid cells and platelets. The local microenvironment is critical to the differentiation of HSCs and to the preservation of their phenotype in vivo. This microenvironment comprises a physical support supplied by the organ matrix as well as tissue specific cytokines, chemokines and growth factors. We investigated the effects of acellular bovine bone marrow extracts (BME) on HSC in vitro and in vivo. We observed a significant increase in the number of myeloid and erythroid colonies in CB mononuclear cells (MNC) or CB CD34+ cells cultured in methylcellulose media supplemented with BME. Similarly, in xeno-transplantation experiments, pretreatment with BME during ex-vivo culture of HSCs induced a significant increase in HSC engraftment in vivo. Indeed, we observed both an increase in the number of differentiated myeloid, lymphoid and erythroid cells and an acceleration of engraftment. These results were obtained using CB MNCs, BM MNCs or CD34+ cells, transplanted in immuno-compromised mice (NOD/SCID or NSG). These findings establish the basis for exploring the use of BME in the expansion of CB HSC prior to HSC Transplantation. This study stresses the importance of the mechanical structure and soluble mediators present in the surrounding niche for the proper activity and differentiation of stem cells. PMID:22768336

  19. Stromal cell–derived factor-1 and hematopoietic cell homing in an adult zebrafish model of hematopoietic cell transplantation

    PubMed Central

    Glass, Tiffany J.; Patrinostro, Xiaobai; Tolar, Jakub; Bowman, Teresa V.; Zon, Leonard I.; Blazar, Bruce R.

    2011-01-01

    In mammals, stromal cell–derived factor-1 (SDF-1) promotes hematopoietic cell mobilization and migration. Although the zebrafish, Danio rerio, is an emerging model for studying hematopoietic cell transplantation (HCT), the role of SDF-1 in the adult zebrafish has yet to be determined. We sought to characterize sdf-1 expression and function in the adult zebrafish in the context of HCT. In situ hybridization of adult zebrafish organs shows sdf-1 expression in kidney tubules, gills, and skin. Radiation up-regulates sdf-1 expression in kidney to nearly 4-fold after 40 Gy. Assays indicate that zebrafish hematopoietic cells migrate toward sdf-1, with a migration ratio approaching 1.5 in vitro. A sdf-1a:DsRed2 transgenic zebrafish allows in vivo detection of sdf-1a expression in the adult zebrafish. Matings with transgenic reporters localized sdf-1a expression to the putative hematopoietic cell niche in proximal and distal renal tubules and collecting ducts. Importantly, transplant of hematopoietic cells into myelosuppressed recipients indicated migration of hematopoietic cells to sdf-1a–expressing sites in the kidney and skin. We conclude that sdf-1 expression and function in the adult zebrafish have important similarities to mammals, and this sdf-1 transgenic vertebrate will be useful in characterizing the hematopoietic cell niche and its interactions with hematopoietic cells. PMID:21622651

  20. Metabolomics Analyses of Cancer Cells in Controlled Microenvironments.

    PubMed

    Gravel, Simon-Pierre; Avizonis, Daina; St-Pierre, Julie

    2016-01-01

    The tumor microenvironment is a complex and heterogeneous milieu in which cancer cells undergo metabolic reprogramming to fuel their growth. Cancer cell lines grown in vitro using traditional culture methods represent key experimental models to gain a mechanistic understanding of tumor biology. This protocol describes the use of gas chromatography-mass spectrometry (GC-MS) to assess metabolic changes in cancer cells grown under varied levels of oxygen and nutrients that may better mimic the tumor microenvironment. Intracellular metabolite changes, metabolite uptake and release, as well as stable isotope ((13)C) tracer analyses are done in a single experimental setup to provide an integrated understanding of metabolic adaptation. Overall, this chapter describes some essential tools and methods to perform comprehensive metabolomics analyses.

  1. Engineering three-dimensional cell mechanical microenvironment with hydrogels.

    PubMed

    Huang, Guoyou; Wang, Lin; Wang, Shuqi; Han, Yulong; Wu, Jinhui; Zhang, Qiancheng; Xu, Feng; Lu, Tian Jian

    2012-12-01

    Cell mechanical microenvironment (CMM) significantly affects cell behaviors such as spreading, migration, proliferation and differentiation. However, most studies on cell response to mechanical stimulation are based on two-dimensional (2D) planar substrates, which cannot mimic native three-dimensional (3D) CMM. Accumulating evidence has shown that there is a significant difference in cell behavior in 2D and 3D microenvironments. Among the materials used for engineering 3D CMM, hydrogels have gained increasing attention due to their tunable properties (e.g. chemical and mechanical properties). In this paper, we provide an overview of recent advances in engineering hydrogel-based 3D CMM. Effects of mechanical cues (e.g. hydrogel stiffness and externally induced stress/strain in hydrogels) on cell behaviors are described. A variety of approaches to load mechanical stimuli in 3D hydrogel-based constructs are also discussed.

  2. Pulsation-limited oxygen diffusion in the tumour microenvironment

    PubMed Central

    Milotti, Edoardo; Stella, Sabrina; Chignola, Roberto

    2017-01-01

    Hypoxia is central to tumour evolution, growth, invasion and metastasis. Mathematical models of hypoxia based on reaction-diffusion equations provide seemingly incomplete descriptions as they fail to predict the measured oxygen concentrations in the tumour microenvironment. In an attempt to explain the discrepancies, we consider both the inhomogeneous distribution of oxygen-consuming cells in solid tumours and the dynamics of blood flow in the tumour microcirculation. We find that the low-frequency oscillations play an important role in the establishment of tumour hypoxia. The oscillations interact with consumption to inhibit oxygen diffusion in the microenvironment. This suggests that alpha-blockers–a class of drugs used to treat hypertension and stress disorders, and known to lower or even abolish low-frequency oscillations of arterial blood flow –may act as adjuvant drugs in the radiotherapy of solid tumours by enhancing the oxygen effect. PMID:28045083

  3. The critical role of the bone microenvironment in cancer metastases.

    PubMed

    Casimiro, Sandra; Guise, Theresa A; Chirgwin, John

    2009-10-30

    Bone metastatic disease is a late-stage event of many common cancers, such as those of prostate and breast. It is incurable and causes severe morbidity. Tumor and bone interact in a vicious cycle, where tumor-secreted factors stimulate bone cells, which in turn release growth factors and cytokines that act back on the tumor cells. Within the vicious cycle are many potential therapeutic targets for novel treatment of bone metastatic disease. Therapeutic strategies can be oriented to inhibit bone cells (osteoclasts and osteoblasts) or tumor responses to factors enriched in the bone microenvironment. Many publications, especially from pre-clinical animal models, show that this approach, especially combination treatments, can reduce tumor burden and tumor-derived bone lesions. This supports a novel paradigm: tumor growth can be effectively inhibited by targeting the bone and its microenvironment rather than the tumor itself alone.

  4. Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

    PubMed Central

    Justus, Calvin R.; Sanderlin, Edward J.; Yang, Li V.

    2015-01-01

    Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention. PMID:25988385

  5. Microsphere cytometry to interrogate microenvironment-dependent cell signaling.

    PubMed

    Ertsås, Henriette Christie; Nolan, Garry P; LaBarge, Mark A; Lorens, James B

    2017-02-20

    Microenvironmental cues comprising surface-mediated and soluble factors control cellular signaling mechanisms underlying normal cellular responses that define homeostatic and diseased cell states. In order to measure cell signaling in single adherent cells, we developed a novel microsphere-based flow cytometry approach. Single normal or neoplastic cells were adhered to uniform microspheres that display mimetic-microenvironments comprising surface combinations of extracellular matrix (ECM) in the presence of soluble agonists/antagonists. Temporal signaling responses were measured with fluorophore-conjugated antibodies that recognize response-dependent epitopes by multiparametric flow cytometry. Using this approach we demonstrate that microenvironment-mimetic combinations of growth factors and extracellular matrix proteins generate distinct cellular signal networks that reveal unique cell signatures in normal and patient biopsy-derived neoplastic cells.

  6. Innate and adaptive immune cells in the tumor microenvironment

    PubMed Central

    Gajewski, Thomas F; Schreiber, Hans; Fu, Yang-Xin

    2014-01-01

    Most tumor cells express antigens that can mediate recognition by host CD8+ T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell–inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system–suppressive pathways. The other major phenotype lacks this T cell–inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect. PMID:24048123

  7. Quantitative Multiscale Cell Imaging in Controlled 3D Microenvironments

    PubMed Central

    Welf, Erik S.; Driscoll, Meghan K.; Dean, Kevin M.; Schäfer, Claudia; Chu, Jun; Davidson, Michael W.; Lin, Michael Z.; Danuser, Gaudenz; Fiolka, Reto

    2016-01-01

    The microenvironment determines cell behavior, but the underlying molecular mechanisms are poorly understood because quantitative studies of cell signaling and behavior have been challenging due to insufficient spatial and/or temporal resolution and limitations on microenvironmental control. Here we introduce microenvironmental selective plane illumination microscopy (meSPIM) for imaging and quantification of intracellular signaling and submicrometer cellular structures as well as large-scale cell morphological and environmental features. We demonstrate the utility of this approach by showing that the mechanical properties of the microenvironment regulate the transition of melanoma cells from actin-driven protrusion to blebbing, and we present tools to quantify how cells manipulate individual collagen fibers. We leverage the nearly isotropic resolution of meSPIM to quantify the local concentration of actin and phosphatidylinositol 3-kinase signaling on the surfaces of cells deep within 3D collagen matrices and track the many small membrane protrusions that appear in these more physiologically relevant environments. PMID:26906741

  8. Microenvironment-Driven Resistance to BRAF Inhibition Comes of Age.

    PubMed

    Menon, Dinoop Ravindran; Schaider, Helmut

    2015-12-01

    Increasingly comprehensive observations indicate that the tumor microenvironment contributes to drug resistance toward small molecule inhibitors. Fedorenko et al. describe a role for fibroblasts in creating a favorable niche for melanoma cell survival if treated with the BRAF inhibitor vemurafenib. TGF-β released by vemurafenib-treated melanoma cells stimulated fibroblasts for increased α-smooth muscle actin, neuregulin (NRG), and fibronectin expression. Off-target effects of vemurafenib led to paradoxical secretion of hepatocyte growth factor (HGF) by fibroblasts. Combined inhibition of BRAF/MET/HER kinases was insufficient to reverse the protective effect of the fibroblasts, whereas reversal was achieved by combined BRAF/PI3K inhibition. A thorough understanding of the complex spatiotemporal interactions in tumor microenvironments holds promise for improved targeting using combination therapies in patients with melanoma.

  9. Pulsation-limited oxygen diffusion in the tumour microenvironment

    NASA Astrophysics Data System (ADS)

    Milotti, Edoardo; Stella, Sabrina; Chignola, Roberto

    2017-01-01

    Hypoxia is central to tumour evolution, growth, invasion and metastasis. Mathematical models of hypoxia based on reaction-diffusion equations provide seemingly incomplete descriptions as they fail to predict the measured oxygen concentrations in the tumour microenvironment. In an attempt to explain the discrepancies, we consider both the inhomogeneous distribution of oxygen-consuming cells in solid tumours and the dynamics of blood flow in the tumour microcirculation. We find that the low-frequency oscillations play an important role in the establishment of tumour hypoxia. The oscillations interact with consumption to inhibit oxygen diffusion in the microenvironment. This suggests that alpha-blockers–a class of drugs used to treat hypertension and stress disorders, and known to lower or even abolish low-frequency oscillations of arterial blood flow –may act as adjuvant drugs in the radiotherapy of solid tumours by enhancing the oxygen effect.

  10. Microenvironment and endocrine resistance in breast cancer: Friend or foe?

    PubMed Central

    Recouvreux, Sol; Sampayo, Rocío; Bessone, María Inés Díaz; Simian, Marina

    2015-01-01

    Breast cancer affects one in eight women around the world. Seventy five percent of these patients have tumors that are estrogen receptor positive and as a consequence receive endocrine therapy. However, about one third eventually develop resistance and cancer reappears. In the last decade our vision of cancer has evolved to consider it more of a tissue-related disease than a cell-centered one. This editorial argues that we are only starting to understand the role the tumor microenvironment plays in therapy resistance in breast cancer. The development of new therapeutic strategies that target the microenvironment will come when we clearly understand this extremely complicated scenario. As such, and as a scientific community, we have extremely challenging work ahead. We share our views regarding these matters. PMID:26677432

  11. Severe sepsis in hematopoietic stem cell transplant recipients*.

    PubMed

    Kumar, Gagan; Ahmad, Shahryar; Taneja, Amit; Patel, Jayshil; Guddati, Achuta Kumar; Nanchal, Rahul

    2015-02-01

    Severe sepsis requires timely management and has high mortality if care is delayed. Hematopoietic stem cell transplant recipients are more likely to be immunocompromised and are predisposed to serious infections. Reports of outcomes of severe sepsis in this population are limited to data from single, tertiary care centers, and national outcomes data are missing. Retrospective analysis of an administrative database. Twenty percent of community hospitals in United States, excluding federal hospitals. Patients with severe sepsis. None. We used International Classification of Diseases, 9th Edition, Clinical Modification codes indicating the presence of sepsis and organ system failure to identify hospitalizations for severe sepsis between 2000 and 2008. We also used International Classification of Diseases, 9th Edition, Clinical Modification codes to identify hematopoietic stem cell transplant recipients. We compared outcomes of hematopoietic stem cell transplant recipients with severe sepsis during engraftment and subsequent admissions with a non-hematopoietic stem cell transplant cohort and excluded solid-organ transplantation from this cohort. We used mixed effect, multivariate logistic regression modeling with propensity score adjustment to examine factors associated with mortality of severe sepsis in hematopoietic stem cell transplant recipients. A total of 21,898 hematopoietic stem cell transplant recipients with severe sepsis were identified. The frequency of severe sepsis in hematopoietic stem cell transplant recipients was five times higher when compared with the non-hematopoietic stem cell transplant cohort. The unadjusted mortality was 32.9% in non-hematopoietic stem cell transplant cohort, which was similar to autologous hematopoietic stem cell transplant recipients (30.1%) and those who did not develop graft-versus-host disease (35%). Mortality was significantly higher in allogeneic transplants (55.1%, p < 0.001) and in those who developed graft

  12. Remodelling the vascular microenvironment of glioblastoma with alpha-particles

    PubMed Central

    Behling, Katja; Maguire, William F.; Di Gialleonardo, Valentina; Heeb, Lukas E.M.; Hassan, Iman F.; Veach, Darren R.; Keshari, Kayvan R.; Gutin, Philip H.; Scheinberg, David A.; McDevitt, Michael R.

    2016-01-01

    Rationale Tumors escape anti-angiogenic therapy by activation of pro-angiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We investigated targeted α-particle therapy with 225Ac-E4G10 as an anti-vascular approach and previously showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here we investigate changes in tumor-vascular morphology and functionality caused by 225Ac-E4G10. Methods We investigated remodeling of tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4 kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphological changes in the tumor blood brain barrier microenvironment. Multi-color flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted magnetic resonance imaged functional changes of the tumor vascular network. Results The mechanism of drug action is a combination of glioblastoma vascular microenvironment remodeling, edema relief, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis was lessened and resulted in increased perfusion and reduced diffusion. Pharmacological uptake of dasatinib into tumor was enhanced following α-particle therapy. Conclusion Targeted anti-vascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of Platelet-derived growth factor driven glioblastoma. PMID:27261519

  13. Lifetime-based sensing:  influence of the microenvironment.

    PubMed

    Draxler, S; Lippitsch, M E

    1996-03-01

    The influence of the microenvironment on the fluorescence behavior of indicator molecules is investigated. A model is developed to describe the fluorescence decay of indicator molecules in a nonuniform medium. Its consequences for fluorescence lifetime-based chemical sensors are discussed and verified in two examples, namely, a pH sensor using a pyrene compound in a hydrogel and a ruthenium complex for oxygen sensing embedded in a polystyrene membrane.

  14. Tumour microenvironment factors shaping the cancer metabolism landscape

    PubMed Central

    Anastasiou, Dimitrios

    2017-01-01

    Cancer cells exhibit metabolic alterations that distinguish them from healthy tissues and make their metabolic processes susceptible to pharmacological targeting. Although typical cell-autonomous features of cancer metabolism have been emerging, it is increasingly appreciated that extrinsic factors also influence the metabolic properties of tumours. This review highlights evidence from the recent literature to discuss how conditions within the tumour microenvironment shape the metabolic character of tumours. PMID:28006817

  15. Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles.

    PubMed

    Behling, Katja; Maguire, William F; Di Gialleonardo, Valentina; Heeb, Lukas E M; Hassan, Iman F; Veach, Darren R; Keshari, Kayvan R; Gutin, Philip H; Scheinberg, David A; McDevitt, Michael R

    2016-11-01

    Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with (225)Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by (225)Ac-E4G10. We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of (225)Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  16. Acidic microenvironment and bone pain in cancer-colonized bone

    PubMed Central

    Yoneda, Toshiyuki; Hiasa, Masahiro; Nagata, Yuki; Okui, Tatsuo; White, Fletcher A

    2015-01-01

    Solid cancers and hematologic cancers frequently colonize bone and induce skeletal-related complications. Bone pain is one of the most common complications associated with cancer colonization in bone and a major cause of increased morbidity and diminished quality of life, leading to poor survival in cancer patients. Although the mechanisms responsible for cancer-associated bone pain (CABP) are poorly understood, it is likely that complex interactions among cancer cells, bone cells and peripheral nerve cells contribute to the pathophysiology of CABP. Clinical observations that specific inhibitors of osteoclasts reduce CABP indicate a critical role of osteoclasts. Osteoclasts are proton-secreting cells and acidify extracellular bone microenvironment. Cancer cell-colonized bone also releases proton/lactate to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Thus, extracellular microenvironment of cancer-colonized bone is acidic. Acidosis is algogenic for nociceptive sensory neurons. The bone is densely innervated by the sensory neurons that express acid-sensing nociceptors. Collectively, CABP is evoked by the activation of these nociceptors on the sensory neurons innervating bone by the acidic extracellular microenvironment created by bone-resorbing osteoclasts and bone-colonizing cancer cells. As current treatments do not satisfactorily control CABP and can elicit serious side effects, new therapeutic interventions are needed to manage CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and by which the expression and function of the acid-sensing nociceptors on the sensory neurons are regulated would facilitate to develop novel therapeutic approaches for the management of CABP. PMID:25987988

  17. Probing Tumor Microenvironment with In Vivo Phage Display

    DTIC Science & Technology

    2013-07-01

    peptides may result in an efficient probe for breast tumor imaging and therapy . 15. SUBJECT TERMS Carcinoma-associated fibroblast; phage display...In Vivo Phage Display PRINCIPAL INVESTIGATOR: Dr. Erkki Ruoslahti CONTRACTING ORGANIZATION: Sanford Burnham Medical Research Institute...COVERED 01 July 2012 – 30 June 2013 4. TITLE AND SUBTITLE Probing Tumor Microenvironment with In Vivo Phage Display 5a. CONTRACT NUMBER W81XWH

  18. Probing Tumor Microenvironment with in Vivo Phage Display

    DTIC Science & Technology

    2013-07-01

    Vivo Phage Display PRINCIPAL INVESTIGATOR: Kazuki N. Sugahara, M.D., Ph.D...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Probing Tumor Microenvironment with In Vivo Phage Display 5b. GRANT NUMBER W81XWH-12-1-0174 5c...cells and the matrix. The goal of our group is to make technical improvements in our phage display system, and find peptides that target carcinoma

  19. Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation.

    PubMed

    Castillo, Eliseo F; Acero, Luis F; Stonier, Spencer W; Zhou, Dapeng; Schluns, Kimberly S

    2010-10-07

    Invariant NKT (iNKT) cells are an innate type of T cells, which respond rapidly on activation. iNKT cells acquire these innate-like abilities during development; however, the signals driving development and functional maturation remain only partially understood. Because interleukin-15 (IL-15) is crucial for iNKT development and is delivered by transpresentation, we set out to identify the cell types providing IL-15 to developing iNKT cells and determine their role at the various states of development and maturation. We report here that transpresentation of IL-15 by parenchymal cells was crucial for generating normal number of iNKTs in the thymus, whereas both hematopoietic and parenchymal cells regulated iNKT cell numbers in the periphery, particularly in the liver. Specifically, dendritic cells contributed to peripheral iNKT cell numbers by up-regulating Bcl-2 expression and promoting extrathymic iNKT cell ex-pansion and their homeostatic proliferation. Whether IL-15 affects functional maturation of iNKT cells was also examined. In IL-15Rα(-/-) mice, CD44(High)NK1.1(+) iNKT cells displayed decreased T-bet expression and in response to α-galactosylceramide, had deficient interferon-γ expression. Such defects could be reversed by exogenous IL-15 signals. Overall, these studies identify stage-specific functions of IL-15, which are determined by the tissue microenvironment and elucidate the importance of IL-15 in functional maturation.

  20. Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation

    PubMed Central

    Castillo, Eliseo F.; Acero, Luis F.; Stonier, Spencer W.; Zhou, Dapeng

    2010-01-01

    Invariant NKT (iNKT) cells are an innate type of T cells, which respond rapidly on activation. iNKT cells acquire these innate-like abilities during development; however, the signals driving development and functional maturation remain only partially understood. Because interleukin-15 (IL-15) is crucial for iNKT development and is delivered by transpresentation, we set out to identify the cell types providing IL-15 to developing iNKT cells and determine their role at the various states of development and maturation. We report here that transpresentation of IL-15 by parenchymal cells was crucial for generating normal number of iNKTs in the thymus, whereas both hematopoietic and parenchymal cells regulated iNKT cell numbers in the periphery, particularly in the liver. Specifically, dendritic cells contributed to peripheral iNKT cell numbers by up-regulating Bcl-2 expression and promoting extrathymic iNKT cell ex-pansion and their homeostatic proliferation. Whether IL-15 affects functional maturation of iNKT cells was also examined. In IL-15Rα−/− mice, CD44HighNK1.1+ iNKT cells displayed decreased T-bet expression and in response to α-galactosylceramide, had deficient interferon-γ expression. Such defects could be reversed by exogenous IL-15 signals. Overall, these studies identify stage-specific functions of IL-15, which are determined by the tissue microenvironment and elucidate the importance of IL-15 in functional maturation. PMID:20581314

  1. Monitoring changes of tumor microenvironment in colorectal submucosa using multiphoton microscopy.

    PubMed

    Qiu, Jingting; Jiang, Weizhong; Yang, Yinghong; Feng, Changyin; Chen, Zhifen; Guan, Guoxian; Zhuo, Shuangmu; Chen, Jianxin

    2015-01-01

    Recently, targeting tumor microenvironment has become a novel approach for cancer therapy. Collagen is one of important components of tissue microenvironment, and has been considered as a new visible target for cancer therapy. In this work, multiphoton microscopy (MPM) was used to monitor the changes of collagen in tumor microenvironment during tumor progression. It was found that MPM facilitates imaging of tumor cells and collagen. MPM images in different tumor microenvironment during tumor progression shows obvious increase in cell number and collagen degration. In addition, the quantitative analysis of collagen content and orientation index in tumor microenvironment shows significant alteration during tumor progression. These results suggest that MPM has the ability to monitor the changes of collagen morphology in tumor microenvironment and quantify content and orientation index of collagen during tumor progression. Therefore this technique is a powerful imaging tool for the investigation of targeting tumor microenvironment for cancer therapy. © Wiley Periodicals, Inc.

  2. Tumor microenvironment contributes to Epstein-Barr virus anti-nuclear antigen-1 antibody production in nasopharyngeal carcinoma.

    PubMed

    Ai, Ping; Li, Zhiping; Jiang, Yong; Song, Changping; Zhang, Lin; Hu, Huaizhong; Wang, Tao

    2017-08-01

    Nuclear antigen-1 (NA1) protein of Epstein-Barr virus (EBV) is expressed in EBV-infected cells in the microenvironment of cancer. Since immune cells infiltrate abundantly in nasopharyngeal carcinoma (NPC) tumor tissues, we hypothesized that the local tumor microenvironment may perform an important role in the production of antibodies directed at NA1. Furthermore, we hypothesized that anti-NA1 antibody originating in the local microenvironment could be secreted into the saliva of patients with NPC. In the present study, 20 healthy controls and 39 patients with NPC treated with intensity-modulated radiation therapy were recruited for the study. Saliva and serum samples were collected from the NPC patients, and nasopharyngeal tissue samples from the patients with NPC. The titers of anti-NA1 antibody [immunoglobulin A (IgA)] were determined by ELISA. Expression of NA1, human leukocyte antigen-antigen D related (HLA-DR), cluster of differentiation (CD)80, CD86, CD3, CD4, CD19 and IgA was detected by immunohistochemical staining on paraffin-embedded nasopharyngeal tissue sections. Anti-NA1 antibodies were detected in the serum and saliva samples of the patients with NPC. In infiltrating cells, expression of HLA-DR, CD80, CD86, CD3, CD4, CD19 and IgA was detected, indicating that dendritic cells, T lymphocytes and B lymphocytes were all present in the local tumor tissues. Furthermore, expression of EBNA1 protein was detected on the membrane of the NPC tumor cells. Therefore, the NPC tumor microenvironment has the potential to initiate a humoral response to EBNA1 by producing IgA antibodies.

  3. SECs (Sinusoidal Endothelial Cells), Liver Microenvironment, and Fibrosis

    PubMed Central

    Natarajan, Vaishaali; Harris, Edward N.

    2017-01-01

    Liver fibrosis is a wound-healing response to chronic liver injury such as alcoholic/nonalcoholic fatty liver disease and viral hepatitis with no FDA-approved treatments. Liver fibrosis results in a continual accumulation of extracellular matrix (ECM) proteins and paves the way for replacement of parenchyma with nonfunctional scar tissue. The fibrotic condition results in drastic changes in the local mechanical, chemical, and biological microenvironment of the tissue. Liver parenchyma is supported by an efficient network of vasculature lined by liver sinusoidal endothelial cells (LSECs). These nonparenchymal cells are highly specialized resident endothelial cell type with characteristic morphological and functional features. Alterations in LSECs phenotype including lack of LSEC fenestration, capillarization, and formation of an organized basement membrane have been shown to precede fibrosis and promote hepatic stellate cell activation. Here, we review the interplay of LSECs with the dynamic changes in the fibrotic liver microenvironment such as matrix rigidity, altered ECM protein profile, and cell-cell interactions to provide insight into the pivotal changes in LSEC physiology and the extent to which it mediates the progression of liver fibrosis. Establishing the molecular aspects of LSECs in the light of fibrotic microenvironment is valuable towards development of novel therapeutic and diagnostic targets of liver fibrosis. PMID:28293634

  4. Chemical and physical microenvironments at the Viking landing sites

    NASA Technical Reports Server (NTRS)

    Clark, B. C.

    1979-01-01

    Physical and chemical considerations permit the division of the near-surface regolith on Mars into at least six zones of distinct microenvironments. The zones are euphotic, duricrust/peds, tempofrost, permafrost, endolithic, and interfacial/transitional. Microenvironments vary significantly in temperature extremes, mean temperature, salt content, relative pressure of water vapor, UV and visible light irradiance, and exposure to ionizing radiation events (100 Mrad) and oxidative molecular species. From what is known of the chemistry of the atmosphere and regolith fines (soil), limits upon the aqueous chemistry of soil pastes may be estimated. Heat of wetting could reach 45 cal/g dry soil; initial pH is indeterminate between 1 and 10; ionic strength and salinity are predicted to be extremely high; freezing point depression is inadequate to provide quantities of liquid water except in special cases. The prospects for biotic survival are grim by terrestrial standards, but the extremes of biological resiliency are inaccessible to evaluation. Second-generation in situ experiments which will better define Martian microenvironments are clearly possible. Antarctic dry valleys are approximations to Martian conditions, but deviate significantly by at least half-a-dozen criteria.

  5. Precision Assembly of Complex Cellular Microenvironments using Holographic Optical Tweezers

    PubMed Central

    Kirkham, Glen R.; Britchford, Emily; Upton, Thomas; Ware, James; Gibson, Graham M.; Devaud, Yannick; Ehrbar, Martin; Padgett, Miles; Allen, Stephanie; Buttery, Lee D.; Shakesheff, Kevin

    2015-01-01

    The accurate study of cellular microenvironments is limited by the lack of technologies that can manipulate cells in 3D at a sufficiently small length scale. The ability to build and manipulate multicellular microscopic structures will facilitate a more detailed understanding of cellular function in fields such as developmental and stem cell biology. We present a holographic optical tweezers based technology to accurately generate bespoke cellular micro-architectures. Using embryonic stem cells, 3D structures of varying geometries were created and stabilized using hydrogels and cell-cell adhesion methods. Control of chemical microenvironments was achieved by the temporal release of specific factors from polymer microparticles positioned within these constructs. Complex co-culture micro-environmental analogues were also generated to reproduce structures found within adult stem cell niches. The application of holographic optical tweezers-based micromanipulation will enable novel insights into biological microenvironments by allowing researchers to form complex architectures with sub-micron precision of cells, matrices and molecules. PMID:25716032

  6. Obesity, metabolism and the microenvironment: Links to cancer

    PubMed Central

    Sundaram, Sneha; Johnson, Amy R.; Makowski, Liza

    2013-01-01

    Historically, cancer research has focused on identifying mutations or amplification of genes within the tumor, which informed the development of targeted therapies against affected pathways. This work often considers tumor cells in isolation; however, it is becoming increasingly apparent that the microenvironment surrounding tumor cells strongly influences tumor onset and progression. This is the so-called “seed and soil” hypothesis wherein the seed (cancer cell) is fed and molded by the metabolites, growth factors, modifications of the extracellular matrix or angiogenic factors provided by the soil (or stroma). Currently, 65% of the US population is obese or overweight; similarly staggering figures are reported in US children and globally. Obesity mediates and can exacerbate, both normal and tumor microenvironment dysfunction. Many obesity-associated endocrine, metabolic and inflammatory mediators are suspected to play a role in oncogenesis by modifying systemic nutrient metabolism and the nutrient substrates available locally in the stroma. It is vitally important to understand the biological processes linking obesity and cancer to develop better intervention strategies aimed at curbing the carcinogenic events associated with obesity. In this review, obesity-driven changes in both the normal and tumor microenvironment, alterations in metabolism, and release of signaling molecules such as endocrine, growth, and inflammatory mediators will be highlighted. In addition, we will discuss the effects of the timing of obesity onset or particular “windows of susceptibility,” with a focus on breast cancer etiology. PMID:24227994

  7. Composite alginate gels for tunable cellular microenvironment mechanics

    PubMed Central

    Khavari, Adele; Nydén, Magnus; Weitz, David A.; Ehrlicher, Allen J.

    2016-01-01

    The mechanics of the cellular microenvironment can be as critical as biochemistry in directing cell behavior. Many commonly utilized materials derived from extra-cellular-matrix create excellent scaffolds for cell growth, however, evaluating the relative mechanical and biochemical effects independently in 3D environments has been difficult in frequently used biopolymer matrices. Here we present 3D sodium alginate hydrogel microenvironments over a physiological range of stiffness (E = 1.85 to 5.29 kPa), with and without RGD binding sites or collagen fibers. We use confocal microscopy to measure the growth of multi-cellular aggregates (MCAs), of increasing metastatic potential in different elastic moduli of hydrogels, with and without binding factors. We find that the hydrogel stiffness regulates the growth and morphology of these cell clusters; MCAs grow larger and faster in the more rigid environments similar to cancerous breast tissue (E = 4–12 kPa) as compared to healthy tissue (E = 0.4–2 kpa). Adding binding factors from collagen and RGD peptides increases growth rates, and change maximum MCA sizes. These findings demonstrate the utility of these independently tunable mechanical/biochemistry gels, and that mechanical confinement in stiffer microenvironments may increase cell proliferation. PMID:27484403

  8. Minireview: Nuclear Receptors as Modulators of the Tumor Microenvironment

    PubMed Central

    Sherman, Mara H.; Downes, Michael; Evans, Ronald M.

    2012-01-01

    Over the past several decades of cancer research, the inherent complexity of tumors has become increasingly appreciated. In addition to acquired cell-intrinsic properties, tumor growth is supported by an abundance of parenchymal, inflammatory and stromal cell types, which infiltrate and surround the tumor. Accumulating evidence demonstrates that numerous components of this supportive milieu, referred to collectively as the tumor microenvironment, are indeed critical during the process of multistep tumorigenesis. These findings highlight the important interplay between cancer cells and tumor-associated cell types, and suggest that cancer therapy should target both neoplastic cells and supportive stromal cells to effectively attenuate tumor growth. The nuclear receptor superfamily encompasses a druggable class of molecules expressed in numerous stromal and parenchymal cell types, whose established physiologic roles suggest therapeutic potential in the context of the reactive tumor microenvironment. In this minireview, we discuss recent evidence that tumor-associated inflammation, angiogenesis, and fibrosis can be modulated at the transcriptional level by nuclear receptors and their ligands. As these processes have been widely implicated in cancer initiation, progression, and resistance to current therapy, nuclear receptors ligands targeting the tumor microenvironment may be potent antitumor agents in combination with chemotherapy. PMID:22135047

  9. The role of nerve microenvironment for neurofibroma development

    PubMed Central

    Liao, Chung-Ping; Pradhan, Sanjay; Chen, Zhiguo; Patel, Amish J.; Booker, Reid C.; Le, Lu Q.

    2016-01-01

    Deregulation of RAS signaling in Neurofibromatosis type 1 (NF1) results in the development of multiple neurofibromas, complex tumor of the peripheral nerves with no effective medical treatment. There is increasing evidences that neurofibroma initiates through loss of NF1 function in the Schwann cell lineage, followed by a cascade of interactions with other cell types in the surrounding tumor microenvironment. In NF1 patients, neurofibromas always develop along peripheral nerves and do not migrate to distant organs, including the central nervous system. In this study, we sought to identify the contributions of these peripheral nerves in neurofibroma formation. Using in vivo and in vitro three-dimensional (3D) culturing system, we show that peripheral nerves are absolutely required for neurofibroma tumorigenesis and report a novel 3D skin raft culture system for neurofibroma formation in vitro to decipher tumor pathogenesis. This interaction between neoplastic Schwann cells and their surrounding neural microenvironment has important implications for understanding early cellular events that dictate tumorigenesis. It also provides fertile ground for the elucidation of intrinsic and extrinsic factors within the nerve microenvironment that likely play essential roles in neurofibroma development and, therefore, viable therapeutic targets in neurofibroma therapy. PMID:27517146

  10. The Two Faces of IL-6 in the Tumor Microenvironment

    PubMed Central

    Fisher, Daniel T.; Appenheimer, Michelle M.; Evans, Sharon S.

    2014-01-01

    Within the tumor microenvironment, IL-6 signaling is generally considered a malevolent player, assuming a dark visage that promotes tumor progression. Chronic IL-6 signaling is linked to tumorigenesis in numerous mouse models as well as in human disease. IL-6 acts intrinsically on tumor cells through numerous downstream mediators to support cancer cell proliferation, survival, and metastatic dissemination. Moreover, IL-6 can act extrinsically on other cells within the complex tumor microenvironment to sustain a pro-tumor milieu by supporting angiogenesis and tumor evasion of immune surveillance. A lesser known role for IL-6 signaling has recently emerged in which it plays a beneficial role, presenting a fairer face that opposes tumor growth by mobilizing anti-tumor T cell immune responses to attain tumor control. Accumulating evidence establishes IL-6 as a key player in the activation, proliferation and survival of lymphocytes during active immune responses. IL-6 signaling can also resculpt the T cell immune response, shifting it from a suppressive to a responsive state that can effectively act against tumors. Finally, IL-6 plays an indispensable role in boosting T cell trafficking to lymph nodes and to tumor sites, where they have the opportunity to become activated and execute their cytotoxic effector functions, respectively. Here, we discuss the dual faces of IL-6 signaling in the tumor microenvironment; the dark face that drives malignancy, and the fairer aspect that promotes anti-tumor adaptive immunity. PMID:24602448

  11. The effects of CA IX catalysis products within tumor microenvironment.

    PubMed

    Santi, Alice; Caselli, Anna; Paoli, Paolo; Corti, Denise; Camici, Guido; Pieraccini, Giuseppe; Taddei, Maria Letizia; Serni, Sergio; Chiarugi, Paola; Cirri, Paolo

    2013-10-29

    Solid tumors are composed of both cancer cells and various types of accessory cells, mainly fibroblasts, that collectively compose the so called tumor-microenvironment. Cancer-associated fibroblasts have been described to actively participate in cancer progression by establishing a cytokine-mediated as well as metabolic crosstalk with cancer cells. In the present paper we show that activated human fibroblasts are able to boost tumor cells proliferation and that this effect is greatly dependent on stromal carbonic anhydrase IX (CA IX) activity. In fact fibroblasts show a strong upregulation of CA IX expression upon activation by cancer cells, while CA IX products, protons and bicarbonate, exert differential effects on cancer cells proliferation. While acidification of extracellular pH, a typical condition of rapidly growing solid tumors, is detrimental for tumor cells proliferation, bicarbonate, through its organication, supplies cancer cells with intermediates useful to sustain their high proliferation rate. Here we propose a new kind of fibroblasts/tumor cells crosstalk within tumor microenvironment, mediated by stromal CA IX products, aimed to favor cancer cells growth, opening new perspectives on CA IX role in tumor microenvironment.

  12. Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments.

    PubMed

    Cipitria, Amaia; Salmeron-Sanchez, Manuel

    2017-08-01

    Engineering cellular microenvironments involves biochemical factors, the extracellular matrix (ECM) and the interaction with neighbouring cells. This progress report provides a critical overview of key studies that incorporate growth factor (GF) signalling and mechanotransduction into the design of advanced microenvironments. Materials systems have been developed for surface-bound presentation of GFs, either covalently tethered or sequestered through physico-chemical affinity to the matrix, as an alternative to soluble GFs. Furthermore, some materials contain both GF and integrin binding regions and thereby enable synergistic signalling between the two. Mechanotransduction refers to the ability of the cells to sense physical properties of the ECM and to transduce them into biochemical signals. Various aspects of the physics of the ECM, i.e. stiffness, geometry and ligand spacing, as well as time-dependent properties, such as matrix stiffening, degradability, viscoelasticity, surface mobility as well as spatial patterns and gradients of physical cues are discussed. To conclude, various examples illustrate the potential for cooperative signalling of growth factors and the physical properties of the microenvironment for potential applications in regenerative medicine, cancer research and drug testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight

    PubMed Central

    Savaskan, Nicolai E.; Fan, Zheng; Broggini, Thomas; Buchfelder, Michael; Eyüpoglu, Ilker Y.

    2015-01-01

    Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets. PMID:26411769

  14. Molecular targeting of liposomal nanoparticles to tumor microenvironment

    PubMed Central

    Zhao, Gang; Rodriguez, B Leticia

    2013-01-01

    Liposomes are biodegradable and can be used to deliver drugs at a much higher concentration in tumor tissues than in normal tissues. Both passive and active drug delivery by liposomal nanoparticles can significantly reduce the toxic side effects of anticancer drugs and enhance the therapeutic efficacy of the drugs delivered. Active liposomal targeting to tumors is achieved by recognizing specific tumor receptors through tumor-specific ligands or antibodies coupled onto the surface of the liposomes, or by stimulus-sensitive drug carriers such as acid-triggered release or enzyme-triggered drug release. Tumors are often composed of tumor cells and nontumor cells, which include endothelial cells, pericytes, fibroblasts, stromal, mesenchymal cells, innate, and adaptive immune cells. These nontumor cells thus form the tumor microenvironment, which could be targeted and modified so that it is unfavorable for tumor cells to grow. In this review, we briefly summarized articles that had taken advantage of liposomal nanoparticles as a carrier to deliver anticancer drugs to the tumor microenvironment, and how they overcame obstacles such as nonspecific uptake, interaction with components in blood, and toxicity. Special attention is devoted to the liposomal targeting of anticancer drugs to the endothelium of tumor neovasculature, tumor associated macrophages, fibroblasts, and pericytes within the tumor microenvironment. PMID:23293520

  15. Chemical and physical microenvironments at the Viking landing sites.

    PubMed

    Clark, B C

    1979-12-01

    Physical and chemical considerations permit the division of the near-surface regolith on Mars into at least six zones of distinct microenvironments. The zones are euphotic, duricrust/peds, tempofrost, permafrost, endolithic, and interfacial/transitional. Microenvironments vary significantly in temperature extremes, mean temperature, salt content, relative pressure of water vapor, UV and visible light irradiance, and exposure to ionizing radiation events (100 Mrad) and oxidative molecular species. From what is known of the chemistry of the atmosphere and regolith fines (soil), limits upon the aqueous chemistry of soil pastes may be estimated. Heat of wetting could reach 45 cal/g dry soil; initial pH is indeterminate between 1 and 10; ionic strength and salinity are predicted to be extremely high; freezing point depression is inadequate to provide quantities of liquid water except in special cases. The prospects for biotic survival are grim by terrestrial standards, but the extremes of biological resiliency are inaccessible to evaluation. Second-generation in situ experiments which will better define Martian microenvironments are clearly possible. Antarctic dry valleys are approximations to Martian conditions, but deviate significantly by at least half-a-dozen criteria.

  16. Current Multistage Drug Delivery Systems Based on the Tumor Microenvironment

    PubMed Central

    Chen, Binlong; Dai, Wenbing; He, Bing; Zhang, Hua; Wang, Xueqing; Wang, Yiguang; Zhang, Qiang

    2017-01-01

    The development of traditional tumor-targeted drug delivery systems based on EPR effect and receptor-mediated endocytosis is very challenging probably because of the biological complexity of tumors as well as the limitations in the design of the functional nano-sized delivery systems. Recently, multistage drug delivery systems (Ms-DDS) triggered by various specific tumor microenvironment stimuli have emerged for tumor therapy and imaging. In response to the differences in the physiological blood circulation, tumor microenvironment, and intracellular environment, Ms-DDS can change their physicochemical properties (such as size, hydrophobicity, or zeta potential) to achieve deeper tumor penetration, enhanced cellular uptake, timely drug release, as well as effective endosomal escape. Based on these mechanisms, Ms-DDS could deliver maximum quantity of drugs to the therapeutic targets including tumor tissues, cells, and subcellular organelles and eventually exhibit the highest therapeutic efficacy. In this review, we expatiate on various responsive modes triggered by the tumor microenvironment stimuli, introduce recent advances in multistage nanoparticle systems, especially the multi-stimuli responsive delivery systems, and discuss their functions, effects, and prospects. PMID:28255348

  17. Composite alginate gels for tunable cellular microenvironment mechanics

    NASA Astrophysics Data System (ADS)

    Khavari, Adele; Nydén, Magnus; Weitz, David A.; Ehrlicher, Allen J.

    2016-08-01

    The mechanics of the cellular microenvironment can be as critical as biochemistry in directing cell behavior. Many commonly utilized materials derived from extra-cellular-matrix create excellent scaffolds for cell growth, however, evaluating the relative mechanical and biochemical effects independently in 3D environments has been difficult in frequently used biopolymer matrices. Here we present 3D sodium alginate hydrogel microenvironments over a physiological range of stiffness (E = 1.85 to 5.29 kPa), with and without RGD binding sites or collagen fibers. We use confocal microscopy to measure the growth of multi-cellular aggregates (MCAs), of increasing metastatic potential in different elastic moduli of hydrogels, with and without binding factors. We find that the hydrogel stiffness regulates the growth and morphology of these cell clusters; MCAs grow larger and faster in the more rigid environments similar to cancerous breast tissue (E = 4–12 kPa) as compared to healthy tissue (E = 0.4–2 kpa). Adding binding factors from collagen and RGD peptides increases growth rates, and change maximum MCA sizes. These findings demonstrate the utility of these independently tunable mechanical/biochemistry gels, and that mechanical confinement in stiffer microenvironments may increase cell proliferation.

  18. Chemical and physical microenvironments at the Viking landing sites

    NASA Technical Reports Server (NTRS)

    Clark, B. C.

    1979-01-01

    Physical and chemical considerations permit the division of the near-surface regolith on Mars into at least six zones of distinct microenvironments. The zones are euphotic, duricrust/peds, tempofrost, permafrost, endolithic, and interfacial/transitional. Microenvironments vary significantly in temperature extremes, mean temperature, salt content, relative pressure of water vapor, UV and visible light irradiance, and exposure to ionizing radiation events (100 Mrad) and oxidative molecular species. From what is known of the chemistry of the atmosphere and regolith fines (soil), limits upon the aqueous chemistry of soil pastes may be estimated. Heat of wetting could reach 45 cal/g dry soil; initial pH is indeterminate between 1 and 10; ionic strength and salinity are predicted to be extremely high; freezing point depression is inadequate to provide quantities of liquid water except in special cases. The prospects for biotic survival are grim by terrestrial standards, but the extremes of biological resiliency are inaccessible to evaluation. Second-generation in situ experiments which will better define Martian microenvironments are clearly possible. Antarctic dry valleys are approximations to Martian conditions, but deviate significantly by at least half-a-dozen criteria.

  19. Combination cancer immunotherapies tailored to the tumour microenvironment.

    PubMed

    Smyth, Mark J; Ngiow, Shin Foong; Ribas, Antoni; Teng, Michele W L

    2016-03-01

    Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many patients with many cancer types in the near future. There are many types of immune processes involving different antitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade the immune response. The tumour microenvironment can help determine which immune suppressive pathways become activated to restrain antitumour immunity. This includes immune checkpoint receptors on effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeutic approaches that target these pathways, particularly immune-checkpoint receptors, can induce durable antitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, many patients do not have a good response to monotherapy approaches and alternative strategies are required to achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells to provoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhance APC function, and using agents that enhance effector-cell activity. In this Review, we discuss the stratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1 expression in the tumour, and how this stratification enables the design of optimal combination cancer therapies tailored to target different tumour microenvironments.

  20. Tumor microenvironment-mediated chemoresistance in breast cancer.

    PubMed

    Velaei, Kobra; Samadi, Nasser; Barazvan, Balal; Soleimani Rad, Jafar

    2016-12-01

    Therapy resistance or tumor relapse in cancer is common. Tumors develop resistance to chemotherapeutic through a variety of mechanisms, with tumor microenvironment (TM) serving pivotal roles. Using breast cancer as a paradigm, we propose that responses of cancer cells to drugs are not exclusively determined by their intrinsic characteristics but are also controlled by deriving signals from TM. Affected microenvironment by chemotherapy is an avenue to promote phenotype which tends to resist on to be ruined. Therefore, exclusively targeting cancer cells does not demolish tumor recurrence after chemotherapy. Regardless of tumor-microenvironment pathways and their profound influence on the responsiveness of treatment, diversity of molecular properties of breast cancer also behave differently in terms of response to chemotherapy. And also it is assumed that there is cross-talk between phenotypic diversity and TM. Collectively, raising complex signal from TM in chemotherapy condition often encourages cancer cells are not killed but strengthen. Here, we summarized how TM modifies responses to chemotherapy in breast cancer. We also discussed successful treatment strategies have been considered TM in breast cancer treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Role of the Microenvironment in Ovarian Cancer Stem Cell Maintenance

    PubMed Central

    Pasquier, Jennifer; Rafii, Arash

    2013-01-01

    Despite recent progresses in cancer therapy and increased knowledge in cancer biology, ovarian cancer remains a challenging condition. Among the latest concepts developed in cancer biology, cancer stem cells and the role of microenvironment in tumor progression seem to be related. Indeed, cancer stem cells have been described in several solid tumors including ovarian cancers. These particular cells have the ability to self-renew and reconstitute a heterogeneous tumor. They are characterized by specific surface markers and display resistance to therapeutic regimens. During development, specific molecular cues from the tumor microenvironment can play a role in maintaining and expanding stemness of cancer cells. The tumor stroma contains several compartments: cellular component, cytokine network, and extracellular matrix. These different compartments interact to form a permissive niche for the cancer stem cells. Understanding the molecular cues underlying this crosstalk will allow the design of new therapeutic regimens targeting the niche. In this paper, we will discuss the mechanisms implicated in the interaction between ovarian cancer stem cells and their microenvironment. PMID:23484135

  2. Precision assembly of complex cellular microenvironments using holographic optical tweezers.

    PubMed

    Kirkham, Glen R; Britchford, Emily; Upton, Thomas; Ware, James; Gibson, Graham M; Devaud, Yannick; Ehrbar, Martin; Padgett, Miles; Allen, Stephanie; Buttery, Lee D; Shakesheff, Kevin

    2015-02-26

    The accurate study of cellular microenvironments is limited by the lack of technologies that can manipulate cells in 3D at a sufficiently small length scale. The ability to build and manipulate multicellular microscopic structures will facilitate a more detailed understanding of cellular function in fields such as developmental and stem cell biology. We present a holographic optical tweezers based technology to accurately generate bespoke cellular micro-architectures. Using embryonic stem cells, 3D structures of varying geometries were created and stabilized using hydrogels and cell-cell adhesion methods. Control of chemical microenvironments was achieved by the temporal release of specific factors from polymer microparticles positioned within these constructs. Complex co-culture micro-environmental analogues were also generated to reproduce structures found within adult stem cell niches. The application of holographic optical tweezers-based micromanipulation will enable novel insights into biological microenvironments by allowing researchers to form complex architectures with sub-micron precision of cells, matrices and molecules.

  3. Intraportal islet transplantation: the impact of the liver microenvironment.

    PubMed

    Delaune, Vaihere; Berney, Thierry; Lacotte, Stéphanie; Toso, Christian

    2017-03-01

    The portal vein remains the preferred site for pancreatic islet transplantation due to its easy access and low morbidity. However, despite great progress in isolation and transplantation protocols over the past few years, it is still associated with the early loss of some 50-70% of transplanted islets. The complex liver microenvironment itself presumably plays an important role in this loss. The present review focuses on the specifics of the liver microenvironment, notably the localized hepatic ischemia/reperfusion injury following transplantation, the low oxygenation of the portal vein, the instant blood-mediated inflammatory reaction, the endogenous liver immune system, and the gut-liver axis, and how they can each have an impact on the transplanted islets. It identifies the potential, or already applied, clinical interventions for improving intraportal islet survival, and pinpoints those promising areas still lacking preclinical research. Future interventions on clinical intraportal islet transplantation need to take into account the global context of the liver microenvironment, with multi-point interventions being most likely to improve early islet survival and engraftment. © 2017 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

  4. Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells.

    PubMed

    Huang, Yu-Ja; Hoffmann, Gwendolyn; Wheeler, Benjamin; Schiapparelli, Paula; Quinones-Hinojosa, Alfredo; Searson, Peter

    2016-02-22

    Galvanotaxis is a complex process that represents the collective outcome of various contributing mechanisms, including asymmetric ion influxes, preferential activation of voltage-gated channels, and electrophoretic redistribution of membrane components. While a large number of studies have focused on various up- and downstream signaling pathways, little is known about how the surrounding microenvironment may interact and contribute to the directional response. Using a customized galvanotaxis chip capable of carrying out experiments in both two- and three-dimensional microenvironments, we show that cell-extracellular matrix (ECM) interactions modulate the galvanotaxis of brain tumor initiating cells (BTICs). Five different BTICs across three different glioblastoma subtypes were examined and shown to all migrate toward the anode in the presence of a direct-current electric field (dcEF) when cultured on a poly-L-ornithine/laminin coated surface, while the fetal-derived neural progenitor cells (fNPCs) migrated toward the cathode. Interestingly, when embedded in a 3D ECM composed of hyaluronic acid and collagen, BTICs exhibited opposite directional response and migrated toward the cathode. Pharmacological inhibition against a panel of key molecules involved in galvanotaxis further revealed the mechanistic differences between 2- and 3D galvanotaxis in BTICs. Both myosin II and phosphoinositide 3-kinase (PI3K) were found to hold strikingly different roles in different microenvironments.

  5. Impact of tumor microenvironment on oncolytic viral therapy

    PubMed Central

    Wojton, Jeffrey; Kaur, Balveen

    2010-01-01

    Interactions between tumor cells and their microenvironment have been shown to play a very significant role in the initiation, progression, and invasiveness of cancer. These tumor-stromal interactions are capable of altering the delivery and effectiveness of therapeutics into the tumor and are also known to influence future resistance and re-growth after treatment. Here we review recent advances in the understanding of the tumor microenvironment and its response to oncolytic viral therapy. The multifaceted environmental response to viral therapy can influence viral infection, replication, and propagation within the tumor. Recent studies have unveiled the complicated temporal changes in the tumor vasculature post OV treatment, and their impact on tumor biology. Similarly, the secreted extracellular matrix in solid tumors can affect both infection and spread of the therapeutic virus. Together, these complex changes in the tumor microenvironment also modulate the activation of the innate antiviral host immune response, leading to quick and efficient viral clearance. In order to combat these detrimental responses, viruses have been combined with pharmacological adjuvants and “armed” with therapeutic genes in order to suppress the pernicious environmental conditions following therapy. In this review we will discuss the impact of the tumor environment on viral therapy and examine some of the recent literature investigating methods of modulating this environment to enhance oncolysis. PMID:20399700

  6. Epigenetic regulation of hematopoietic stem cell aging

    SciTech Connect

    Beerman, Isabel

    2014-12-10

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.

  7. [Pegfilgrastim in hematopoietic stem cell transplantation].

    PubMed

    Fernández Alvarez, R

    2010-12-01

    Pegylation implies progress in filgrastim therapy. The addition of one molecule of polyethylene glycol (PEG) increases the drug's half-life by reducing renal excretion. A single dose of pegfilgrastim is equivalent to a daily administration of G-CSF for recovering from neutropenia after cancer chemotherapy. Pegfilgrastim is also useful to mobilize hematopoietic stem cells. Several studies have researched its efficacy in this context, in patients with myeloma or lymphoma. Outcomes suggest that it has an efficacy similar to daily G-CSF. In allogeneic donors, a single 12-mg dose of pegfilgrastim produces sufficient increase of CD34+ in peripheral blood, with acceptable toxicity. There is interest on the data about the various functional and biologic properties of hematopoietic stem cells mobilized with pegfilgrastim compared to G-CSF, and on the effect that these differences may have on the graft composition. The administration of a single dose of pegfilgrastim after autologous transplantation has been shown to shorten the time for leukocyte recovery in a manner similar to G-CSF

  8. The biology of hematopoietic stem cells.

    PubMed

    Szilvassy, Stephen J

    2003-01-01

    Rarely has so much interest from the lay public, government, biotechnology industry, and special interest groups been focused on the biology and clinical applications of a single type of human cell as is today on stem cells, the founder cells that sustain many, if not all, tissues and organs in the body. Granting organizations have increasingly targeted stem cells as high priority for funding, and it appears clear that the evolving field of tissue engineering and regenerative medicine will require as its underpinning a thorough understanding of the molecular regulation of stem cell proliferation, differentiation, self-renewal, and aging. Despite evidence suggesting that embryonic stem (ES) cells might represent a more potent regenerative reservoir than stem cells collected from adult tissues, ethical considerations have redirected attention upon primitive cells residing in the bone marrow, blood, brain, liver, muscle, and skin, from where they can be harvested with relative sociological impunity. Among these, it is arguably the stem and progenitor cells of the mammalian hematopoietic system that we know most about today, and their intense study in rodents and humans over the past 50 years has culminated in the identification of phenotypic and molecular genetic markers of lineage commitment and the development of functional assays that facilitate their quantitation and prospective isolation. This review focuses exclusively on the biology of hematopoietic stem cells (HSCs) and their immediate progeny. Nevertheless, many of the concepts established from their study can be considered fundamental tenets of an evolving stem cell paradigm applicable to many regenerating cellular systems.

  9. Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

    PubMed Central

    Dickinson, Anne M.; Norden, Jean; Li, Shuang; Hromadnikova, Ilona; Schmid, Christoph; Schmetzer, Helga; Jochem-Kolb, Hans

    2017-01-01

    The success of hematopoietic stem cell transplantation (HSCT) lies with the ability of the engrafting immune system to remove residual leukemia cells via a graft-versus-leukemia effect (GvL), caused either spontaneously post-HSCT or via donor lymphocyte infusion. GvL effects can also be initiated by allogenic mismatched natural killer cells, antigen-specific T cells, and activated dendritic cells of leukemic origin. The history and further application of this GvL effect and the main mechanisms will be discussed and reviewed in this chapter. PMID:28638379

  10. Drug hypersensitivity reactions during hematopoietic stem cell transplantation.

    PubMed

    Bircher, Andreas J; Scherer Hofmeier, Kathrin

    2012-01-01

    Drugs may elicit a considerable variety of clinical signs, often affecting the skin and the mucous membranes. The most common are maculopapular exanthema, urticaria and angioedema. More rarely pustular, vesiculobullous, vasculitic and lichenoid lesions may be observed. Apart from the morphology, also the chronology of the occurrence and the evolution of the single skin lesions and the exanthema are paramount in the clinical diagnosis. Often, the skin is the only affected organ; however, it may herald a systemic involvement of internal organs, such as in severe drug-induced hypersensitivity syndromes or anaphylaxis. Cutaneous manifestations, particularly maculopapular exanthemas have a high incidence among patients treated with hematopoietic stem cell transplantation. In many cases, a virus- or drug-induced origin or a combination of both is responsible. However, the transplantation itself may also induce similar skin changes. These exanthemas include most often graft-versus-host disease, and rarely engraftment syndrome or eruption of lymphocyte recovery. The elucidation of the underlying cause of the exanthemas occurring in immune compromised patients and the determination of the correct diagnosis remain challenging. An extensive differential diagnosis has to be put forward. This includes several groups of disorders with sometimes very similar cutaneous manifestations. Manifestations form the underlying disease, complications from therapy, infections and drug reactions are the most common differential diagnoses.

  11. Hematopoietic stem cell transplantation for auto immune rheumatic diseases

    PubMed Central

    Ramaswamy, Subramanian; Jain, Sandeep; Ravindran, Vinod

    2016-01-01

    Stem cells have their origins in the embryo and during the process of organogenesis, these differentiate into specialized cells which mature to form tissues. In addition, stem cell are characterized by an ability to indefinitely self renew. Stem cells are broadly classified into embryonic stem cells and adult stem cells. Adult stem cells can be genetically reprogrammed to form pluripotent stem cells and exist in an embroyonic like state. In the early phase of embryogenesis, human embryonic stem cells only exist transiently. Adult stem cells are omnipresent in the body and function to regenerate during the process of apoptosis or tissue repair. Hematopoietic stem cells (HSC) are adult stem cells that form blood and immune cells. Autoimmune responses are sustained due to the perennial persistence of tissue self autoantigens and/or auto reactive lymphocytes. Immune reset is a process leading to generation of fresh self-tolerant lymphocytes after chemotherapy induced elimination of self or autoreactive lymphocytes. This forms the basis for autologous HSC transplantation (HSCT). In the beginning HSCT had been limited to refractory autoimmune rheumatic diseases (AIRD) due to concern about transplant related mortality and morbidity. However HSCT for AIRD has come a long way with better understanding of patient selection, conditioning regime and supportive care. In this narrative review we have examined the available literature regarding the HSCT use in AIRD. PMID:27011918

  12. Pleiotrophin mediates hematopoietic regeneration via activation of RAS.

    PubMed

    Himburg, Heather A; Yan, Xiao; Doan, Phuong L; Quarmyne, Mamle; Micewicz, Eva; McBride, William; Chao, Nelson J; Slamon, Dennis J; Chute, John P

    2014-11-01

    Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice,