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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. [Hematopoietic microenvironment: cellular and extracellular matrix elements].

    PubMed

    Minguell, J J; Fernández, M; Tetas, M; Martínez, J; Bruzzone, M; Rodríguez, J P

    1988-06-01

    In bone marrow, cellular stroma together with extracellular matrix (EM) provide an adequate microenvironment for the proliferation and differentiation of hemopoietic progenitor cells. In this article we describe studies on the cell characteristics of a main stromal phenotype, a fibroblast-like cell and its ability to produce in vitro EM components. Comparative studies were performed in fibroblast cultures derived from normal and acute lymphoblastic leukemic (ALL) bone marrow. The grow characteristics of fibroblasts from ALL marrow as well as its capacity to synthetize collagen, fibronectin and GAGs are impaired when compared to fibroblast from normal marrow. Thus, in ALL the impaired production of EM biomolecules by a transient damaged population of stromal cells, may contribute to the development of a defective microenvironment for hemopoiesis. PMID:3154858

  3. Minireview: Complexity of Hematopoietic Stem Cell Regulation in the Bone Marrow Microenvironment

    PubMed Central

    Hoffman, Corey M.

    2014-01-01

    Hematopoiesis in vertebrates is sustained over the duration of an organism's lifetime due to strict regulation of the highly hierarchical hematopoietic system, where a few immature hematopoietic stem cells (HSCs) continuously regenerate the entire blood supply, which is constantly being replaced. Although HSCs self-regulate through cell-autonomous processes, they also receive a variety of signals from their microenvironment or niche. Within the microenvironment, HSCs are regulated through both cell-cell interactions and secreted signals, including hormones. HSCs at the apex of the blood supply integrate these signals to produce progeny to support hematopoiesis while simultaneously maintaining a stem cell pool. In the past 10 years, advances in genetic models and flow cytometry have provided the tools to test how the microenvironment regulates HSCs. This review is organized in 3 main parts and will focus on cellular components of the HSC niche that are potential targets for hormonal signals, then review critical regulatory signals in the HSC niche, and finally highlight the emerging role of hormonal and paracrine signals in the bone marrow. PMID:25083740

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

    PubMed

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

    2015-09-01

    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

  5. 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

  6. 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

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

    PubMed

    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

  8. Quantitative Imaging of Hematopoietic Stem and Progenitor Cell localization and hypoxic status in the Bone Marrow microenvironment

    PubMed Central

    Nombela-Arrieta, César; Pivarnik, Gregory; Winkel, Beatrice; Canty, Kimberly J.; Harley, Brendan; Mahoney, John E.; Park, Shin-Young; Lu, Jiayun; Protopopov, Alexei; Silberstein, Leslie E.

    2014-01-01

    The existence of a hematopoietic stem cell niche as a spatially confined regulatory entity relies on the notion that hematopoietic stem and progenitor cells (HSPCs) are strategically positioned in unique bone marrow (BM) microenvironments with defined anatomical and functional features. Here, we employ a powerful imaging cytometry platform to perform a comprehensive quantitative analysis of HSPC distribution in BM cavities of femoral bones. We find that HSPCs preferentially localize in endosteal zones, where the majority closely interacts with sinusoidal and non-sinusoidal BM microvessels, which form a distinctive circulatory system. In situ tissue analysis reveals that HSPCs exhibit a hypoxic profile, defined by strong retention of pimonidazole and expression of HIF-1α, regardless of localization throughout the BM, adjacency to vascular structures or cell cycle status. These studies argue that the characteristic hypoxic state of HSPCs is not solely the result of a minimally oxygenated niche but may be partially regulated by cell-specific mechanisms. PMID:23624405

  9. The construction of an in vitro three-dimensional hematopoietic microenvironment for mouse bone marrow cells employing porous carriers.

    PubMed

    Tomimori, Y; Takagi, M; Yoshida, T

    2000-10-01

    Spatial development of mouse bone marrow cellsemploying porous carriers was investigated in order todesign a bioreactor with a three-dimensionalhematopoietic microenvironment. Three types of porouscarriers were used for examining the spatialdevelopment of anchorage-dependent primary stromalcells as feeder cells. Stromal cells were found tospread well at a high density on a polyester nonwovendisc carrier (Fibra cel (FC)) under a scanningelectron microscope, while cells on porous cellulosebeads (Microcube (MC), 500 mum pore diameter)spread at a low density; cells on another type ofcellulose porous beads (CPB, 100 mum pore diameter)were globular. Mouse bone marrow cells wereinoculated to dishes containing three types of porouscarriers which shared more than 30% of the bottomsurface in a dish. The concentration of stromal cellsin the well containing FC was lower than that on theother two carriers. However, the weekly output oftotal hematopoietic cell (suspension cells) increasedbetween day 21 and 28 in the culture using FC while itdecreased monotonously in the cultures by use of theother two carriers. The proportion of progenitorcells (BFU-E, CFU-GM) in the total hematopoietic cellpopulation, after showing an initial decrease,increased after 1 week in the culture using FC whilethe proportion decreased monotonously to zero in thecultures using MC and CPB. PMID:19003386

  10. 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.

  11. [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. PMID:26117052

  12. Specially modified stromal and immune microenvironment in injected bone marrow following intrabone transplantation facilitates allogeneic hematopoietic stem cell engraftment.

    PubMed

    Chen, Chen; Su, Yingjun; Chen, Jianwu; Song, Yajuan; Zhuang, Ran; Xiao, Bo; Guo, Shuzhong

    2016-07-01

    For allogeneic hematopoietic stem cell transplantation (HSCT), the first key step is the engraftment of hematopoietic stem cells (HSCs) across the major histocompatibility complex (MHC) barrier. Intrabone bone marrow transplantation (IBBMT) could replace more recipient stromal cells with donor cells and facilitate allogeneic organ transplantation compared with the conventional intravenous approach. However, it remains unknown whether and how IBBMT reconstructs the immune microenvironment for allogeneic HSCs. We explored where the BM microenvironment changes by determining BM stromal cell chimerism and measuring the change in CXCL-12 expression and regulatory T cells in recipient BM. We found that most stromal cells were replaced by allogeneic cells in the injected BM, with higher expression of immune regulatory cytokines (interleukin-10) compared with the contralateral BM and the intravenous group BM. This difference was independent of injury caused by intrabone injection. Consistent with the microenvironment modification, the allogeneic the engraftment rate and reconstitution capacity of HSCs were enhanced in the injected BM compared with the contralateral BM and intravenous group BM. Surgical removal of the injected bone at 7 days rather than 21 days reduced the levels of allogeneic granulocytes and HSCs in the peripheral blood. In conclusion, IBBMT specially modifies stromal cells in the injected BM which provide immune protective cues that improve the engraftment of allogeneic HSCs in an early period. PMID:27090963

  13. Increased Type 1 Immune Response in the Bone Marrow Immune Microenvironment of Patients with Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Wang, Yu-Tong; Kong, Yuan; Song, Yang; Han, Wei; Zhang, Yuan-Yuan; Zhang, Xiao-Hui; Chang, Ying-Jun; Jiang, Zheng-Fan; Huang, Xiao-Jun

    2016-08-01

    Poor graft function (PGF) is a severe complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The question of whether the bone marrow (BM) immune microenvironment is involved in the pathogenesis of PGF remains unresolved. In total, 10 patients with PGF, 30 matched patients with good graft function after allo-HSCT, and 15 healthy donors were enrolled in this nested case-control study. The Th1, Th2, Tc1, Tc2, and active phenotypes were analyzed by flow cytometry. IFN-γ and IL-4 levels in BM plasma were evaluated using cytometric beads assay. Relative to other subjects, patients with PGF had significantly higher proportions of stimulated CD4(+) and CD8(+) T cells that produced IFN-γ (Th1 and Tc1 cells) but notably decreased proportions of IL-4-producing T cells (Th2 and Tc2 cells), resulting in a shift of the IFN-γ/IL-4 ratio towards a type 1 response and an elevated percentage of activated CD8(+) T cells. Changes in IFN-γ and IL-4 levels in BM plasma were consistent with the cellular results. Our results suggest that dysregulated T cell responses may contribute to the occurrence of PGF after HSCT. PMID:27131864

  14. Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas

    PubMed Central

    Le, Lu Q.; Shipman, Tracey; Burns, Dennis K.; Parada, Luis F.

    2009-01-01

    SUMMARY The tumor predisposition disorder Neurofibromatosis type I (NF1) is one of the most common genetic disorders of the nervous system. It is caused by mutation in the Nf1 tumor suppressor gene, which encodes a GTPase Activating Protein (GAP) that negatively regulates p21-RAS. The development of malignant nerve tumors and neurofibromas, the most frequent tumors in NF1, is a serious complication of the disease. However, little is known about the molecular mechanisms mediating the initiation and progression of these complex tumors, as well as the identity of the specific cell type that gives rise to dermal or cutaneous neurofibromas. In this study, we identify a population of stem/progenitor cells residing in the dermis termed Skin Derived Precursors (SKPs) that, through loss of Nf1, form neurofibromas. We propose that SKPs, or their derivatives, are the cell of origin of dermal neurofibroma. We also provide evidence that additional signals from the non-neoplastic cells in the tumor microenvironment play essential roles in neurofibromagenesis. PMID:19427294

  15. 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

  16. 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

  17. Breast cancer cells compete with hematopoietic stem and progenitor cells for intercellular adhesion molecule 1-mediated binding to the bone marrow microenvironment.

    PubMed

    Dhawan, Abhishek; Friedrichs, Jens; Bonin, Malte von; Bejestani, Elham Peshali; Werner, Carsten; Wobus, Manja; Chavakis, Triantafyllos; Bornhäuser, Martin

    2016-08-01

    Adhesion-based cellular interactions involved in breast cancer metastasis to the bone marrow remain elusive. We identified that breast cancer cells directly compete with hematopoietic stem and progenitor cells (HSPCs) for retention in the bone marrow microenvironment. To this end, we established two models of competitive cell adhesion-simultaneous and sequential-to study a potential competition for homing to the niche and displacement of the endogenous HSPCs upon invasion by tumor cells. In both models, breast cancer cells but not non-tumorigenic cells competitively reduced adhesion of HSPCs to bone marrow-derived mesenchymal stromal cells (MSCs) in a tumor cell number-dependent manner. Higher adhesive force between breast cancer cells and MSCs, as compared with HSPCs, assessed by quantitative atomic force microscopy-based single-cell force spectroscopy could partially account for tumor cell mediated reduction in HSPC adhesion to MSCs. Genetic inactivation and blockade studies revealed that homophilic interactions between intercellular adhesion molecule 1 (ICAM-1) expressed on tumor cells and MSCs, respectively, regulate the competition between tumor cells and HSPCs for binding to MSCs. Moreover, tumor cell-secreted soluble ICAM-1(sICAM-1) also impaired HSPC adhesion via blocking CD18-ICAM-1 binding between HSPCs and MSCs. Xenotransplantation studies in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice revealed reduction of human HSPCs in the bone marrow via metastatic breast cancer cells. These findings point to a direct competitive interaction between disseminated breast cancer cells and HSPCs within the bone marrow micro environment. This interaction might also have implications on niche-based tumor support. Therefore, targeting this cross talk may represent a novel therapeutic strategy. PMID:27207667

  18. Characterization of purified intraembryonic hematopoietic stem cells as a tool to define their site of origin

    PubMed Central

    Bertrand, Julien Y.; Giroux, Sébastien; Golub, Rachel; Klaine, Michèle; Jalil, Abdelali; Boucontet, Laurent; Godin, Isabelle; Cumano, Ana

    2005-01-01

    Little is known about hematopoietic stem cell (HSC) development from mesoderm. To gain more information on the intraembryonic HSC site of origin, we purified multipotent hematopoietic progenitors from the aorta–gonads–mesonephros (AGM) of mice. This population, expressing c-Kit, AA4.1, CD31, and CD41, but not Flk1, and mainly negative for CD45, proved capable of long-term reconstitution in sublethally irradiated Rag2γc-/- recipients. We assigned the expression of GATA-2, GATA-3, and lmo2 to AGM-HSC, whereas erythromyeloid progenitors express only GATA-2. This unique combination of surface markers and transcription factors could be allocated in the AGM to the intraaortic clusters and the subaortic patches underlying aortic endothelial cells. Taken together, those data indicate that embryonic HSCs (i) differ from their fetal liver and adult counterpart by the low expression of CD45, (ii) do not colocalize with aortic endothelial cells as previously thought, and (iii) are localized, at 10.5 days postcoïtum, in the splanchnic mesoderm underlying aortic endothelial cells, within GATA-3+CD31+ cell clusters. PMID:15623562

  19. Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

    SciTech Connect

    Corcelle, V.; Stieger, B.; Gjinovci, A.; Wollheim, C.B.; Gauthier, B.R. . E-mail: Benoit.Gauthier@medecine.unige.ch

    2006-09-10

    Despite extensive studies, the hematopoietic versus hepatic origin of liver progenitor oval cells remains controversial. The aim of this study was to determine the origin of such cells after liver injury and to establish an oval cell line. Rat liver injury was induced by subcutaneous insertion of 2-AAF pellets for 7 days with subsequent injection of CCl{sub 4}. Livers were removed 9 to 13 days post-CCl{sub 4} treatment. Immunohistochemistry was performed using anti-c-kit, OV6, Thy1, CK19, AFP, vWF and Rab3b. Isolated non-parenchymal cells were grown on mouse embryonic fibroblast, and their gene expression profile was characterized by RT-PCR. We identified a subpopulation of OV6/CK19/Rab3b-expressing cells that was activated in the periportal region of traumatized livers. We also characterized a second subpopulation that expressed the HSCs marker c-kit but not Thy1. Although we successfully isolated both cell types, OV6/CK19/Rab3b{sup +} cells fail to propagate while c-kit {sup +}-HSCs appeared to proliferate for up to 7 weeks. Cells formed clusters which expressed c-kit, Thy1 and albumin. Our results indicate that a bona fide oval progenitor cell population resides within the liver and is distinct from c-kit {sup +}-HSCs. Oval cells require the hepatic niche to proliferate, while cells mobilized from the circulation proliferate and transdifferentiate into hepatocytes without evidence of cell fusion.

  20. 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. PMID:17704789

  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. Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function.

    PubMed

    Wang, Weihuan; Zimmerman, Grant; Huang, Xiaoran; Yu, Shuiliang; Myers, Jay; Wang, Yiwei; Moreton, Stephen; Nthale, Joseph; Awadallah, Amad; Beck, Rose; Xin, Wei; Wald, David; Huang, Alex Y; Zhou, Lan

    2016-03-15

    More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients. PMID:26801976

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

    PubMed

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

    2016-09-01

    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

  5. Extrinsic allospecific signals of hematopoietic origin dictate iNKT cell lineage-fate decisions during development

    PubMed Central

    Strong, Beverly S. I.; Newkold, Tess J.; Lee, Amanda E.; Turner, Lucas E.; Alhajjat, Amir M.; Heusel, Jonathan W.; Shaaban, Aimen F.

    2016-01-01

    Invariant NKT (iNKT) cells are critical to the maintenance of tolerance toward alloantigens encountered during postnatal life pointing to the existence of a process for self-education. However, the impact of developmentally encountered alloantigens in shaping the phenotype and function of iNKT cells has not been described. To better understand this process, the current report examined naïve iNKT cells as they matured in an allogeneic environment. Following the prenatal transfer of fetal hematopoietic cells between age-matched allogeneic murine fetuses, cell-extrinsic signals appeared to dictate allospecific patterns of Ly49 receptor expression and lineage diversity in developing iNKT cells. Regulation for this process arose from cells of hematopoietic origin requiring only rare exposure to facilitate broad changes in developing iNKT cells. These findings highlight surprisingly asymmetric allospecific alterations in iNKT cells as they develop and mature in an allogeneic environment and establish a new paradigm for study of the self-education of iNKT cells. PMID:27354027

  6. Involvement of cells of hematopoietic origin in genetically determined resistance of Syrian hamsters to vesicular stomatitis virus.

    PubMed Central

    Fultz, P N; Shadduck, J A; Kang, C Y; Streilein, J W

    1981-01-01

    Susceptibility of Syrian hamsters of the inbred LSH and MHA strains to injection of as few as 10 plaque-forming units of vesicular stomatitis virus (VSV) was shown to occur only after intraperitoneal and intrapleural injection and not after injection of VSV intravenously, intranasally, or in the footpads. Despite the fact that fewer LSH hamsters died when VSV was injected via the latter routes, the histopathology of the VSV-induced disease at early times after infection was identical irrespective of the route of virus administration. Histological examination of tissues at various times after administration of VSV by the various routes revealed that VSV exhibited tropism for lymphoreticular tissue, with the greatest amount of necrosis in the splenic periarteriolar lymphoid sheath. A similar pattern also was observed in VSV-infected tissues from genetically resistant UT1 hamsters. Infectivity titrations of various tissues at different times after intraperitoneal injection of VSV revealed that resistant UT1 hamsters began to clear virus from tissues between 40 and 48 h postinfection, whereas virus titers remained high in susceptible animals. Resistance of UT1 hamsters appeared to require an intact spleen since survival of splenectomized animals was less than that of sham-splenectomized UT1 controls. Sublethal whole-body irradiation was also able to reduce resistance of UT1 hamsters (survival was reduced from 100 to 50%). Bone marrow cells from resistant (UT1 X LSH) F1 females were transferred into lethally irradiated susceptible LSH hamsters, and hematopoietic chimeras were produced. After intraperitoneal injection of 100 plaque-forming units of VSV, all of the female chimeras survived, but only 33% of male chimeras survived. These data indicate that resistance to VSV in Syrian hamsters is mediated, at least partially, by cells of hematopoietic origin. Images PMID:6273320

  7. 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

  8. Targeting the Microenvironment in Acute Myeloid Leukemia

    PubMed Central

    Rashidi, Armin; Uy, Geoffrey L.

    2015-01-01

    The bone marrow microenvironment plays a critical role in the development, progression, and relapse of acute myeloid leukemia (AML). Similar to normal hematopoietic stem cells, AML blasts express receptors on their surface, allowing them to interact with specific components of the marrow microenvironment. These interactions contribute to both chemotherapy resistance and disease relapse. Preclinical studies and early phase clinical trials have demonstrated the potential for targeting the tumor-microenvironment interactions in AML. Agents currently under investigation include hypoxia-inducible agents and inhibitors of CXCR4 and adhesion molecules such as VLA-4 and E-selectin. PMID:25921388

  9. 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

    2008-09-01

    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

  10. 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

  11. A 54-Year-Old Woman with Donor Cell Origin of Multiple Myeloma after Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of CML

    PubMed Central

    Maestas, Erika; Jain, Shikha; Stiff, Patrick

    2016-01-01

    Chronic myeloid leukemia is a myeloproliferative disorder that may be treated with hematopoietic stem cell transplantation (HSCT). While posttransplantation relapse of disease resulting from a failure to eradicate the patient's original leukemia could occur, patients may also rarely develop a secondary malignancy or myelodysplastic syndrome (MDS) of donor origin termed donor cell leukemia (DCL). Cases of donor-derived acute myeloid leukemia (AML) or MDS after HSCT or solid tumor transplantation have been published. However, very few cases of donor-derived multiple myeloma (MM) exist. We describe a patient who developed a donor-derived MM following allogeneic HSCT from a sibling donor. PMID:26989529

  12. 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.

  13. Hematopoietic stem cells: multiparameter regulation.

    PubMed

    Song, Kedong; Li, Liying; Wang, Yiwei; Liu, Tianqing

    2016-04-01

    Hematopoietic stem cells (HSCs) are capable to self-renew with multi-potency which generated much excitement in clinical therapy. However, the main obstacle of HSCs in clinical application was insufficient number of HSCs which were derived from either bone marrow, peripheral blood or umbilical cord blood. This review briefly discusses the indispensable utility of growth factors and cytokines, stromal cells, extracellular matrix, bionic scaffold and microenvironment aiming to control the hematopoiesis in all directions and provide a better and comprehensive understanding for in vitro expansion of hematopoietic stem cells. PMID:26883144

  14. Biology of Marrow Failure Syndromes: Role of Microenvironment and Niches

    PubMed Central

    Balderman, Sophia R.; Calvi, Laura M.

    2015-01-01

    The marrow microenvironment and its components regulate hematopoietic stem and progenitor cell (HSC) fate. An abnormality in the marrow microenvironment and specific dysfunction of the HSC niche could play a critical role in initiation, disease progression and response to therapy of marrow failure syndromes. Therefore, the identification of changes in the HSC niche in marrow failure syndromes should lead to further knowledge of the signals that disrupt the normal microenvironment. In turn, niche disruption may contribute to disease morbidity resulting in pancytopenia and clonal evolution, and its understanding could point to new therapeutic targets for these conditions. We briefly (a) review evidence for the importance of the marrow microenvironment as a regulator of normal hematopoiesis, (b) summarize the current knowledge regarding the role of dysfunctions in the marrow microenvironment in marrow failure syndromes, and (c) propose a strategy through which niche stimulation can complement current treatment for MDS. PMID:25696837

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

    PubMed

    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

  16. 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

  17. Tumor microenvironment and nanotherapeutics

    PubMed Central

    Upreti, Meenakshi; Jyoti, Amar; Sethi, Pallavi

    2014-01-01

    Recent studies delineate a predominant role for the tumor microenvironment in tumor growth and progression. Improved knowledge of cancer biology and investigation of the complex functional interrelation between the cellular and noncellular compartments of the tumor microenvironment have provided an ideal platform for the evolution of novel cancer nanotherapies. In addition, multifunctional “smart” nanoparticles carrying imaging agents and delivering multiple drugs targeted preferentially to the tumor/tumor microenvironment will lead to early diagnosis and better treatment for patients with cancer. The emerging knowledge of the tumor microenvironment has enabled rational designing of nanoparticles for combinatorial treatment strategies that include radiotherapy, antiangiogenesis and chemotherapy. This multimodality approach is thus expected to achieve therapeutic efficacy and enhance the quality of life of cancer patients. This review highlights the unique characteristics of the tumor microenvironment that are exploited by nanotechnology to develop novel drug delivery systems aimed to target the tumor/tumor microenvironment. PMID:24634853

  18. 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. PMID:26940270

  19. Imaging the Tumor Microenvironment

    PubMed Central

    LeBleu, Valerie

    2015-01-01

    The tumor microenvironment is a complex, heterogeneous, and dominant component of solid tumors. Cancer imaging strategies of a subset of characteristics of the tumor microenvironment are under active development and currently used modalities and novel approaches are summarized here. Understanding the dynamic and evolving functions of the tumor microenvironment is critical to accurately inform imaging and clinical care of cancer. Novel insights into distinct roles of the tumor microenvironment in cancer progression urge careful interpretation of imaging data and impel the development of novel modalities. PMID:26049696

  20. 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

  1. Tumor microenvironment indoctrination

    PubMed Central

    2012-01-01

    Nastiness of cancer does not only reside in the corruption of cancer cells by genetic aberrations that drive their sustained proliferative power—the roots of malignancy—but also in its aptitude to reciprocally sculpt its surrounding environment and cellular stromal ecosystem, in such a way that the corrupted tumor microenvironment becomes a full pro-tumorigenic entity. Such a contribution had been appreciated three decades ago already, with the discovery of tumor angiogenesis and extracellular matrix remodeling. Nevertheless, the recent emergence of the tumor microenvironment as the critical determinant in cancer biology is paralleled by the promising therapeutic potential it carries, opening alternate routes to fight cancer. The study of the tumor microenvironment recruited numerous lead-scientists over the years, with distinct perspectives, and some of them have kindly accepted to contribute to the elaboration of this special issue entitled Tumor microenvironment indoctrination: An emerging hallmark of cancer. PMID:22863738

  2. Prostate Cancer and Parasitism of the Bone Hematopoietic Stem Cell Niche

    PubMed Central

    Yu, Chunyan; Shiozawa, Yusuke; Taichman, Russell S.; McCauley, Laurie K.; Pienta, Kenneth J.; Keller, Evan T.

    2013-01-01

    A subpopulation of men that appear cured of prostate cancer (PCa) develop bone metastases many years after prostatectomy. This observation indicates that PCa cells were present outside of the prostate at the time of prostatectomy and remained dormant. Several lines of evidence indicate that there are disseminated tumor cells (DTCs) in the bone marrow at the time of prostatectomy. DTCs parasitize the bone microenvironment, where they derive support and impact the microenvironment itself. These DTCs appear to be a heterogeneous population of PCa cells; however, some of them appear to have some aspects of a cancer stem cell (CSC) phenotype as they can develop into clinically detectable metastases. The concept of CSC is controversial; however, several markers of CSC have been identified for PCa, which may represent cells of either basal or luminal origin. These DTCs have now been shown to compete for the hematopoietic stem cell niche in bone, where they may be placed in a dormant state. Interaction with a variety of host factors, including cytokine and cells, may impact the metastatic development and progression, including the dormant state. For example, myeloid cells have been shown to impact both the premetastatic niche and established tumors. Understanding the concepts of how PCa successfully parasitizes the bone microenvironment is paramount toward identifying therapeutic candidates to prevent or diminish PCa bone metastases. PMID:22856431

  3. An Irradiation-Altered Bone Marrow Microenvironment Impacts Anabolic Actions of PTH

    PubMed Central

    Koh, A. J.; Novince, C. M.; Li, X.; Wang, T.; Taichman, R. S.

    2011-01-01

    PTH stimulates bone formation and increases hematopoietic stem cells through mechanisms as yet uncertain. The purpose of this study was to identify mechanisms by which PTH links actions on cells of hematopoietic origin with osteoblast-mediated bone formation. C57B6 mice (10 d) were nonlethally irradiated and then administered PTH for 5–20 d. Irradiation reduced bone marrow cellularity with retention of cells lining trabeculae. PTH anabolic activity was greater in irradiated vs. nonirradiated mice, which could not be accounted for by altered osteoblasts directly or osteoclasts but instead via an altered bone marrow microenvironment. Irradiation increased fibroblast growth factor 2, TGFβ, and IL-6 mRNA levels in the bone marrow in vivo. Irradiation decreased B220 cell numbers, whereas the percent of Lin−Sca-1+c-kit+ (LSK), CD11b+, CD68+, CD41+, Lin−CD29+Sca-1+ cells, and proliferating CD45−Nestin+ cells was increased. Megakaryocyte numbers were reduced with irradiation and located more closely to trabecular surfaces with irradiation and PTH. Bone marrow TGFβ was increased in irradiated PTH-treated mice, and inhibition of TGFβ blocked the PTH augmentation of bone in irradiated mice. In conclusion, irradiation created a permissive environment for anabolic actions of PTH that was TGFβ dependent but osteoclast independent and suggests that a nonosteoclast source of TGFβ drives mesenchymal stem cell recruitment to support PTH anabolic actions. PMID:22045660

  4. 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

  5. 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

  6. MicroRNAs are shaping the hematopoietic landscape

    PubMed Central

    Bissels, Ute; Bosio, Andreas; Wagner, Wolfgang

    2012-01-01

    Hematopoiesis is regulated by microRNAs (miRNAs). These small regulatory RNAs are master regulators of developmental processes that modulate expression of several target genes post-transcriptionally. Various miRNAs are up-regulated at specific stages during hematopoietic development and the functional relevance of miRNAs has been proven at many different stages of lineage specification. Knockout of specific miRNAs can produce dramatic phenotypes leading to severe hematopoietic defects. Furthermore, several studies demonstrated that specific miRNAs are differentially expressed in hematopoietic stem cells. However, the emerging picture is extremely complex due to differences between species, cell type dependent variation in miRNA expression and differential expression of diverse target genes that are involved in various regulatory networks. There is also evidence that miRNAs play a role in cellular aging or in the inter-cellular crosstalk between hematopoietic cells and their microenvironment. The field is rapidly evolving due to new profiling tools and deep sequencing technology. The expression profiles of miRNAs are of diagnostic relevance for classification of different diseases. Recent reports on the generation of induced pluripotent stem cells with miRNAs have fuelled the hope that specific miRNAs and culture conditions facilitate directed differentiation or culture expansion of the hematopoietic stem cell pool. This review summarizes our current knowledge about miRNA expression in hematopoietic stem and progenitor cells, and their role in the hematopoietic stem cell niche. PMID:22058204

  7. 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

  8. Single-Cell Cytokine Profiling to Investigate Cellular Functional Diversity in Hematopoietic Malignancies.

    PubMed

    Chen, Jonathan J; Kwak, Minsuk; Fan, Rong

    2016-01-01

    Single-cell analysis of cytokine production is increasingly recognized as an important method to understand the inflammatory microenvironment and hematopoietic disease state. Certain cytokines are critical to the regulation of lineage specification, and the aberrant production of these cytokines can contribute to lineage reprogramming. Here, we describe of a platform combining subnanoliter microchambers and a high-density antibody barcode array for the study of single-cell cytokine secretions in hematopoietic cancer cell populations. PMID:27581152

  9. 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.

  10. 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

  11. 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

  12. Gelatinous marrow transformation and hematopoietic atrophy in a miniature horse stallion.

    PubMed

    Beeler-Marfisi, J; Gallastegui Menoyo, A; Beck, A; König, J; Hewson, J; Bienzle, D

    2011-03-01

    Gelatinous marrow transformation, or serous atrophy of bone marrow fat, has been noted in livestock, laboratory animals, and wildlife in association with an inadequate plane of nutrition, inanition, or intoxication. This is a report of gelatinous marrow transformation and hematopoietic marrow atrophy in a 5-year-old miniature horse stallion. The horse had oral malformations leading to poor food assimilation and emaciation. A bone marrow biopsy obtained to investigate persistent anemia and leukopenia showed hematopoietic atrophy and replacement of fat with a granular extracellular substance, which stained with alcian blue, consistent with acidic mucopolysaccharide content. Surgical correction of the dental abnormalities resulted in improved food assimilation, weight gain, and resolution of cytopenias. In humans, gelatinous bone marrow transformation and hematopoietic atrophy are commonly associated with malnutrition from anorexia nervosa and other causes. The cause of hematopoietic atrophy is unknown but may relate to a nonsupportive marrow microenvironment and inadequate hematopoietic substrate availability. Similar pathogenic mechanisms were suspected in this horse. PMID:20587692

  13. 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

  14. 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. PMID:26106136

  15. 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.

  16. TNFα and Endothelial Cells Modulate Notch Signaling in the Bone Marrow Microenvironment during Inflammation

    PubMed Central

    Fernandez, Luis; Rodriguez, Sonia; Huang, Hui; Chora, Angelo; Mumaw, Christin; Cruz, Eugenia; Pollok, Karen; Cristina, Filipa; Price, Joanne E.; Ferkowicz, Michael J.; Scadden, David T.; Clauss, Matthias; Cardoso, Angelo A.; Carlesso, Nadia

    2009-01-01

    Objective Homeostasis of the hematopoietic compartment is challenged and maintained during conditions of stress by mechanisms that are poorly defined. To understand how the bone marrow (BM) microenvironment influences hematopoiesis, we explored the role of Notch signaling and bone marrow endothelial cells in providing microenvironmental cues to hematopoietic cells in the presence of inflammatory stimuli. Methods The human BM endothelial cell line BMEC and primary human BM endothelial cells were analyzed for expression of Notch ligands and the ability to expand hematopoietic progenitors in an in vitro co-culture system. In vivo experiments were carried out to identify modulation of Notch signaling in BM endothelial and hematopoietic cells in mice challenged with TNFα or LPS, or in Tie2-tmTNFα transgenic mice characterized by constitutive TNFα activation. Results BM endothelial cells were found to express Jagged ligands and to greatly support progenitor’s colony-forming ability. This effect was markedly decreased by Notch antagonists and augmented by increasing levels of Jagged2. Physiologic upregulation of Jagged2 expression on BMEC was observed upon TNFα activation. Injection of TNFα or LPS upregulated 3 to 4 fold Jagged2 expression on murine BM endothelial cells in vivo and resulted in increased Notch activation on murine hematopoietic stem/progenitor cells. Similarly, constitutive activation of endothelial cells in Tie2-tmTNFα mice was characterized by increased expression of Jagged2 and by augmented Notch activation on hematopoietic stem/progenitor cells. Conclusions Our results provide the first evidence that BM endothelial cells promote expansion of hematopoietic progenitor cells by a Notch-dependent mechanism and that TNFα and LPS can modulate the levels of Notch ligand expression and Notch activation in the bone marrow microenvironment in vivo. PMID:18439488

  17. Are hematopoietic stem cells involved in hepatocarcinogenesis?

    PubMed Central

    Antonino, Matteo; Del Prete, Valentina; Neve, Viviana; Scavo, Maria Principia; Barone, Michele

    2014-01-01

    The liver has three cell lineages able to proliferate after a hepatic injury: the mature hepatocyte, the ductular “bipolar” progenitor cell termed “oval cell” and the putative periductular stem cell. Hepatocytes can only produce other hepatocytes whereas ductular progenitor cells are considerate bipolar since they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential and may be multipotent, being this aspect still under investigation. They originate in the bone marrow since their progeny express genetic markers of donor hematopoietic cells after bone marrow transplantation. Since the liver is the hematopoietic organ of the fetus, it is possible that hematopoietic stem cells may reside in the liver of the adult. This assumption is proved by the finding that oval cells express hematopoietic markers like CD34, CD45, CD 109, Thy-1, c-kit, and others, which are also expressed by bone marrow-derived hematopoietic stem cells (BMSCs). Few and discordant studies have evaluated the role of BMSC in hepatocarcinogenesis so far and further studies in vitro and in vivo are warranted in order to definitively clarify such an issue. PMID:25202697

  18. Role of osteoclasts in regulating hematopoietic stem and progenitor cells

    PubMed Central

    Miyamoto, Takeshi

    2013-01-01

    Bone marrow (BM) cavities are utilized for hematopoiesis and to maintain hematopoietic stem cells (HSCs). HSCs have the ability to self-renew as well as to differentiate into multiple different hematopoietic lineage cells. HSCs produce their daughter cells throughout the lifespan of individuals and thus, maintaining HSCs is crucial for individual life. BM cavities provide a specialized microenvironment termed “niche” to support HSCs. Niches are composed of various types of cells such as osteoblasts, endothelial cells and reticular cells. Osteoclasts are unique cells which resorb bones and are required for BM cavity formation. Loss of osteoclast function or differentiation results in inhibition of BM cavity formation, an osteopetrotic phenotype. Osteoclasts are also reportedly required for hematopoietic stem and progenitor cell (HSPC) mobilization to the periphery from BM cavities. Thus, lack of osteoclasts likely results in inhibition of HSC maintenance and HSPC mobilization. However, we found that osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization by using three independent osteoclast-less animal models. In this review, I will discuss the roles of osteoclasts in hematopoietic stem cell maintenance and mobilization. PMID:24147255

  19. Origins.

    ERIC Educational Resources Information Center

    Online-Offline, 1999

    1999-01-01

    Provides an annotated list of resources dealing with the theme of origins of life, the universe, and traditions. Includes Web sites, videos, books, audio materials, and magazines with appropriate grade levels and/or subject disciplines indicated; professional resources; and learning activities. (LRW)

  20. Engineering the Human Thymic Microenvironment to Support Thymopoiesis in Vivo

    PubMed Central

    Chung, Brile; Montel-Hagen, Amélie; Ge, Shundi; Blumberg, Garrett; Kim, Kenneth; Klein, Sam; Zhu, Yuhua; Parekh, Chintan; Balamurugan, Arumugam; Yang, Otto O.; Crooks, Gay M.

    2014-01-01

    A system that allows manipulation of the human thymic microenvironment is needed both to elucidate the extrinsic mechanisms that control human thymopoiesis, and to develop potential cell therapies for thymic insufficiency. In this report, we developed an implantable thymic microenvironment composed of two human thymic stroma populations critical for thymopoiesis; thymic epithelial cells (TECs) and thymic mesenchyme (TM). TECs and TM from postnatal human thymi were cultured in specific conditions, allowing cell expansion and manipulation of gene expression, prior to re-aggregation into a functional thymic unit. Human CD34+ hematopoietic stem and progenitor cells (HSPC) differentiated into T cells in the aggregates in vitro and in vivo following inguinal implantation of aggregates in immune deficient mice. Cord blood HSPC previously engrafted into murine bone marrow, migrated to implants and differentiated into human T cells with a broad T cell receptor repertoire. Furthermore, lentiviral-mediated expression of vascular endothelial growth factor in TM enhanced implant size and function, and significantly increased thymocyte production. These results demonstrate an in vivo system for the generation of T cells from human HSPC, and represent the first model to allow manipulation of gene expression and cell composition in the microenvironment of the human thymus. PMID:24801626

  1. 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

  2. Hematopoietic stem cells: an overview.

    PubMed

    Mosaad, Youssef Mohamed

    2014-12-01

    Considerable efforts have been made in recent years in understanding the mechanisms that govern hematopoietic stem cell (HSC) origin, development, differentiation, self-renewal, aging, trafficking, plasticity and transdifferentiation. Hematopoiesis occurs in sequential waves in distinct anatomical locations during development and these shifts in location are accompanied by changes in the functional status of the stem cells and reflect the changing needs of the developing organism. HSCs make a choice of either self-renewal or committing to differentiation. The balance between self-renewal and differentiation is considered to be critical to the maintenance of stem cell numbers. It is still under debate if HSC can rejuvenate infinitely or if they do not possess ''true" self-renewal and undergo replicative senescence such as any other somatic cell. Gene therapy applications that target HSCs offer a great potential for the treatment of hematologic and immunologic diseases. However, the clinical success has been limited by many factors. This review is intended to summarize the recent advances made in the human HSC field, and will review the hematopoietic stem cell from definition through development to clinical applications. PMID:25457002

  3. Hematopoietic Stem Cell: Self-renewal versus Differentiation

    PubMed Central

    Seita, Jun; Weissman, Irving L.

    2010-01-01

    The mammalian blood system, containing more than ten distinct mature cell types, stands on one specific cell type, hematopoietic stem cell (HSC). Within the system, only HSC possess the ability of both multi-potency and self-renewal. Multi-potency is the ability to differentiate into all functional blood cells. Self-renewal is the ability to give rise to HSC itself without differentiation. Since mature blood cells are predominantly short lived, HSC continuously provide more differentiated progenitors while properly maintaining the HSC pool size properly throughout life by precisely balancing self-renewal and differentiation. Thus, understanding the mechanisms of self-renewal and differentiation of HSC has been a central issue. In this review, we focus on the hierarchical structure of the hematopoietic system, the current understanding of microenvironment and molecular cues regulating self-renewal and differentiation of adult HSC, and the currently emerging systems approaches to understand HSC biology. PMID:20890962

  4. Ectopic bone formation in severely combat-injured orthopedic patients -- a hematopoietic niche.

    PubMed

    Davis, Thomas A; Lazdun, Yelena; Potter, Benjamin K; Forsberg, Jonathan A

    2013-09-01

    Combat-related heterotopic ossification (HO) has emerged as a common and problematic complication of modern wartime extremity injuries, contributing to substantial patient morbidity and loss of function. We have previously reported that HO-forming patients exhibit a more pronounced systemic and local inflammatory response very early in the wound healing process. Moreover, traumatized muscle-derived mesenchymal progenitor cells from these patients have a skewed differentiation potential toward bone. Here, we demonstrate that HO lesions excised from this patient population contain highly vascularized, mature, cancellous bone containing adipogenic marrow. Histologic analysis showed immature hematopoietic cells located within distinct foci in perivascular regions. The adipogenic marrow often contained low numbers of functional erythroid (BFU-E), myeloid (CFU-GM, CFU-M) and multilineage (CFU-GEMM) colony-forming hematopoietic progenitor cells (HPCs). Conversely, tissue from control muscle and non-HO traumatic wound granulation tissue showed no evidence of hematopoietic progenitor cell activity. In summary, our findings suggest that ectopic bone can provide an appropriate hematopoietic microenvironment for supporting the proliferation and differentiation of HPCs. This reactive and vibrant cell population may help maintain normal hematopoietic function, particularly in those with major extremity amputations who have sustained both massive blood loss, prompting systemic marrow stimulation, as well as loss of available native active marrow space. These findings begin to characterize the functional biology of ectopic bone and elucidate the interactions between HPC and non-hematopoietic cell types within the ectopic intramedullary hematopoietic microenvironmental niche identified. PMID:23727270

  5. 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

  6. 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

  7. An overlooked tumor promoting immunoregulation by non-hematopoietic stromal cells.

    PubMed

    Bose, Anamika; Ghosh, Tithi; Baral, Rathindranath

    2016-08-01

    Multidirectional complex communication between tumor-residing hematopoietic and non-hematopoietic stromal cells (NHSCs) decisively regulates cancer development, progression and therapeutic responses. HSCs predominantly participate in the immune regulations, while, NHSCs, provide parenchymal support or serve as a conduit for other cells or support angiogenesis. However, recent reports suggest NHSCs can additionally participate in ongoing tumor promoting immune reactions within tumor-microenvironment (TME). In this review, based on the state-of-art knowledge and accumulated evidence by us, we discuss the role of quite a few NHSCs in tumor from immunological perspectives. Understanding such consequence of NHSCs will surely pave the way in crafting effective cancer management. PMID:27311851

  8. Histological and In Vivo Microscopic Analysis of the Bone Marrow Microenvironment in a Murine Model of Chronic Myelogenous Leukemia.

    PubMed

    Weissenberger, Eva S; Krause, Daniela S

    2016-01-01

    Imaging of the leukemic bone marrow microenvironment, also called the leukemic bone marrow niche, is an essential method to determine and to evaluate the progression of chronic myelogenous leukemia (CML) and other leukemias in murine models. In this chapter we introduce the murine model of CML primarily used in our laboratory by describing blood and bone marrow analysis as well as the method of histological sectioning and immunohistochemistry in combination with various stainings that can help to understand the complex interaction between leukemic cells, their normal hematopoietic counterparts, and the bone marrow microenvironment. We conclude with describing how to image the bone marrow niche using in vivo microscopy. PMID:27581139

  9. 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. PMID:26276713

  10. Hematopoietic stem cell transplantation

    PubMed Central

    Hatzimichael, Eleftheria; Tuthill, Mark

    2010-01-01

    More than 25,000 hematopoietic stem cell transplantations (HSCTs) are performed each year for the treatment of lymphoma, leukemia, immune-deficiency illnesses, congenital metabolic defects, hemoglobinopathies, and myelodysplastic and myeloproliferative syndromes. Before transplantation, patients receive intensive myeloablative chemoradiotherapy followed by stem cell “rescue.” Autologous HSCT is performed using the patient’s own hematopoietic stem cells, which are harvested before transplantation and reinfused after myeloablation. Allogeneic HSCT uses human leukocyte antigen (HLA)-matched stem cells derived from a donor. Survival after allogeneic transplantation depends on donor–recipient matching, the graft-versus-host response, and the development of a graft versus leukemia effect. This article reviews the biology of stem cells, clinical efficacy of HSCT, transplantation procedures, and potential complications. PMID:24198516

  11. Human cord cell hematopoiesis in three-dimensional nonwoven fibrous matrices: in vitro simulation of the marrow microenvironment.

    PubMed

    Li, Y; Ma, T; Kniss, D A; Yang, S T; Lasky, L C

    2001-06-01

    Current hematopoietic culture systems mainly utilize two-dimensional devices with limited ability to promote self-renewal of early progenitors. In vivo-like three-dimensional (3-D) culture environments might be conducive to regulating stem cell proliferation and differentiation similar to in vivo hematopoiesis. The few 3-D cultures reported in the literature either produced few progenitors or provided little information about microenvironment. In this study, we constructed a 3-D hematopoietic microenvironment composed of nonwoven matrix and human cord blood (CB) cells to simulate the marrow microenvironment and expand cord progenitors. Nonwoven polyethylene terephthalate (PET) fabric with defined microstructure was used as the 3-D scaffold and the PET surface was modified by hydrolysis to improve cell adhesion. Different cell organizations were formed in a 3-D matrix in a developmental manner, from individual cells and cells bridging between fibers to large cell aggregates. Both stromal and hematopoietic cells were distributed spatially within the scaffold. Compared to two-dimensional (2-D) CD34(+) cell culture, 3-D culture produced 30-100% higher total cells and progenitors without exogenous cytokines. With thrombopoietin and flt-3/flk-2 ligand, it supported two- to three-fold higher total cell number (62.1- vs. 24.6-fold), CD34(+) cell number (6.8- vs. 2.8-fold) and colony-forming unit (CFU) number for 7-9 weeks (n = 6), indicating a hematopoiesis pathway that promoted progenitor production. Culture in 3-D nonwoven matrices enhanced cell-cell and cell-matrix interactions and allowed 3-D distribution of stromal and hematopoietic cells. The formation of cell aggregates and higher progenitor content indicated that the spatial microenvironment in 3-D culture played an important role in promoting hematopoiesis. This 3-D culture system can be used as an in vitro model to study stem cell or progenitor behavior, and to achieve sustained progenitor expansion. PMID

  12. Spleens of myelofibrosis patients contain malignant hematopoietic stem cells

    PubMed Central

    Wang, Xiaoli; Prakash, Sonam; Lu, Min; Tripodi, Joseph; Ye, Fei; Najfeld, Vesna; Li, Yan; Schwartz, Myron; Weinberg, Rona; Roda, Paul; Orazi, Attilio; Hoffman, Ronald

    2012-01-01

    Cancer stem cell behavior is thought to be largely determined by intrinsic properties and by regulatory signals provided by the microenvironment. Myelofibrosis (MF) is characterized by hematopoiesis occurring not only in the marrow but also in extramedullary sites such as the spleen. In order to study the effects of these different microenvironments on primitive malignant hematopoietic cells, we phenotypically and functionally characterized splenic and peripheral blood (PB) MF CD34+ cells from patients with MF. MF spleens contained greater numbers of malignant primitive HPCs than PB. Transplantation of PB MF CD34+ cells into immunodeficient (NOD/SCID/IL2Rγnull) mice resulted in a limited degree of donor cell chimerism and a differentiation program skewed toward myeloid lineages. By contrast, transplanted splenic MF CD34+ cells achieved a higher level of chimerism and generated both myeloid and lymphoid cells that contained molecular or cytogenetic abnormalities indicating their malignant nature. Only splenic MF CD34+ cells were able to sustain hematopoiesis for prolonged periods (9 months) and were able to engraft secondary recipients. These data document the existence of MF stem cells (MF-SCs) that reside in the spleens of MF patients and demonstrate that these MF-SCs retain a differentiation program identical to that of normal hematopoietic stem cells. PMID:23023702

  13. 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

  14. Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation.

    PubMed

    Vasanthakumar, Aparna; Zullow, Hayley; Lepore, Janet B; Thomas, Kenya; Young, Natalie; Anastasi, John; Reardon, Catherine A; Godley, Lucy A

    2015-12-01

    Epigenetic alterations play a central role in the control of normal and malignant blood cell development. We demonstrate here that expression of a truncated DNA methyltransferase 3B isoform DNMT3B7, which has been shown to alter cellular epigenetic patterns, decreases the overall number of hematopoietic stem and progenitor cells (HSPCs), and markedly diminishes blood cell reconstitution within the female hormonal microenvironment. Gene expression profiling of HSPCs isolated from DNMT3B7 transgenic embryos identified Apolipoprotein E (Apoe) as overexpressed. The CpG island controlling Apoe expression had lower levels of modified cytosines in DNMT3B7 transgenic HSPCs, corresponding with the observed increase in gene expression. Furthermore, we observed that spleens and bone marrows of female mice transplanted with DNMT3B7 transgenic HSPCs express very high levels of Apoe. Finally, the introduction of Apoe-overexpressing HSPCs into male recipients decreased bone marrow engraftment, recapitulating our original observations in female recipients. Our work reveals a dynamic interplay between the intrinsic epigenetic changes in HSPCs and extrinsic endocrine factors acting on these cells to regulate the efficiency of HSPC engraftment and reconstitution. We have identified a novel mechanism by which gender-specific hormones modulate HSPC function, which could serve as a target for augmenting hematopoiesis in cases with limited HSC functionality. PMID:26417967

  15. Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities.

    PubMed

    Shay, G; Hazlehurst, L; Lynch, C C

    2016-01-01

    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

  16. Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome

    PubMed Central

    Balderman, Sophia R.; Li, Allison J.; Hoffman, Corey M.; Frisch, Benjamin J.; Goodman, Alexandra N.; LaMere, Mark W.; Georger, Mary A.; Evans, Andrew G.; Liesveld, Jane L.; Becker, Michael W.

    2016-01-01

    In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival. PMID:26637787

  17. Chemopreventive agents targeting tumor microenvironment.

    PubMed

    Sharma, Sharada H; Thulasingam, Senthilkumar; Nagarajan, Sangeetha

    2016-01-15

    Recent studies have shown that tumor development and progression depend not only on the perturbed genes that govern cell proliferation, but is also highly determined by the non-tumor cells of the stromal compartment surrounding the tumor called tumor microenvironment (TME). These findings highlight the importance of targeting the microenvironment in combination with therapies aimed at tumor cells as a valuable approach. The innate and adaptive immune cells in the TME interact among themselves and also with the endothelial cells, pericytes and mast cells of the stromal compartment through various autocrine and paracrine manner to regulate abnormal cell proliferation. Direct cytotoxic killing of cancer cells and/or reversion of the immunosuppressive TME are to be considered as better strategies for chemoprevention and chemotherapy. With a growing emphasis on a "hallmark targeting" strategy for cancer therapy, the TME now appears as a promising target for cancer prevention using natural products. Clarification on the nontumor stromal cells, the mediators involved, interactions with immune response cells, and immune-evasive mechanisms are needed in order to manipulate the characteristics of the TME by natural pharmacological agents to design effective therapies. This review will provide a glimpse on the roles played by various non-tumor cells in tumor progression and their intervention by pharmacological agents. PMID:26679106

  18. 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.

  19. Endothelin-1 in the tumor microenvironment correlates with melanoma invasion.

    PubMed

    Chiriboga, Luis; Meehan, Shane; Osman, Iman; Glick, Michael; de la Cruz, Gelo; Howell, Brittny S; Friedman-Jiménez, George; Schneider, Robert J; Jamal, Sumayah

    2016-06-01

    Endothelin-1 (ET-1) is a vasoactive peptide that also plays a role in the tanning response of the skin. Animal and cell culture studies have also implicated ET-1 in melanoma progression, but no association studies have been performed to link ET-1 expression and melanoma in humans. Here, we present the first in-vivo study of ET-1 expression in pigmented lesions in humans: an ET-1 immunohistochemical screen of melanocytic nevi, melanoma in situ lesions, invasive melanomas, metastatic melanomas, and blue nevi was performed. Twenty-six percent of melanocytic nevi and 44% of melanoma in situ lesions demonstrate ET-1 expression in the perilesional microenvironment, whereas expression in nevus or melanoma cells was rare to absent. In striking contrast, 100% of moderately to highly pigmented invasive melanomas contained numerous ET-1-positive cells in the tumor microenvironment, with 79% containing ET-1-positive melanoma cells, confirmed by co-staining with melanoma tumor marker HMB45. Hypopigmented invasive melanomas had reduced ET-1 expression, suggesting a correlation between ET-1 expression and pigmented melanomas. ET-1-positive perilesional cells were CD68-positive, indicating macrophage origin. Sixty-two percent of highly pigmented metastatic melanomas demonstrated ET-1 expression in melanoma cells, in contrast to 28.2% of hypopigmented specimens. Eighty-nine percent of benign nevi, known as blue nevi, which have a dermal localization, were associated with numerous ET-1-positive macrophages in the perilesional microenvironment, but no ET-1 expression was detected in the melanocytes. We conclude that ET-1 expression in the microenvironment increases with advancing stages of melanocyte transformation, implicating a critical role for ET-1 in melanoma progression, and the importance of the tumor microenvironment in the melanoma phenotype. PMID:26825037

  20. 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

  1. Commensal bacteria modulate the tumor microenvironment.

    PubMed

    Poutahidis, Theofilos; Erdman, Susan E

    2016-09-28

    It has been recently shown that gut microbes modulate whole host immune and hormonal factors impacting the fate of distant preneoplastic lesions toward malignancy or regression. This raises the possibility that the tumor microenvironment interacts with broader systemic microbial-immune networks. These accumulated findings suggest novel therapeutic opportunities for holobiont engineering in emerging tumor microenvironments. PMID:26739062

  2. Metabolic exchanges within tumor microenvironment.

    PubMed

    Chiarugi, Paola; Cirri, Paolo

    2016-09-28

    Tumor progression toward malignancy often requires a metabolic rewiring of cancer cells to meet changes in metabolic demand to forefront nutrient and oxygen withdrawal, together with strong anabolic requests to match high proliferation rate. Tumor microenvironment highly contributes to metabolic rewiring of cancer cells, fostering complete nutrient exploitation, favoring OXPHOS of lipids and glutamine at the expense of glycolysis and enhancing exchanges via extracellular microvesicles or exosomes of proteins, lipids and small RNAs among tumor and stromal cells. Noteworthy, the same molecular drivers of metabolic reprogramming within tumor and stroma are also able to elicit motility, survival and self-renewal on cancer cells, thereby sustaining successful escaping strategies to circumvent the hostile hypoxic, acidic and inflammatory environment. This review highlights the emerging role of nutrients and vesicle-mediated exchanges among tumor and stromal cells, defining their molecular pathways and offering new perspectives to develop treatments targeting this complex metabolic rewiring. PMID:26546872

  3. 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

  4. Acidic extracellular microenvironment and cancer

    PubMed Central

    2013-01-01

    Acidic extracellular pH is a major feature of tumor tissue, extracellular acidification being primarily considered to be due to lactate secretion from anaerobic glycolysis. Clinicopathological evidence shows that transporters and pumps contribute to H+ secretion, such as the Na+/H+ exchanger, the H+-lactate co-transporter, monocarboxylate transporters, and the proton pump (H+-ATPase); these may also be associated with tumor metastasis. An acidic extracellular pH not only activates secreted lysosomal enzymes that have an optimal pH in the acidic range, but induces the expression of certain genes of pro-metastatic factors through an intracellular signaling cascade that is different from hypoxia. In addition to lactate, CO2 from the pentose phosphate pathway is an alternative source of acidity, showing that hypoxia and extracellular acidity are, while being independent from each other, deeply associated with the cellular microenvironment. In this article, the importance of an acidic extracellular pH as a microenvironmental factor participating in tumor progression is reviewed. PMID:24004445

  5. 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. PMID:26880643

  6. [Physiological regulation of hematopoietic stem cell and its molecular basis].

    PubMed

    Dong, Fang; Hao, Sha; Cheng, Hui; Cheng, Tao

    2016-08-25

    As a classical type of tissue stem cells, hematopoietic stem cell (HSC) is the earliest discovered and has been widely applied in the clinic as a great successful example for stem cell therapy. Thus, HSC research represents a leading field in stem cell biology and regenerative medicine. Self-renewal, differentiation, quiescence, apoptosis and trafficking constitute major characteristics of functional HSCs. These characteristics also signify different dynamic states of HSC through physiological interactions with the microenvironment cues in vivo. This review covers our current knowledge on the physiological regulation of HSC and its underlying molecular mechanisms. It is our hope that this review will not only help our colleagues to understand how HSC is physiologically regulated but also serve as a good reference for the studies on stem cell and regenerative medicine in general. PMID:27546503

  7. 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

  8. Differential regulation of myeloid leukemias by the bone marrow microenvironment.

    PubMed

    Krause, Daniela S; Fulzele, Keertik; Catic, André; Sun, Chia Chi; Dombkowski, David; Hurley, Michael P; Lezeau, Sanon; Attar, Eyal; Wu, Joy Y; Lin, Herbert Y; Divieti-Pajevic, Paola; Hasserjian, Robert P; Schipani, Ernestina; Van Etten, Richard A; Scadden, David T

    2013-11-01

    Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-β1 (TGF-β1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML. PMID:24162813

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

    PubMed

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

    2011-02-01

    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) CD56(bright)CD16(-)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

  10. Ophthalmic Manifestations of Hematopoietic Malignancy.

    PubMed

    Yoshida-Hata, Natsuyo; Katai, Naomichi; Oshitari, Toshiyuki

    2016-01-01

    Purpose. To report the ocular findings in patients with hematopoietic malignancy with optic nerve involvement and abducens nerve palsy. Methods. The medical records of all cases of hematopoietic cancer with ophthalmic involvements seen in the Department of Ophthalmology of the National Center for Global Health and Medicine between 2009 and 2014 were reviewed. Results. Eight patients with hematopoietic cancer with optic nerve invasion or abducens nerve palsy were studied. The primary diseases were 3 cases of multiple myeloma, 1 case of acute lymphocytic leukemia, 1 case of follicular lymphoma, and 3 cases of AIDS-related lymphoma. Six cases had optic nerve invasion, 2 cases had abducens nerve palsy, and 1 case had optic nerve invasion of both eyes. The median visual acuity of eyes with optic nerve invasion was 0.885 logarithm of the minimum angle of resolution (logMAR) units. The final visual acuity of eyes with optic nerve invasion was 1.25 logMAR units, and that of those with sixth-nerve palsy was -0.1 logMAR units. Six cases died during the five-year follow-up period. An ophthalmic involvement in patients with hematopoietic cancer, especially AIDS-related lymphoma, was associated with poor prognosis. Conclusion. Because ophthalmic involvement in patients with hematopoietic malignancy has a poor prognosis, an early diagnosis of the cancers by the ophthalmologic findings by ophthalmologists could improve the prognosis. PMID:27375913

  11. Ophthalmic Manifestations of Hematopoietic Malignancy

    PubMed Central

    2016-01-01

    Purpose. To report the ocular findings in patients with hematopoietic malignancy with optic nerve involvement and abducens nerve palsy. Methods. The medical records of all cases of hematopoietic cancer with ophthalmic involvements seen in the Department of Ophthalmology of the National Center for Global Health and Medicine between 2009 and 2014 were reviewed. Results. Eight patients with hematopoietic cancer with optic nerve invasion or abducens nerve palsy were studied. The primary diseases were 3 cases of multiple myeloma, 1 case of acute lymphocytic leukemia, 1 case of follicular lymphoma, and 3 cases of AIDS-related lymphoma. Six cases had optic nerve invasion, 2 cases had abducens nerve palsy, and 1 case had optic nerve invasion of both eyes. The median visual acuity of eyes with optic nerve invasion was 0.885 logarithm of the minimum angle of resolution (logMAR) units. The final visual acuity of eyes with optic nerve invasion was 1.25 logMAR units, and that of those with sixth-nerve palsy was −0.1 logMAR units. Six cases died during the five-year follow-up period. An ophthalmic involvement in patients with hematopoietic cancer, especially AIDS-related lymphoma, was associated with poor prognosis. Conclusion. Because ophthalmic involvement in patients with hematopoietic malignancy has a poor prognosis, an early diagnosis of the cancers by the ophthalmologic findings by ophthalmologists could improve the prognosis. PMID:27375913

  12. 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.

  13. T-cell exhaustion in the tumor microenvironment

    PubMed Central

    Jiang, Y; Li, Y; Zhu, B

    2015-01-01

    T-cell exhaustion was originally identified during chronic infection in mice, and was subsequently observed in humans with cancer. The exhausted T cells in the tumor microenvironment show overexpressed inhibitory receptors, decreased effector cytokine production and cytolytic activity, leading to the failure of cancer elimination. Restoring exhausted T cells represents an inspiring strategy for cancer treatment, which has yielded promising results and become a significant breakthrough in the cancer immunotherapy. In this review, we overview the updated understanding on the exhausted T cells in cancer and their potential regulatory mechanisms and discuss current therapeutic interventions targeting exhausted T cells in clinical trials. PMID:26086965

  14. Regulation of Hematopoietic Stem Cell Activity by Inflammation

    PubMed Central

    Schuettpelz, Laura G.; Link, Daniel C.

    2013-01-01

    Hematopoietic stem cells (HSCs) are quiescent cells with self-renewal capacity and the ability to generate all mature blood cells. HSCs normally reside in specialized niches in the bone marrow that help maintain their quiescence and long-term repopulating activity. There is emerging evidence that certain cytokines induced during inflammation have significant effects on HSCs in the bone marrow. Type I and II interferons, tumor necrosis factor, and lipopolysaccharide (LPS) directly stimulate HSC proliferation and differentiation, thereby increasing the short-term output of mature effector leukocytes. However, chronic inflammatory cytokine signaling can lead to HSC exhaustion and may contribute the development of hematopoietic malignancies. Pro-inflammatory cytokines such as G-CSF can also indirectly affect HSCs by altering the bone marrow microenvironment, disrupting the stem cell niche, and leading to HSC mobilization into the blood. Herein, we review our current understanding of the effects of inflammatory mediators on HSCs, and we discuss the potential clinical implications of these findings with respect to bone marrow failure and leukemogenesis. PMID:23882270

  15. SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Fernandes, Sandra; Brooks, Robert; Gumbleton, Matthew; Park, Mi-Young; Russo, Christopher M.; Howard, Kyle T.; Chisholm, John D.; Kerr, William G.

    2015-01-01

    Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometimes untreatable disease due to toxic conditioning regimens and Graft-versus-Host-Disease. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PCs) and produces an immunosuppressive microenvironment ideal for incoming allogeneic grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach by creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) mobilizes functional HS-PC, accelerates hematologic recovery, and enhances donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize autologous and allogeneic HSCT. PMID:26052545

  16. 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

  17. Late Adherent Human Bone Marrow Stromal Cells Form Bone and Restore the Hematopoietic Microenvironment In Vivo

    PubMed Central

    Vianna, Verônica Fernandes; Bonfim, Danielle Cabral; Cavalcanti, Amanda dos Santos; Fernandes, Marco Cury; Kahn, Suzana Assad; Casado, Priscila Ladeira; Lima, Inayá Correa; Murray, Samuel S.; Murray, Elsa J. Brochmann; Duarte, Maria Eugenia Leite

    2013-01-01

    Bone marrow stromal cells (BMSCs) are a valuable resource for skeletal regenerative medicine because of their osteogenic potential. In spite of the very general term “stem cell,” this population of cells is far from homogeneous, and different BMSCs clones have greatly different phenotypic properties and, therefore, potentially different therapeutic potential. Adherence to a culture flask surface is a primary defining characteristic of BMSCs. We hypothesized that based on the adherence time we could obtain an enriched population of cells with a greater therapeutic potential. We characterized two populations of bone marrow-derived cells, those that adhered by three days (R-cells) and those that did not adhere by three days but did by six days (L-cells). Clones derived from L-cells could be induced into adipogenic, chondrogenic, and osteogenic differentiation in vitro. L-cells appeared to have greater proliferative capacity, as manifested by larger colony diameter and clones with higher CD146 expression. Only clones from L-cells developed bone marrow stroma in vivo. We conclude that the use of late adherence of BMSCs is one parameter that can be used to enrich for cells that will constitute a superior final product for cell therapy in orthopedics. PMID:23710460

  18. Two Hemocyte Lineages Exist in Silkworm Larval Hematopoietic Organ

    PubMed Central

    Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

    2010-01-01

    Background Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. Methodology/Principal Findings To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. Conclusions/Significance From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori. PMID:20676370

  19. The hematopoietic system in the context of regenerative medicine.

    PubMed

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

    2016-04-15

    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

  20. 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.

  1. Endothelium and NOTCH specify and amplify aorta-gonad-mesonephros-derived hematopoietic stem cells.

    PubMed

    Hadland, Brandon K; Varnum-Finney, Barbara; Poulos, Michael G; Moon, Randall T; Butler, Jason M; Rafii, Shahin; Bernstein, Irwin D

    2015-05-01

    Hematopoietic stem cells (HSCs) first emerge during embryonic development within vessels such as the dorsal aorta of the aorta-gonad-mesonephros (AGM) region, suggesting that signals from the vascular microenvironment are critical for HSC development. Here, we demonstrated that AGM-derived endothelial cells (ECs) engineered to constitutively express AKT (AGM AKT-ECs) can provide an in vitro niche that recapitulates embryonic HSC specification and amplification. Specifically, nonengrafting embryonic precursors, including the VE-cadherin-expressing population that lacks hematopoietic surface markers, cocultured with AGM AKT-ECs specified into long-term, adult-engrafting HSCs, establishing that a vascular niche is sufficient to induce the endothelial-to-HSC transition in vitro. Subsequent to hematopoietic induction, coculture with AGM AKT-ECs also substantially increased the numbers of HSCs derived from VE-cadherin⁺CD45⁺ AGM hematopoietic cells, consistent with a role in supporting further HSC maturation and self-renewal. We also identified conditions that included NOTCH activation with an immobilized NOTCH ligand that were sufficient to amplify AGM-derived HSCs following their specification in the absence of AGM AKT-ECs. Together, these studies begin to define the critical niche components and resident signals required for HSC induction and self-renewal ex vivo, and thus provide insight for development of defined in vitro systems targeted toward HSC generation for therapeutic applications. PMID:25866967

  2. 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

  3. Spatial Heterogeneity in the Tumor Microenvironment.

    PubMed

    Yuan, Yinyin

    2016-01-01

    Recent developments in studies of tumor heterogeneity have provoked new thoughts on cancer management. There is a desperate need to understand influence of the tumor microenvironment on cancer development and evolution. Applying principles and quantitative methods from ecology can suggest novel solutions to fulfil this need. We discuss spatial heterogeneity as a fundamental biological feature of the microenvironment, which has been largely ignored. Histological samples can provide spatial context of diverse cell types coexisting within the microenvironment. Advanced computer-vision techniques have been developed for spatial mapping of cells in histological samples. This has enabled the applications of experimental and analytical tools from ecology to cancer research, generating system-level knowledge of microenvironmental spatial heterogeneity. We focus on studies of immune infiltrate and tumor resource distribution, and highlight statistical approaches for addressing the emerging challenges based on these new approaches. PMID:27481837

  4. Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Szyska, Martin; Na, Il-Kang

    2016-01-01

    The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT. The complex balance between immunosuppressive and cell-depleting treatments, GvHD and immune reconstitution, as well as the desirable graft-versus-tumor (GvT) effect remains a great challenge for clinicians. PMID:27066008

  5. Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Szyska, Martin; Na, Il-Kang

    2016-01-01

    The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT. The complex balance between immunosuppressive and cell-depleting treatments, GvHD and immune reconstitution, as well as the desirable graft-versus-tumor (GvT) effect remains a great challenge for clinicians. PMID:27066008

  6. The microenvironment reprograms circuits in tumor cells

    PubMed Central

    Cai, Qingchun; Xu, Yan

    2015-01-01

    In the course of multistep oncogenesis, initially normal cells acquire several new functions that render them malignant. We have recently demonstrated that the peritoneal microenvironment promotes resistance to anoikis in ovarian cancer cells by reprogramming SRC/AKT/ERK signaling and metabolism. These findings have prognostic and therapeutic implications. PMID:27308400

  7. Mucins in pancreatic cancer and its microenvironment

    PubMed Central

    Kaur, Sukhwinder; Kumar, Sushil; Momi, Navneet; Sasson, Aaron R.; Batra, Surinder K.

    2014-01-01

    Pancreatic cancer remains a lethal malignancy with poor prognosis owing to therapeutic resistance, frequent recurrence and the absence of treatment strategies that specifically target the tumour and its supporting stroma. Deregulated cell-surface proteins drive neoplastic transformations and are envisioned to mediate crosstalk between the tumour and its microenvironment. Emerging studies have elaborated on the role of mucins in diverse biological functions, including enhanced tumorigenicity, invasiveness, metastasis and drug resistance through their characteristic O-linked and N-linked oligosaccharides (glycans), extended structures and unique domains. Multiple mucin domains differentially interact and regulate different components of the tumour microenvironment. This Review discusses: the expression pattern of various mucins in the pancreas under healthy, inflammatory, and cancerous conditions; the context-dependent attributes of mucins that differ under healthy and pathological conditions; the contribution of the tumour microenvironment in pancreatic cancer development and/or progression; diagnostic and/or prognostic efficacy of mucins; and mucin-based therapeutic strategies. Overall, this information should help to delineate the intricacies of pancreatic cancer by exploring the family of mucins, which, through various mechanisms in both tumour cells and the microenvironment, worsen disease outcome. PMID:23856888

  8. Making a Hematopoietic Stem Cell

    PubMed Central

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

    2016-01-01

    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. PMID:26526106

  9. 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

  10. DNA methylation in hematopoietic development and disease.

    PubMed

    Gore, Aniket V; Weinstein, Brant M

    2016-09-01

    DNA methylation is an important epigenetic modification that can have profound and widespread effects on gene expression and on cellular fate and function. Recent work has indicated that DNA methylation plays a critical role in hematopoietic development and hematopoietic disease. DNA methyltransferases and Ten-eleven translocation enzymes are required to add and remove methyl "marks" from DNA, respectively, and both sets of genes have been found necessary for proper formation and maintenance of hematopoietic stem cells and for differentiation of downstream hematopoietic lineages during development. DNA methylation and demethylation enzymes have also been implicated in hematopoietic disorders such as acute myeloid leukemia and myelodysplastic syndrome. Here, we review some of the recent literature regarding the role of DNA methylation in hematopoietic health and disease. PMID:27178734

  11. Cathepsin X is secreted by human osteoblasts, digests CXCL-12 and impairs adhesion of hematopoietic stem and progenitor cells to osteoblasts

    PubMed Central

    Staudt, Nicole D.; Aicher, Wilhelm K.; Kalbacher, Hubert; Stevanovic, Stefan; Carmona, Adriana K.; Bogyo, Matthew; Klein, Gerd

    2010-01-01

    Background Hematopoietic stem cells are retained within discrete bone marrow niches through the effects of cell adhesion molecules and chemokine gradients. However, a small proportion of hematopoietic stem cells can also be found trafficking in the peripheral blood. During induced stem cell mobilization a proteolytic microenvironment is generated, but whether proteases are also involved in physiological trafficking of hematopoietic stem cells is not known. In the present study we examined the expression, secretion and function of the cysteine protease cathepsin X by cells of the human bone marrow. Design and Methods Human osteoblasts, bone marrow stromal cells and hematopoietic stem and progenitor cells were analyzed for the secretion of cathepsin X by western blotting, active site labeling, immunofluorescence staining and activity assays. A possible involvement of cathepsin X in cell adhesion and CXCL-12-mediated cell migration was studied in functional assays. Matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) analysis revealed the digestion mechanism of CXCL-12 by cathepsin X. Results Osteoblasts and stromal cells secrete cathepsin X, whereas hematopoietic stem and progenitor cells do not. Using a cathepsin X-selective substrate, we detected the catalytic activity of cathepsin X in cell culture supernatants of osteoblasts. Activated cathepsin X is able to reduce cellular adhesive interactions between CD34+ hematopoietic stem and progenitor cells and adherent osteoblasts. The chemokine CXCL-12, a highly potent chemoattractant for hematopoietic stem cells secreted by osteoblasts, is readily digested by cathepsin X. Conclusions The exo-peptidase cathepsin X has been identified as a new member of the group of CXCL-12-degrading enzymes secreted by non-hematopoietic bone marrow cells. Functional data indicate that cathepsin X can influence hematopoietic stem and progenitor cell trafficking in the bone marrow. PMID:20494937

  12. 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.

  13. Murine Hematopoietic Stem cells and Progenitors Express Adrenergic Receptors

    PubMed Central

    Muthu, Kuzhali; Iyer, Sivaraman; He, L-K.; Szilagyi, Andrea; Gamelli, Richard L; Shankar, Ravi; Jones, Stephen B

    2007-01-01

    Association between the nervous and immune system is well documented. Immune cells originate within the bone marrow that is innervated. Thermal injury induces adrenergic stimulation, augments monocytopoiesis and alters the β-adrenergic receptor (AR) profile of bone marrow monocyte committed progenitors. This provides an impetus to study AR expression in hematopoietic progenitors along myeloid lineage. Using FACS analysis and confocal microscopy, we report the expression of α1-, α2- and β2- AR in enriched populations of ER-MP20+ and ER-MP12+ myeloid progenitors, CD117+ and CD34+ multi-potential progenitors and more importantly pluripotent stem cells suggesting a plausible role for catecholamine in hematopoietic development. PMID:17428548

  14. 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. PMID:27389708

  15. 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. PMID:26774386

  16. 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

  17. 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

  18. Adult hematopoietic stem cells lacking Hif-1α self-renew normally

    PubMed Central

    Vukovic, Milica; Sepulveda, Catarina; Subramani, Chithra; Guitart, Amélie V.; Mohr, Jasmine; Allen, Lewis; Panagopoulou, Theano I.; Paris, Jasmin; Lawson, Hannah; Villacreces, Arnaud; Armesilla-Diaz, Alejandro; Gezer, Deniz; Holyoake, Tessa L.; Ratcliffe, Peter J.

    2016-01-01

    The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α–deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α–deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance. PMID:27060169

  19. Adult hematopoietic stem cells lacking Hif-1α self-renew normally.

    PubMed

    Vukovic, Milica; Sepulveda, Catarina; Subramani, Chithra; Guitart, Amélie V; Mohr, Jasmine; Allen, Lewis; Panagopoulou, Theano I; Paris, Jasmin; Lawson, Hannah; Villacreces, Arnaud; Armesilla-Diaz, Alejandro; Gezer, Deniz; Holyoake, Tessa L; Ratcliffe, Peter J; Kranc, Kamil R

    2016-06-01

    The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance. PMID:27060169

  20. Monitoring immune responses in the tumor microenvironment.

    PubMed

    Wargo, Jennifer A; Reddy, Sangeetha M; Reuben, Alexandre; Sharma, Padmanee

    2016-08-01

    Immune monitoring in the tumor microenvironment allows for important insights into immune mechanisms of response and resistance to various cancer treatments; however clinical challenges exist using current strategies. Significant questions remain regarding monitoring of archival versus fresh tissue, assessment of static versus dynamic markers, evaluation of limited tissue samples, and the translation of insights gained from immunologically 'hot' tumors such as melanoma to other 'cold' tumor microenvironments prevalent in other cancer types. Current and emerging immune monitoring strategies will be examined herein, and genomic-based assays complementing these techniques will also be discussed. Finally, host genomic and external environmental factors influencing anti-tumor immune responses will be considered, including the role of the gut microbiome. Though optimal immune monitoring techniques are in evolution, great promise exists in recent advances that will help guide patient selection as far as type, sequence, and combination of therapeutic regimens to enhance anti-tumor immunity and clinical responses. PMID:27240055

  1. Engineering the CNS stem cell microenvironment

    PubMed Central

    Williams, Cicely A; Lavik, Erin B

    2010-01-01

    The loss of neural tissue underlies the symptomatology of several neurological insults of disparate etiology, including trauma, cerebrovascular insult and neurodegenerative disease. Restoration of damaged neural tissue through the use of exogenous or endogenous neural stem or progenitor cells is an enticing therapeutic option provided one can control their proliferation, migration and differentiation. Initial attempts at CNS tissue engineering relied on the intrinsic cellular properties of progenitor cells; however, it is now appreciated that the microenvironment surrounding the cells plays an indispensible role in regulating stem cell behavior. This article focuses on attempts to engineer the neural stem cell microenvironment by utilizing the major cellular components of the niche (endothelial cells, astrocytes and ependymal cells) and the extracellular matrix in which they are embedded. PMID:19903005

  2. 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

  3. 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

  4. Interaction of tumor cells with the microenvironment

    PubMed Central

    2011-01-01

    Recent advances in tumor biology have revealed that a detailed analysis of the complex interactions of tumor cells with their adjacent microenvironment (tumor stroma) is mandatory in order to understand the various mechanisms involved in tumor growth and the development of metastasis. The mutual interactions between tumor cells and cellular and non-cellular components (extracellular matrix = ECM) of the tumor microenvironment will eventually lead to a loss of tissue homeostasis and promote tumor development and progression. Thus, interactions of genetically altered tumor cells and the ECM on the one hand and reactive non-neoplastic cells on the other hand essentially control most aspects of tumorigenesis such as epithelial-mesenchymal-transition (EMT), migration, invasion (i.e. migration through connective tissue), metastasis formation, neovascularisation, apoptosis and chemotherapeutic drug resistance. In this mini-review we will focus on these issues that were recently raised by two review articles in CCS. PMID:21914164

  5. Neuropharmacologic Approaches to Restore the Brain's Microenvironment.

    PubMed

    Li, Weizhe; Tong, Hsin-I; Gorantla, Santhi; Poluektova, Larisa Y; Gendelman, Howard E; Lu, Yuanan

    2016-09-01

    Maintaining the central nervous system microenvironment after injury, infection, inflammatory and degenerative diseases is contingent upon adequate control of glial homeostatic functions. Disease is caused by microbial, environmental and endogenous factors that compromise ongoing nervous system functions. The final result is neuronal injury, dropout and nerve connection loss, and these underlie the pathobiology of Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, stroke, and bacterial, parasitic and viral infections. However, what promotes disease are homeostatic changes in the brain's microenvironment affected by innate glial immune pro-inflammatory and adaptive immune responses. These events disturb the brain's metabolic activities and communication abilities. How the process affects the brain's regulatory functions that can be harnessed for therapeutic gain is the subject at hand. Specific examples are provided that serve to modulate inflammation and improve disease outcomes specifically for HIV-associated neurocognitive disorders. PMID:27352074

  6. Defined three-dimensional microenvironments boost induction of pluripotency.

    PubMed

    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. PMID:26752655

  7. 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.

  8. 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

  9. 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. PMID:27581017

  10. 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. PMID:22677297

  11. 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.

  12. 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.

  13. 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. PMID:26849037

  14. Temperature and humidity within the clothing microenvironment.

    PubMed

    Sullivan, P J; Mekjavić, I B

    1992-03-01

    The present study investigates clothing microenvironment conditions that may develop during prolonged exposure of workers to a hot environment. Five subjects were exposed to a linear increase in ambient temperature from 20-40 degrees C over a 90-min period, and then remained at 40 degrees C for an additional 90 min. During the exposures, subjects were clad in four types of helicopter personnel suits (Gore-Tex, Cotton Ventile, Nomex/Insulite, and Nomex/Neoprene), incorporating both dry-suit and wet-suit designs. Continuous assessment was made of skin temperature, rectal temperature, and of microenvironment temperature, relative humidity, and vapor pressure (T mu, RH mu, and VP mu) 8 mm from the surface of the skin. Results indicate that although microenvironment temperatures were similar among suits and slightly lower than that of the environment, the RH mu and VP mu were much greater than those of the ambient air. The Nomex/Insulite and Nomex/Neoprene suits showed the highest VP mu, of which only the Nomex/Insulite resulted in significantly greater increases in rectal temperature, likely due to complete covering of the body with the impermeable insulite component. The present study demonstrates the need to discern between the ambient conditions and the conditions encountered next to the skin when protective clothing is worn. PMID:1567319

  15. Experiments on gene transferring to primary hematopoietic cells by liposome.

    PubMed

    Hu, L; Zhang, B

    2000-01-01

    Liposomes have showed many advantages in mediating exogenous gene into many cell types in vitro and in vivo. But few data are available concerning gene transfer into hematopoietic cells. In this report, we described two-marker genes (Neo R and Lac Z) co-transferred into hematopoietic cells of human and mouse by using liposome in vitro. The efficiency of gene transfer was tested by X-gal staining and observation of colony formation. The X-gal blue staining rate of transduced cells was about (13.33 +/- 2.68)% in human and about (16.28 +/- 2.95)% in mouse without G418 selection. After G418 selection, the blue cell rate was (46.06 +/- 3.47)% in human and (43.45 +/- 4.1)% in mouse, which were markedly higher than those before selection, suggesting that high-efficiency gene transfer and expression could be attained in primary hematopoietic cells using this easy and harmless transduction protocol. At the same time, this protocol provided experimental data for clinicians to investigate the biology of marrow reconstitution and trace the origin of relapse after autologous bone marrow transplantation for the patients with leukemia. PMID:12840913

  16. Myocardial infarction activates CCR2+ hematopoietic stem and progenitor cells

    PubMed Central

    Dutta, Partha; Sager, Hendrik B.; Stengel, Kristy R.; Naxerova, Kamila; Courties, Gabriel; Saez, Borja; Silberstein, Lev; Heidt, Timo; Sebas, Matthew; Sun, Yuan; Wojtkiewicz, Gregory; Feruglio, Paolo Fumene; King, Kevin; Baker, Joshua N.; van der Laan, Anja M.; Borodovsky, Anna; Fitzgerald, Kevin; Hulsmans, Maarten; Hoyer, Friedrich; Iwamoto, Yoshiko; Vinegoni, Claudio; Brown, Dennis; Di Carli, Marcelo; Libby, Peter; Hiebert, Scott; Scadden, David; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias

    2015-01-01

    SUMMARY Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlate closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2+CD150+CD48− LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. CCR2+ HSPC have fourfold higher proliferation rates than CCR2−CD150+CD48− LSK cells, display a myeloid differentiation bias, and dominate the migratory HSPC population. We further demonstrate the myeloid translocation gene 16 (Mtg16) regulates CCR2+ HSPC emergence. Mtg16−/− mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury, and identify potential therapeutic targets to modulate leukocyte output after MI. PMID:25957903

  17. 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. PMID:26590762

  18. (Lymph)angiogenic influences on hematopoietic cells in acute myeloid leukemia

    PubMed Central

    Lee, Ji Yoon; Kim, Hee-Je

    2014-01-01

    The purpose of this review is to provide an overview of the effect of (lymph)angiogenic cytokines on hematopoietic cells involved in acute myeloid leukemia (AML). Like angiogenesis, lymphangiogenesis occurs in pathophysiological conditions but not in healthy adults. AML is closely associated with the vasculature system, and the interplay between lymphangiogenic cytokines maintains leukemic blast survival in the bone marrow (BM). Once AML is induced, proangiogenic cytokines function as angiogenic or lymphangiogenic factors and affect hematopoietic cells, including BM-derived immune cells. Simultaneously, the representative cytokines, VEGFs and their receptors are expressed on AML blasts in vascular and osteoblast niches in both the BM and the peripheral circulation. After exposure to (lymph)angiogenic cytokines in leukemogenesis and infiltration, immune cell phenotypes and functions are affected. These dynamic behaviors in the BM reflect the clinical features of AML. In this review, we note the importance of lymphangiogenic factors and their receptors in hematopoietic cells in AML. Understanding the functional characterization of (lymph)angiogenic factors in the BM niche in AML will also be helpful in interrupting the engraftment of leukemic stem cells and for enhancing immune cell function by modulating the tumor microenvironment. PMID:25412683

  19. 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

  20. Hematopoietic Age at Onset of Triple-Negative Breast Cancer Dictates Disease Aggressiveness and Progression.

    PubMed

    Marsh, Timothy; Wong, Irene; Sceneay, Jaclyn; Barakat, Amey; Qin, Yuanbo; Sjödin, Andreas; Alspach, Elise; Nilsson, Björn; Stewart, Sheila A; McAllister, Sandra S

    2016-05-15

    Triple-negative breast cancer (TNBC) is considered an early onset subtype of breast cancer that carries with it a poorer prognosis in young rather than older women for reasons that remain poorly understood. Hematopoiesis in the bone marrow becomes altered with age and may therefore affect the composition of tumor-infiltrating hematopoietic cells and subsequent tumor progression. In this study, we investigated how age- and tumor-dependent changes to bone marrow-derived hematopoietic cells impact TNBC progression. Using multiple mouse models of TNBC tumorigenesis and metastasis, we found that a specific population of bone marrow cells (BMC) upregulated CSF-1R and secreted the growth factor granulin to support stromal activation and robust tumor growth in young mice. However, the same cell population in old mice expressed low levels of CSF1R and granulin and failed to promote tumor outgrowth, suggesting that age influences the tumorigenic capacity of BMCs in response to tumor-associated signals. Importantly, BMCs from young mice were sufficient to activate a tumor-supportive microenvironment and induce tumor progression in old mice. These results indicate that hematopoietic age is an important determinant of TNBC aggressiveness and provide rationale for investigating age-stratified therapies designed to prevent the protumorigenic effects of activated BMCs. Cancer Res; 76(10); 2932-43. ©2016 AACR. PMID:27197230

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

    PubMed

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

    2016-08-01

    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

  2. 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

  3. A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells.

    PubMed

    Reinisch, Andreas; Thomas, Daniel; Corces, M Ryan; Zhang, Xiaohua; Gratzinger, Dita; Hong, Wan-Jen; Schallmoser, Katharina; Strunk, Dirk; Majeti, Ravindra

    2016-07-01

    Xenotransplantation models represent powerful tools for the investigation of healthy and malignant human hematopoiesis. However, current models do not fully mimic the components of the human bone marrow (BM) microenvironment, and they enable only limited engraftment of samples from some human malignancies. Here we show that a xenotransplantation model bearing subcutaneous humanized ossicles with an accessible BM microenvironment, formed by in situ differentiation of human BM-derived mesenchymal stromal cells, enables the robust engraftment of healthy human hematopoietic stem and progenitor cells, as well as primary acute myeloid leukemia (AML) samples, at levels much greater than those in unmanipulated mice. Direct intraossicle transplantation accelerated engraftment and resulted in the detection of substantially higher leukemia-initiating cell (LIC) frequencies. We also observed robust engraftment of acute promyelocytic leukemia (APL) and myelofibrosis (MF) samples, and identified LICs in these malignancies. This humanized ossicle xenotransplantation approach provides a system for modeling a wide variety of human hematological diseases. PMID:27213817

  4. Endoplasmic reticulum stress regulation in hematopoietic stem cells.

    PubMed

    Miharada, Kenichi

    2016-08-01

    Adult hematopoietic stem cells (HSCs) reside in bone marrow and are maintained in a dormant state within a special microenvironment, their so-called "niche". Detaching from the niche induces cell cycle progression, resulting in a reduction of the reconstitution capacity of HSCs. In contrast, fetal liver HSCs actively divide without losing their stem cell potentials. Thus, it has been unclear what types of cellular responses and metabolic changes occur in growing HSCs. We previously discovered that HSCs express relatively low levels of endoplasmic reticulum (ER) chaperone proteins governing protein folding, making HSCs vulnerable to an elevation of stress signals caused by accumulation of un-/misfolded proteins (ER stress) upon in vitro culture. Interestingly, fetal liver HSCs do not show ER stress elevation despite unchanged levels of chaperone proteins. Our latest studies utilizing multiple mouse models revealed that in the fetal liver bile acids as chemical chaperones play a key role supporting the protein folding which results in the suppression of ER stress induction. These findings highlight the importance of ER stress regulations in hematopoiesis. PMID:27599423

  5. l-Arginine is a Radioprotector for Hematopoietic Progenitor Cells

    PubMed Central

    Pearce, Linda L.; Zheng, Xichen; Martinez-Bosch, Sandra; Kerr, Patrick P.; Khlangwiset, Pornsri; Epperly, Michael W.; Fink, Mitchell P.; Greenberger, Joel S.; Peterson, Jim

    2012-01-01

    l-Arginine is shown to protect hematopoietic progenitor (32D cl 3) cells from death due to exposure to γ radiation (137Cs). Some of the other intermediates in the urea cycle, namely ornithine and citrulline, plus urea itself, were not found to have any significant impact on cell survival after irradiation. Intriguingly, supplementation of irradiated cells with l-arginine results in decreased production of peroxynitrite, suggesting that suppression of superoxide generation by nitric oxide synthase in one or more microenvironments is an important factor in the observed radioprotection. The absence of any radioprotective effect of l-arginine in cells at 3% oxygen also confirms the involvement of one or more oxygen-derived species. Knockdown experiments with nitric oxide synthase (NOS) siRNAs in cells and NOS knockout animals confirm that the observed radioprotection is associated with nNOS (NOS-1). l-Arginine also ameliorates the transient inhibition of the electron-transport chain complex I that occurs within 30 min of completing the dose (10 Gy) and that appears to be a functional marker for postirradiation mitochondrial oxidant production. PMID:22175298

  6. L-arginine is a radioprotector for hematopoietic progenitor cells.

    PubMed

    Pearce, Linda L; Zheng, Xichen; Martinez-Bosch, Sandra; Kerr, Patrick P; Khlangwiset, Pornsri; Epperly, Michael W; Fink, Mitchell P; Greenberger, Joel S; Peterson, Jim

    2012-06-01

    L-arginine is shown to protect hematopoietic progenitor (32D cl 3) cells from death due to exposure to γ radiation ((137)Cs). Some of the other intermediates in the urea cycle, namely ornithine and citrulline, plus urea itself, were not found to have any significant impact on cell survival after irradiation. Intriguingly, supplementation of irradiated cells with L-arginine results in decreased production of peroxynitrite, suggesting that suppression of superoxide generation by nitric oxide synthase in one or more microenvironments is an important factor in the observed radioprotection. The absence of any radioprotective effect of L-arginine in cells at 3% oxygen also confirms the involvement of one or more oxygen-derived species. Knockdown experiments with nitric oxide synthase (NOS) siRNAs in cells and NOS knockout animals confirm that the observed radioprotection is associated with nNOS (NOS-1). L-arginine also ameliorates the transient inhibition of the electron-transport chain complex I that occurs within 30 min of completing the dose (10 Gy) and that appears to be a functional marker for postirradiation mitochondrial oxidant production. PMID:22175298

  7. 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. PMID:26255648

  8. Cancer Microenvironment and Inflammation: Role of Hyaluronan

    PubMed Central

    Nikitovic, Dragana; Tzardi, Maria; Berdiaki, Aikaterini; Tsatsakis, Aristidis; Tzanakakis, George N.

    2015-01-01

    The role of inflammation in the development of cancer was described as early as the nineteenth century. Abundant evidence supports the preposition that various cancers are triggered by infection and chronic inflammatory disease whereas, evading immune destruction has been proposed as one of the new “hallmarks of cancer.” Changes of the tumor microenvironment have been closely correlated to cancer-mediated inflammation. Hyaluronan (HA), an important extracellular matrices component, has become recognized as an active participant in inflammatory, angiogenic, fibrotic, and cancer promoting processes. This review discusses how HA and specific HA-binding proteins participate in and regulate cancer-related inflammatory processes. PMID:25926834

  9. Matrix Metalloproteinases: Regulators of the Tumor Microenvironment

    PubMed Central

    Kessenbrock, Kai; Plaks, Vicki; Werb, Zena

    2010-01-01

    Extracellular proteolysis mediates tissue homeostasis. In cancer, altered proteolysis leads to unregulated tumor growth, tissue remodeling, inflammation, tissue invasion, and metastasis. The matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with tumorigenesis. Recent technological developments have markedly advanced our understanding of MMPs as modulators of the tumor microenvironment. In addition to their role in extracellular matrix turnover and cancer cell migration, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in a nonproteolytic manner. These aspects of MMP function are reorienting our approaches to cancer therapy. PMID:20371345

  10. 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.

  11. 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

  12. Parasitic Infections in Hematopoietic Stem Cell Transplantation.

    PubMed

    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

  13. Hematopoietic Stem Cells, Their Niche, and the Concept of Co-Culture Systems: A Critical Review.

    PubMed

    Vaidya, Anuradha; Kale, Vaijayanti

    2015-01-01

    Hematopoietic stem cells (HSCs) have the ability to self-renew and give rise to all lineages of blood cells. HSCs reside in niches that are local tissue microenvironments that maintain and regulate them. Although much progress has been made in elucidating the location and cellular components of the HSC niche, however it still remains incompletely defined. Transplantation using HSCs has been applied for the treatment of several diseases but with limited success. Furthermore, although human HSC transplantation has been widely used to rescue the patients after cytoablative therapies, quantitative in vivo human assays for hematopoietic cells have been considered to be neither ethical nor practical. Since HSCs persist in small quantities in the body, understanding the mechanism that govern their fate is essential for the advancement of HSC expansion and transplantation in the future. Since bone marrow is the primary site of HSC maintenance and hematopoiesis, defining the niche components that work in concert to regulate hematopoiesis is crucial to improve regeneration following injury or following HSC transplantation and to also understand how disordered niche function could contribute to disease. In recent years, there has been a growing realization of the limitations in identifying the primitive HSCs by its phenotype alone and therefore the concept of co-culture systems (functional in vitro assays) has become increasingly important to demonstrate the presence of primitive hematopoietic cells by estimating their biological functions. This system has provided a basis for the development of powerful assay procedures for expanding, quantitating and distinguishing cells at discrete stages of early hematopoietic cell differentiation. PMID:26665935

  14. Radioimmunotherapy for hematopoietic cell transplantation.

    PubMed

    Jurcic, Joseph G

    2013-04-01

    Radioimmunotherapy (RIT) represents an attractive strategy to deliver radiation selectively to tumor and other target organs while minimizing toxicity to normal tissues. RIT with β-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of conditioning before hematopoietic cell transplantation (HCT) in leukemia. Similarly, RIT directed against CD20 has shown promise in the setting of autologous and allogeneic HCT for B-cell lymphomas. α-particle immunotherapy with isotopes such as bismuth-213, actinium-225 and astatinine-211 offers the possibility of more selective and efficient killing of target cells while sparing the surrounding normal cells. Pretargeting strategies may further improve target:normal organ dose ratios. While RIT has demonstrated significant antitumor activity, ultimately, randomized studies will be required to determine if conditioning regimens that include this therapeutic modality can improve patient outcomes after HCT. PMID:23557421

  15. 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.

  16. Endothelial-to-hematopoietic transition: Notch-ing vessels into blood.

    PubMed

    Kanz, Dirk; Konantz, Martina; Alghisi, Elisa; North, Trista E; Lengerke, Claudia

    2016-04-01

    During development, hematopoietic stem cells (HSCs) are formed in a temporally and spatially restricted manner, arising from specialized endothelial cells (ECs) in the ventral wall of the dorsal aorta within the evolutionary conserved aorta-gonad-mesonephros region. Our understanding of the processes regulating the birth of HSCs from ECs has been recently advanced by comprehensive molecular analyses of developing murine hematopoietic cell populations complemented by studies in the zebrafish model, with the latter offering unique advantages for genetic studies and direct in vivo visualization of HSC emergence. Here, we provide a concise review of the current knowledge and recent advances regarding the cellular origin and molecular regulation of HSC development, with particular focus on the process of endothelial-to-hematopoietic transition and its primary regulator, the Notch signaling pathway. PMID:27015586

  17. Exploiting the tumor microenvironment for theranostic imaging

    PubMed Central

    Stasinopoulos, Ioannis; Penet, Marie-France; Chen, Zhihang; Kakkad, Samata; Glunde, Kristine; Bhujwalla, Zaver M.

    2011-01-01

    The integration of chemistry and molecular biology with imaging is providing some of the most exciting opportunities in the treatment of cancer. The field of theranostic imaging, where diagnosis is combined with therapy, is particularly suitable for a disease as complex as cancer, especially now that genomic and proteomic profiling can provide an extensive `fingerprint' of each tumor. Using this information, theranostic agents can be shaped for personalized treatment to target specific compartments, such as the tumor microenvironment (TME), whilst minimizing damage to normal tissue. These theranostic agents can also be used to target multiple pathways or networks by incorporating multiple small interfering RNAs (siRNAs) within a single agent. A decade ago genetic alterations were the primary focus in cancer research. Now it is apparent that the tumor physiological microenvironment, interactions between cancer cells and stromal cells, such as endothelial cells, fibroblasts and macrophages, the extracellular matrix (ECM), and a host of secreted factors and cytokines, influence progression to metastatic disease, aggressiveness and the response of the disease to treatment. In this review, we outline some of the characteristics of the TME, describe the theranostic agents currently available to target the TME and discuss the unique opportunities the TME provides for the design of novel theranostic agents for cancer therapy. PMID:21793072

  18. Engineering Strategies to Mimic the Glioblastoma Microenvironment

    PubMed Central

    Rape, Andrew; Ananthanarayanan, Badriprasad; Kumar, Sanjay

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and deadly brain tumor, with a mean survival time of only 21 months. Despite the dramatic improvements in our understanding of GBM fueled by recent revolutions in molecular and systems biology, treatment advances for GBM have progressed inadequately slowly, which is due in part to the wide cellular and molecular heterogeneity both across tumors and within a single tumor. Thus, there is increasing clinical interest in targeting cell-extrinsic factors as way of slowing or halting the progression of GBM. These cell-extrinsic factors, collectively termed the microenvironment, include the extracellular matrix, blood vessels, stromal cells that surround tumor cells, and all associated soluble and scaffold-bound signals. In this review, we will first describe the regulation of GBM tumors by these microenvironmental factors. Next, we will discuss the various in vitro approaches that have been exploited to recapitulate and model the GBM tumor microenvironment in vitro. We conclude by identifying future challenges and opportunities in this field, including the development of microenvironmental platforms amenable to high-throughput discovery and screening. We anticipate that these ongoing efforts will prove to be valuable both as enabling tools for accelerating our understanding of microenvironmental regulation in GBM and as foundations for next-generation molecular screening platforms that may serve as a conceptual bridge between traditional reductionist systems and animal or clinical studies. PMID:25174308

  19. Tumor microenvironment and metabolism in prostate cancer.

    PubMed

    Chiarugi, Paola; Paoli, Paolo; Cirri, Paolo

    2014-04-01

    Prostate cancer is no longer viewed mostly as a disease of abnormally proliferating epithelial cells, but rather as a disease affecting the complex interactions between the cells of the prostate epithelial compartment and the surrounding stromal compartment in which they live. Indeed, the microenvironment in which tumor cells evolve towards an aggressive phenotype is highly heterogeneous, as it is composed of different cell populations such as endothelial cells, fibroblasts, macrophages, and lymphocytes, either resident or trans-differentiated by bone marrow-derived mesenchymal stem cells recruited at the tumor site. Cancer-associated fibroblasts, the most abundant population within this microenvironment, exert a mandatory role in prostate cancer progression as they metabolically sustain cancer cell survival and growth, recruit inflammatory and immune cells, and promote cancer cells stemness and epithelial mesenchymal transition, thereby favoring metastatic dissemination of aggressive cancers. The interruption of this two-compartment crosstalk, together with the idea that stromal cells are mostly vulnerable, being drug-sensitive, could lead to the development of anticancer therapies that target tumor stromal elements. PMID:24787298

  20. 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

  1. The contribution of the Tie2+ lineage to primitive and definitive hematopoietic cells.

    PubMed

    Tang, Yuefeng; Harrington, Anne; Yang, Xuehui; Friesel, Robert E; Liaw, Lucy

    2010-09-01

    The regulatory elements of the Tie2/Tek promoter are commonly used in mouse models to direct transgene expression to endothelial cells. Tunica intima endothelial kinase 2 (Tie2) is also expressed in hematopoietic cells, although this has not been fully characterized. We determine the lineages of adult hematopoietic cells derived from Tie2-expressing populations using Tie2-Cre;Rosa26R-EYFP mice. In Tie2-Cre;Rosa26R-EYFP mice, analysis of bone marrow cells showed Cre-mediated recombination in 85% of the population. In adult bone marrow and spleen, we analyzed subclasses of early hematopoietic progenitors, T cells, monocytes, granulocytes, and B cells. We found that ∼ 84% of each lineage was EYFP(+), and nearly all cells that come from Tie2-expressing lineages are CD45(+), confirming widespread contribution to definitive hematopoietic cells. In addition, more than 82% of blood cells within the embryonic yolk sac were of Tie2(+) origin. Our findings of high levels of Tie2-Cre recombination in the hematopoietic lineage have implications for the use of the Tie2-Cre mouse as a lineage-restricted driver strain. PMID:20645309

  2. The Biology of Allogeneic Hematopoietic Cell Resistance

    PubMed Central

    Shizuru, Judith A.; Bhattacharya, Deepta; Cavazzana-Calvo, Marina

    2016-01-01

    At the most basic level, success of an allogeneic hematopoietic cell transplantation (HCT) procedure relies upon the engraftment of recipients with donor hematopoietic stem cells (HSCs) that will generate blood formation for the life of that individual. The formula to achieve durable HSC engraftment involves multiple factors including the recipient conditioning regimen, the nature of the genetic disparity between donor and recipient, and the content of the hematopoietic graft. Animal and clinical studies have shown that the biology of host resistance is complex, involving both immune and nonimmune elements. In this article, we review the factors that contribute to host resistance, describe emerging concepts on the basic biology of resistance, and discuss hematopoietic resistance as it relates specifically to patients with severe combined immunodeficiencies (SCID)— disorders that bring unique insights into the dynamics of cell replacement by allogeneic HSCs and progenitor cells. PMID:19913629

  3. 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

  4. TGFβ restores hematopoietic homeostasis after myelosuppressive chemotherapy

    PubMed Central

    Brenet, Fabienne; Kermani, Pouneh; Spektor, Roman; Rafii, Shahin

    2013-01-01

    Myelosuppression is a life-threatening complication of antineoplastic therapy, but treatment is restricted to a few cytokines with unilineage hematopoietic activity. Although hematopoietic stem cells (HSCs) are predominantly quiescent during homeostasis, they are rapidly recruited into cell cycle by stresses, including myelosuppressive chemotherapy. Factors that induce HSCs to proliferate during stress have been characterized, but it is not known how HSC quiescence is then reestablished. In this study, we show that TGFβ signaling is transiently activated in hematopoietic stem and progenitor cells (HSPCs) during hematopoietic regeneration. Blockade of TGFβ signaling after chemotherapy accelerates hematopoietic reconstitution and delays the return of cycling HSCs to quiescence. In contrast, TGFβ blockade during homeostasis fails to induce cycling of HSPCs. We identified the cyclin-dependent kinase inhibitor Cdkn1c (p57) as a key downstream mediator of TGFβ during regeneration because the recovery of chimeric mice, incapable of expressing p57 in HSPCs, phenocopies blockade of TGFβ signaling after chemotherapy. This study demonstrates that context-dependent activation of TGFβ signaling is central to an unrecognized counterregulatory mechanism that promotes homeostasis once hematopoiesis has sufficiently recovered from myelosuppressive chemotherapy. These results open the door to new, potentially superior, approaches to promote multilineage hematopoietic recovery by blocking the TGFβ signaling that dampens regeneration. PMID:23440043

  5. 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.

  6. Extracellular vesicles in lung microenvironment and pathogenesis.

    PubMed

    Fujita, Yu; Kosaka, Nobuyoshi; Araya, Jun; Kuwano, Kazuyoshi; Ochiya, Takahiro

    2015-09-01

    Increasing attention is being paid to the role of extracellular vesicles (EVs) in various lung diseases. EVs are released by a variety of cells, including respiratory cells and immune cells, and they encapsulate various molecules, such as proteins and microRNAs, as modulators of intercellular communication. Cancer cell-derived EVs play crucial roles in promoting tumor progression and modifying their microenvironment. By contrast, noncancerous cell-derived EVs demonstrate protective functions against injury, such as tissue recovery and repair, to maintain physiological homeostasis. Airway cells in contact with harmful substances may alter their EV composition and modify the balanced reciprocal interactions with surrounding mesenchymal cells. We summarize the novel findings of EV function in various lung diseases, primarily chronic obstructive pulmonary disease (COPD) and lung cancer. PMID:26231094

  7. 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.

  8. Sensitivity of Dendritic Cells to Microenvironment Signals

    PubMed Central

    Motta, Juliana Maria; Rumjanek, Vivian Mary

    2016-01-01

    Dendritic cells are antigen-presenting cells capable of either activating the immune response or inducing and maintaining immune tolerance. They do this by integrating stimuli from the environment and changing their functional status as a result of plasticity. The modifications suffered by these cells have consequences in the way the organism may respond. In the present work two opposing situations known to affect dendritic cells are analyzed: tumor growth, leading to a microenvironment that favors the induction of a tolerogenic profile, and organ transplantation, which leads to a proinflammatory profile. Lessons learned from these situations may help to understand the mechanisms of modulation resulting not only from the above circumstances, but also from other pathologies. PMID:27088097

  9. The Tumor Microenvironment in Colorectal Carcinogenesis

    PubMed Central

    Peddareddigari, Vijay G.; Wang, Dingzhi

    2010-01-01

    Colorectal cancer is the second leading cause of cancer-related mortality in the United States. Therapeutic developments in the past decade have extended life expectancy in patients with metastatic disease. However, metastatic colorectal cancers remain incurable. Numerous agents that were demonstrated to have significant antitumor activity in experimental models translated into disappointing results in extending patient survival. This has resulted in more attention being focused on the contribution of tumor microenvironment to the progression of a number of solid tumors including colorectal cancer. A more complete understanding of interactions between tumor epithelial cells and their stromal elements will enhance therapeutic options and improve clinical outcome. Here we will review the role of various stromal components in colorectal carcinogenesis and discuss the potential of targeting these components for the development of future therapeutic agents. PMID:21209781

  10. 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.

  11. Morphological plasticity of astroglia: Understanding synaptic microenvironment

    PubMed Central

    2015-01-01

    Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecular machinery on the scale of nanoscopic astroglial compartments remains a challenge. Here we briefly summarize the current knowledge regarding the cellular organisation of astroglia in the synaptic microenvironment and discuss molecular mechanisms potentially involved in use‐dependent astroglial morphogenesis. We also discuss recent observations concerning morphological astroglial plasticity, the respective monitoring methods, and some of the newly emerging techniques that might help with conceptual advances in the area. GLIA 2015;63:2133–2151 PMID:25782611

  12. 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

  13. 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. PMID:26655999

  14. Role of the tumor microenvironment in pancreatic adenocarcinoma.

    PubMed

    Sun, Xian-Jun; Jiang, Ting-Hui; Zhang, Xiao-Ping; Mao, Ai-Wu

    2016-01-01

    Pancreatic cancer is a devastating disease with proclivity for early metastasis, which accounts for its poor prognosis. The clinical problem of pancreatic cancer is its resistance to conventional therapies, such as chemotherapy or radiation. Based upon these challenges, the focus of research on pancreatic cancer has shifted gradually towards the tumor microenvironment. The cancer microenvironment consists of various components, including fibroblasts, endothelial cells, immune cells, and endocrine cells, that interact with each other, and with the cancer cells in a complex fashion. Evidence is accumulating that the cancer microenvironment plays an active role in disease progression, and efforts are being made to target this interplay between cancer cells and host cells, to improve the prognosis of the disease. In the present review, we describe the cellular microenvironment of pancreatic ductal adenocarcinoma (PDA), the major type of pancreatic cancer. Our hope is that a better understanding of the cellular microenvironment of PDA will eventually lead to better treatments for this disease. PMID:26709759

  15. Functional Interference in the Bone Marrow Microenvironment by Disseminated Breast Cancer Cells.

    PubMed

    Dhawan, Abhishek; von Bonin, Malte; Bray, Laura J; Freudenberg, Uwe; Pishali Bejestani, Elham; Werner, Carsten; Hofbauer, Lorenz C; Wobus, Manja; Bornhäuser, Martin

    2016-08-01

    Skeletal metastasis of breast cancer is associated with a poor prognosis and significant morbidity. Investigations in other solid tumors have revealed an impairment in hematopoietic function upon bone marrow invasion. However, the interaction between disseminated breast cancer cells and the bone marrow microenvironment which harbors them has not been addressed comprehensively. Employing advanced co-culture assays, proteomic studies, organotypic models as well as in vivo xenotransplant models, we define the consequences of this interaction on the stromal compartment of bone marrow, affected molecular pathways and subsequent effects on the hematopoietic stem and progenitor cells (HSPCs). The results showed a basic fibroblast growth factor (bFGF)-mediated, synergistic increase in proliferation of breast cancer cells and mesenchymal stromal cells (MSCs) in co-culture. The stromal induction was associated with elevated phosphoinositide-3 kinase (PI3K) signaling in the stroma, which coupled with elevated bFGF levels resulted in increased migration of breast cancer cells towards the MSCs. The perturbed cytokine profile in the stroma led to reduction in the osteogenic differentiation of MSCs via downregulation of platelet-derived growth factor-BB (PDGF-BB). Long term co-cultures of breast cancer cells, HSPCs, MSCs and in vivo studies in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl) /SzJ (NSG) mice showed a reduced support for HSPCs in the altered niche. The resultant non- conducive phenotype of the niche for HSPC support emphasizes the importance of the affected molecular pathways in the stroma as clinical targets. These findings can be a platform for further development of therapeutic strategies aiming at the blockade of bone marrow support to disseminated breast cancer cells. Stem Cells 2016;34:2224-2235. PMID:27090603

  16. Identification of kinase inhibitor targets in the lung cancer microenvironment by chemical and phosphoproteomics

    PubMed Central

    Gridling, Manuela; Ficarro, Scott B.; Breitwieser, Florian P.; Song, Lanxi; Parapatics, Katja; Colinge, Jacques; Haura, Eric B.; Marto, Jarrod A.; Superti-Furga, Giulio; Bennett, Keiryn L.; Rix, Uwe

    2014-01-01

    A growing number of gene mutations, which are recognized as cancer drivers, can be successfully targeted with drugs. The redundant and dynamic nature of oncogenic signaling networks and complex interactions between cancer cells and the microenvironment, however, can cause drug resistance. Whereas these challenges can be addressed by developing drug combinations or polypharmacology drugs, this benefits greatly from a detailed understanding of the proteome-wide target profiles. Using mass spectrometry-based chemical proteomics, we report the comprehensive characterization of the drug-protein interaction networks for the multikinase inhibitors dasatinib and sunitinib in primary lung cancer tissue specimens derived from patients. We observed in excess of 100 protein kinase targets plus various protein complexes involving, for instance, AMPK, TBK1 (sunitinib) and ILK (dasatinib). Importantly, comparison with lung cancer cell lines and mouse xenografts thereof showed that most targets were shared between cell lines and tissues. Several targets, however, were only present in tumor tissues. In xenografts, most of these proteins were of mouse origin suggesting that they originate from the tumor microenvironment. Furthermore, intersection with subsequent global phosphoproteomic analysis identified several activated signaling pathways. These included MAPK, immune and integrin signaling, which were affected by these drugs in both cancer cells and the microenvironment. Thus, the combination of chemical and phosphoproteomics can generate a systems view of proteins, complexes and signaling pathways that are simultaneously engaged by multi-targeted drugs in cancer cells and the tumor microenvironment. This may allow for the design of novel anticancer therapies that concurrently target multiple tumor compartments. PMID:25189542

  17. A three-dimensional culture system for the growth of hematopoietic cells.

    PubMed

    Naughton, B A; Jacob, L; Naughton, G K

    1990-01-01

    A physiological three-dimensional culture system was developed for the growth of human bone marrow. Bone marrow stromal cells were established on a nylon filtration screen template, suspended in liquid medium and grown to 70% confluence, and inoculated with hematopoietic cells. An intricate microenvironment is established to support hematopoiesis, which proceeds in a three-dimensional orientation. Analysis of the adherent zone of these cultures with flow cytometry and progenitor cell assays reveals multilineage hematologic expression and active proliferation of immature cells for the 12 week experimental period. Similar results were obtained with rat bone marrow cultures using this methodology. The suspended nylon mesh system is novel in that it supports the growth of several hematologic lineages concurrently. This system may lend itself to the growth of purged or untreated bone marrow for transplantation. PMID:2308994

  18. 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

  19. 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. PMID:26828013

  20. Engineering humanized mice for improved hematopoietic reconstitution

    PubMed Central

    Drake, Adam C; Chen, Qingfeng; Chen, Jianzhu

    2012-01-01

    Humanized mice are immunodeficient animals engrafted with human hematopoietic stem cells that give rise to various lineages of human blood cells throughout the life of the mouse. This article reviews recent advances in the generation of humanized mice, focusing on practical considerations. We discuss features of different immunodeficient recipient mouse strains, sources of human hematopoietic stem cells, advances in expansion and genetic modification of hematopoietic stem cells, and techniques to modulate the cytokine environment of recipient mice, in order to enhance reconstitution of specific human blood lineage cells. We highlight the opportunities created by new technologies and discuss practical considerations on how to make best use of the widening array of basic models for specific research applications. PMID:22425741

  1. Long noncoding RNAs in hematopoietic malignancies.

    PubMed

    Rodríguez-Malavé, Norma I; Rao, Dinesh S

    2016-05-01

    Recent years have witnessed the discovery of several classes of noncoding RNAs (ncRNAs), which are indispensable for the regulation of cellular processes. Many of these RNAs are regulatory in nature with functions in gene expression regulation such as piwi-interacting RNAs, small interfering RNAs and micro RNAs. Long noncoding RNAs (lncRNAs) comprise the most recently characterized class. LncRNAs are involved in transcriptional regulation, chromatin remodeling, imprinting, splicing, and translation, among other critical functions in the cell. Recent studies have elucidated the importance of lncRNAs in hematopoietic development. Dysregulation of lncRNA expression is a feature of various diseases and cancers, and is also seen in hematopoietic malignancies. This article focuses on lncRNAs that have been implicated in the pathogenesis of hematopoietic malignancies. PMID:26612601

  2. Sphingolipid signaling and hematopoietic malignancies: to the rheostat and beyond.

    PubMed

    Loh, Kenneth C; Baldwin, Dianna; Saba, Julie D

    2011-11-01

    Sphingosine-1-phosphate (S1P) is a bioactive lipid with diverse functions including the promotion of cell survival, proliferation and migration, as well as the regulation of angiogenesis, inflammation, immunity, vascular permeability and nuclear mechanisms that control gene transcription. S1P is derived from metabolism of ceramide, which itself has diverse and generally growth-inhibitory effects through its impact on downstream targets involved in regulation of apoptosis, senescence and cell cycle progression. Regulation of ceramide, S1P and the biochemical steps that modulate the balance and interconversion of these two lipids are major determinants of cell fate, a concept referred to as the "sphingolipid rheostat." There is abundant evidence that the sphingolipid rheostat plays a role in the origination, progression and drug resistance patterns of hematopoietic malignancies. The pathway has also been exploited to circumvent the problem of chemotherapy resistance in leukemia and lymphoma. Given the broad effects of sphingolipids, targeting multiple steps in the metabolic pathway may provide possible therapeutic avenues. However, new observations have revealed that sphingolipid signaling effects are more complex than previously recognized, requiring a revision of the sphingolipid rheostat model. Here, we summarize recent insights regarding the sphingolipid metabolic pathway and its role in hematopoietic malignancies. PMID:21707493

  3. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth

    PubMed Central

    Yao, Jun; Lowery, Frank J.; Zhang, Qingling; Huang, Wen-Chien; Li, Ping; Li, Min; Wang, Xiao; Zhang, Chenyu; Wang, Hai; Ellis, Kenneth; Cheerathodi, Mujeeburahiman; McCarty, Joseph H.; Palmieri, Diane; Saunus, Jodi; Lakhani, Sunil; Huang, Suyun; Sahin, Aysegul A.; Aldape, Kenneth D.; Steeg, Patricia S.; Yu, Dihua

    2016-01-01

    Summary Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites1. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs2. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth3,4. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important tumor suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. PTEN level in PTEN-loss brain metastatic tumor cells is restored after leaving brain microenvironment. This brain microenvironment-dependent, reversible PTEN mRNA and protein down-regulation is epigenetically regulated by microRNAs (miRNAs) from astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting miRNAs to metastatic tumor cells, while astrocyte-specific depletion of PTEN-targeting miRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumor cells leads to an increased secretion of cytokine chemokine (C-C motif) ligand 2 (CCL2), which recruits Iba1+ myeloid cells that reciprocally enhance outgrowth of brain metastatic tumor cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumor cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic

  4. 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.

  5. 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

  6. 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. PMID:26614899

  7. BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo

    PubMed Central

    Crisan, Mihaela; Solaimani Kartalaei, Parham; Neagu, Alex; Karkanpouna, Sofia; Yamada-Inagawa, Tomoko; Purini, Caterina; Vink, Chris S.; van der Linden, Reinier; van Ijcken, Wilfred; Chuva de Sousa Lopes, Susana M.; Monteiro, Rui; Mummery, Christine; Dzierzak, Elaine

    2016-01-01

    Summary Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment. PMID:26923823

  8. BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo.

    PubMed

    Crisan, Mihaela; Solaimani Kartalaei, Parham; Neagu, Alex; Karkanpouna, Sofia; Yamada-Inagawa, Tomoko; Purini, Caterina; Vink, Chris S; van der Linden, Reinier; van Ijcken, Wilfred; Chuva de Sousa Lopes, Susana M; Monteiro, Rui; Mummery, Christine; Dzierzak, Elaine

    2016-03-01

    Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment. PMID:26923823

  9. 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

  10. Spatiotemporal dynamics of the biological interface between cancer and the microenvironment: a fractal anomalous diffusion model with microenvironment plasticity

    PubMed Central

    2012-01-01

    Background The invasion-metastasis cascade of cancer involves a process of parallel progression. A biological interface (module) in which cells is linked with ECM (extracellular matrix) by CAMs (cell adhesion molecules) has been proposed as a tool for tracing cancer spatiotemporal dynamics. Methods A mathematical model was established to simulate cancer cell migration. Human uterine leiomyoma specimens, in vitro cell migration assay, quantitative real-time PCR, western blotting, dynamic viscosity, and an in vivo C57BL6 mouse model were used to verify the predictive findings of our model. Results The return to origin probability (RTOP) and its related CAM expression ratio in tumors, so-called "tumor self-seeding", gradually decreased with increased tumor size, and approached the 3D Pólya random walk constant (0.340537) in a periodic structure. The biphasic pattern of cancer cell migration revealed that cancer cells initially grew together and subsequently began spreading. A higher viscosity of fillers applied to the cancer surface was associated with a significantly greater inhibitory effect on cancer migration, in accordance with the Stokes-Einstein equation. Conclusion The positional probability and cell-CAM-ECM interface (module) in the fractal framework helped us decipher cancer spatiotemporal dynamics; in addition we modeled the methods of cancer control by manipulating the microenvironment plasticity or inhibiting the CAM expression to the Pólya random walk, Pólya constant. PMID:22889191

  11. 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. PMID:26047326

  12. 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

  13. Microcavity arrays as an in vitro model system of the bone marrow niche for hematopoietic stem cells.

    PubMed

    Wuchter, Patrick; Saffrich, Rainer; Giselbrecht, Stefan; Nies, Cordula; Lorig, Hanna; Kolb, Stephanie; Ho, Anthony D; Gottwald, Eric

    2016-06-01

    In previous studies human mesenchymal stromal cells (MSCs) maintained the "stemness" of human hematopoietic progenitor cells (HPCs) through direct cell-cell contact in two-dimensional co-culture systems. We establish a three-dimensional (3D) co-culture system based on a custom-made chip, the 3(D)-KITChip, as an in vitro model system of the human hematopoietic stem cell niche. This array of up to 625 microcavities, with 300 μm size in each orientation, was inserted into a microfluidic bioreactor. The microcavities of the 3(D)-KITChip were inoculated with human bone marrow MSCs together with umbilical cord blood HPCs. MSCs used the microcavities as a scaffold to build a complex 3D mesh. HPCs were distributed three-dimensionally inside this MSC network and formed ß-catenin- and N-cadherin-based intercellular junctions to the surrounding MSCs. Using RT(2)-PCR and western blots, we demonstrate that a proportion of HPCs maintained the expression of CD34 throughout a culture period of 14 days. In colony-forming unit assays, the hematopoietic stem cell plasticity remained similar after 14 days of bioreactor co-culture, whereas monolayer co-cultures showed increasing signs of HPC differentiation and loss of stemness. These data support the notion that the 3D microenvironment created within the microcavity array preserves vital stem cell functions of HPCs more efficiently than conventional co-culture systems. PMID:26829941

  14. 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

  15. 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

  16. Roles of Tumor Microenvironment in Hepatocelluar Carcinoma

    PubMed Central

    Seo, Haeng R.

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most malignant human cancers, with a high mortality rate worldwide despite its early diagnosis in patients and improvement in therapeutic technology. Most cases of liver cancer show a strong resistance to anticancer therapy. Moreover, liver cancer patients generally have poor tolerance to chemotherapy due to liver dysfunction. In these situations, liver-targeting drugs with fewer side effects and a high efficacy are urgently needed during drug discovery for liver cancer. Researchers have aimed to derive target genes and drug candidates for HCC; however, the development of targeted drugs has not yet improved the outcome significantly. Recently, the role of the tumor microenvironment (TME) in HCC has been probed to combat this deadly disease. A deeper knowledge of the crosstalk between tumor cells and their TME is needed to fully understand tumor development, progression and chemo-resistance in HCC because this cancer develops from chronically damaged tissue that contains large amounts of inflammation and fibrosis. In this review, we summarize how distinct stromal cells of TME are involved in tumorigenesis and chemo-resistance in HCC and the significant challenge to recapitulate tumor complexity and heterogeneity enhancement.

  17. Tumor microenvironment and cancer therapy resistance.

    PubMed

    Sun, Yu

    2016-09-28

    Innate resistance to various therapeutic interventions is a hallmark of cancer. In recent years, however, acquired resistance has emerged as a daunting challenge to anticancer treatments including chemotherapy, radiation and targeted therapy, which abolishes the efficacy of otherwise successful regimens. Cancer cells gain resistance through a variety of mechanisms in both primary and metastatic sites, involving cell intrinsic and extrinsic factors, but the latter often remains overlooked. Mounting evidence suggests critical roles played by the tumor microenvironment (TME) in multiple aspects of cancer progression particularly therapeutic resistance. The TME decreases drug penetration, confers proliferative and antiapoptotic advantages to surviving cells, facilitates resistance without causing genetic mutations and epigenetic changes, collectively modifying disease modality and distorting clinical indices. Recent studies have set the baseline for future investigation on the intricate relationship between cancer resistance and the TME in pathological backgrounds. This review provides an updated outline of research advances in TME biology and highlights the prospect of targeting the TME as an essential strategy to overcome cancer resistance and improve therapeutic outcomes through precise intervention. In the long run, continued inputs into translational medicine remain highly desired to achieve durable responses in the current era of personalized clinical oncology. PMID:26272180

  18. 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

  19. [The immunosuppressive microenvironment of malignant gliomas].

    PubMed

    Borisov, K E; Sakaeva, D D

    2015-01-01

    The dogma of the central nervous system (CNS) as an immune-privileged site has been substantially revised in recent years. CNS is an immunocompetent organ and actively interacts with the immune system. Microglia plays a leading role in a CNS immune response. However, in malignant gliomas, there is M2-polarization of microglia acquiring immunosuppressive and tumor-supportive properties. It occurs under the influence of tumor cytokines, such as transforming growth factor-β, interleukin-10, and prostaglandin E2. M2-polarized microglia exhibits reduced phagocytic activity, changes in the expression of many cellular determinants, or inverse of their functions, STAT3 activation, and production of immunosuppressive cytokines that suppress the function of cytotoxic CD8+ T cells or CD4+ T-helper cells type I. Myeloid-derived suppressor cells and regulatory T-lymphocytes, which have been recruited from peripheral blood into tumor tissue, also have immunosuppressive properties. The development of new treatment options for malignant gliomas must consider the role of the microenvironment in maintaining tumor vitality and progression. PMID:26841651

  20. [Colonic microenvironment in familial helicobacter infection].

    PubMed

    Shcherbakov, P L; Vorob'ev, A A; Nesvizhskiĭ, Iu V; Mitrokhin, S D; Kudriavtseva, L V; Minaev, V I; Filin, V A; Petrova, N N; Zaĭtseva, S V

    1998-01-01

    To elucidate the significance of the familial microenvironment in the genesis of Helicobacter infection, a clinical and instrumental investigation was made of 13 families selected by the probands who had digestive diseases associated with H. pylori: gastroduodenitis and duodenal ulcer disease. The occurrence of Helicobacter infection and gastritis in the family members was ascertained to be largely determined by their concurrent residence in the limited area, i.e. by the way of life. The contribution of the "family" factor in antral gastritis, fundal gastritis, and H. pylori infection was 60.0, 40.0, and about 90.0%, respectively. The patients with gastroenterological abnormalities associated with H. pylori were found to show changes in the species-specific and quantitative composition of the colonic microbiocenosis, which were symptomatic and revealed by bacteriological studies in 47.5% of cases and severe in 32.5%. When antihelicobacter therapy is planned, a through treatment of all family members and, if possible, pets should be made. Colonic microbiocenosis should be monitored while treating Helicobacter infection. PMID:9662996

  1. Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

    PubMed Central

    Weinstein, Aliyah M.; Storkus, Walter J.

    2016-01-01

    The inflammatory status of the tumor microenvironment (TME) has been heavily investigated in recent years. Chemokine and cytokine signaling pathways such as CCR7, CXCR5, lymphotoxin, and IL-36, which are involved in the generation of secondary lymphoid organs and effector immune responses, are now recognized as having value both as prognostic factors and as immunomodulatory therapeutics in the context of cancer. Furthermore, when produced in the TME, these mediators have been shown to promote the recruitment of immune cells, including T cells, B cells, dendritic cells (DC), and other specialized immune cell subsets such as follicular dendritic cells (FDC) and T follicular helper (Tfh) cells, in association with the formation of “tertiary” lymphoid structures (TLS) within or adjacent to sites of disease. Although TLS are composed of a heterogeneous collection of immune cell types, whose composition differs based on cancer subtype, the qualitative presence of TLS has been shown to represent a biomarker of good prognosis for cancer patients. A comprehensive understanding of the role each of these pathways plays within the TME may support the rational design of future immunotherapies to selectively promote/bolster TLS formation and function, leading to improved clinical outcomes across the vast range of solid cancer types. PMID:26216634

  2. In utero hematopoietic cell transplantation for hemoglobinopathies

    PubMed Central

    Derderian, S. Christopher; Jeanty, Cerine; Walters, Mark C.; Vichinsky, Elliott; MacKenzie, Tippi C.

    2014-01-01

    In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to circumvent the challenges of postnatal hematopoietic stem cell (HSC) transplantation. The goal of IUHCTx is to introduce donor cells into a naïve host prior to immune maturation, thereby inducing donor–specific tolerance. Thus, this technique has the potential of avoiding host myeloablative conditioning with cytotoxic agents. Over the past two decades, several attempts at IUHCTx have been made to cure numerous underlying congenital anomalies with limited success. In this review, we will briefly review the history of IUHCTx and give a perspective on alpha thalassemia major, one target disease for its clinical application. PMID:25628564

  3. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment.

    PubMed

    Lavin, Yonit; Winter, Deborah; Blecher-Gonen, Ronnie; David, Eyal; Keren-Shaul, Hadas; Merad, Miriam; Jung, Steffen; Amit, Ido

    2014-12-01

    Macrophages are critical for innate immune defense and also control organ homeostasis in a tissue-specific manner. They provide a fitting model to study the impact of ontogeny and microenvironment on chromatin state and whether chromatin modifications contribute to macrophage identity. Here, we profile the dynamics of four histone modifications across seven tissue-resident macrophage populations. We identify 12,743 macrophage-specific enhancers and establish that tissue-resident macrophages have distinct enhancer landscapes beyond what can be explained by developmental origin. Combining our enhancer catalog with gene expression profiles and open chromatin regions, we show that a combination of tissue- and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages. The environment is capable of shaping the chromatin landscape of transplanted bone marrow precursors, and even differentiated macrophages can be reprogrammed when transferred into a new microenvironment. These results provide a comprehensive view of macrophage regulatory landscape and highlight the importance of the microenvironment, along with pioneer factors in orchestrating identity and plasticity. PMID:25480296

  4. The tumor microenvironment shapes hallmarks of mature B-cell malignancies.

    PubMed

    Shain, K H; Dalton, W S; Tao, J

    2015-09-01

    B-cell tumorigenesis results from a host of known and unknown genetic anomalies, including non-random translocations of genes that normally function as determinants of cell proliferation or cell survival to regions juxtaposed to active immunoglobulin heavy chain enhancer elements, chromosomal aneuploidy, somatic mutations that further affect oncogenic signaling and loss of heterozygosity of tumor-suppressor genes. However, it is critical to recognize that even in the setting of a genetic disease, the B-cell/plasma cell tumor microenvironment (TME) contributes significantly to malignant transformation and pathogenesis. Over a decade ago, we proposed the concept of cell adhesion-mediated drug resistance to delineate a form of TME-mediated drug resistance that protects hematopoietic tumor cells from the initial effect of diverse therapies. In the interim, it has been increasingly appreciated that TME also contributes to tumor initiation and progression through sustained growth/proliferation, self-renewal capacity, immune evasion, migration and invasion as well as resistance to cell death in a host of B-cell malignancies, including mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia, chronic lymphocytic leukemia and multiple myeloma. Within this review, we propose that TME and the tumor co-evolve as a consequence of bidirectional signaling networks. As such, TME represents an important target and should be considered integral to tumor progression and drug response. PMID:25639873

  5. TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis.

    PubMed

    Principe, Daniel R; DeCant, Brian; Mascariñas, Emman; Wayne, Elizabeth A; Diaz, Andrew M; Akagi, Naomi; Hwang, Rosa; Pasche, Boris; Dawson, David W; Fang, Deyu; Bentrem, David J; Munshi, Hidayatullah G; Jung, Barbara; Grippo, Paul J

    2016-05-01

    In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas global loss of TGFβ signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFβ1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFβ-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8(+) T cells led to enhanced infiltration and granzyme B-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFβ expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFβ may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFβ signals in the epithelium. Cancer Res; 76(9); 2525-39. ©2016 AACR. PMID:26980767

  6. 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

  7. 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

  8. 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

  9. 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. PMID:25794825

  10. The arterial microenvironment: the where and why of atherosclerosis.

    PubMed

    Yurdagul, Arif; Finney, Alexandra C; Woolard, Matthew D; Orr, A Wayne

    2016-05-15

    The formation of atherosclerotic plaques in the large and medium sized arteries is classically driven by systemic factors, such as elevated cholesterol and blood pressure. However, work over the past several decades has established that atherosclerotic plaque development involves a complex coordination of both systemic and local cues that ultimately determine where plaques form and how plaques progress. Although current therapeutics for atherosclerotic cardiovascular disease primarily target the systemic risk factors, a large array of studies suggest that the local microenvironment, including arterial mechanics, matrix remodelling and lipid deposition, plays a vital role in regulating the local susceptibility to plaque development through the regulation of vascular cell function. Additionally, these microenvironmental stimuli are capable of tuning other aspects of the microenvironment through collective adaptation. In this review, we will discuss the components of the arterial microenvironment, how these components cross-talk to shape the local microenvironment, and the effect of microenvironmental stimuli on vascular cell function during atherosclerotic plaque formation. PMID:27208212

  11. The Mammary Gland Microenvironment Directs Progenitor Cell Fate In Vivo

    PubMed Central

    Bussard, Karen M.; Smith, Gilbert H.

    2011-01-01

    The mammary gland is a unique organ that continually undergoes postnatal developmental changes. In mice, the mammary gland is formed via signals from terminal end buds, which direct ductal growth and elongation. Intriguingly, it is likely that the entire cellular repertoire of the mammary gland is formed from a single antecedent cell. Furthermore, in order to produce progeny of varied lineages (e.g., luminal and myoepithelial cells), signals from the local tissue microenvironment influence mammary stem/progenitor cell fate. Data have shown that cells from the mammary gland microenvironment reprogram adult somatic cells from other organs (testes, nerve) into cells that produce milk and express mammary epithelial cell proteins. Similar results were found for human tumorigenic epithelial carcinoma cells. Presently, it is unclear how the deterministic power of the mammary gland microenvironment controls epithelial cell fate. Regardless, signals generated by the microenvironment have a profound influence on progenitor cell differentiation in vivo. PMID:21647291

  12. Biomechanical force in blood development: extrinsic physical cues drive pro-hematopoietic signaling

    PubMed Central

    Lee, Hyun Jung; Li, Nan; Evans, Siobahn M.; Diaz, Miguel F.; Wenzel, Pamela L.

    2013-01-01

    The hematopoietic system is dynamic during development and in adulthood, undergoing countless spatial and temporal transitions during the course of one’s life. Microenvironmental cues in the many unique hematopoietic niches differ, characterized by distinct soluble molecules, membrane-bound factors, and biophysical features that meet the changing needs of the blood system. Research from the last decade has revealed the importance of substrate elasticity and biomechanical force in determination of stem cell fate. Our understanding of the role of these factors in hematopoiesis is still relatively poor; however, the developmental origin of blood cells from the endothelium promts a model for comparison. Many endothelial mechanical sensors and second messenger systems may also determine hematopoietic stem cell fate, self renewal, and homing behaviors. Further, the intimate contact of hematopoietic cells with mechanosensitive cell types, including osteoblasts, endothelial cells, mesenchymal stem cells, and pericytes, places them in close proximity to paracrine signaling downstream of mechanical signals. The objective of this review is to present an overview of the sensors and intracellular signaling pathways activated by mechanical cues and highlight the role of mechanotransductive pathways in hematopoiesis. PMID:23850217

  13. 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. PMID:26997358

  14. Hematopoiesis and hematopoietic organs in arthropods.

    PubMed

    Grigorian, Melina; Hartenstein, Volker

    2013-03-01

    Hemocytes (blood cells) are motile cells that move throughout the extracellular space and that exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and the body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self-renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review, we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species. PMID:23319182

  15. Hematopoiesis and Hematopoietic Organs in Arthropods

    PubMed Central

    Grigorian, Melina; Hartenstein, Volker

    2013-01-01

    Hemocytes (blood cells) are motile cells moving throughout the extracellular space and exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species. PMID:23319182

  16. Supportive Care of Hematopoietic Cell Transplant Patients

    PubMed Central

    Jim, Heather S. L.; Syrjala, Karen L.; Rizzo, Doug

    2012-01-01

    Hematopoietic cell transplant survivors face a number of challenges including low energy and stamina, “chemo-brain” and emotional distress, and late effects that can compromise functioning or lead to early mortality. This session will review the most recent interventions and recommendations to avoid or mitigate these complications. PMID:22226095

  17. 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

  18. 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

  19. Analysis of the Contribution of Nonresident Progenitor Cells and Hematopoietic Cells to Reparative Dentinogenesis Using Parabiosis Model in Mice

    PubMed Central

    Frozoni, Marcos; Zaia, Alexandre Augusto; Line, Sergio Roberto Peres; Mina, Mina

    2013-01-01

    Introduction The aim of this study was to analyze the contribution of nonresident progenitor/stem cells and hematopoietic cells to reparative dentinogenesis. Methods Parabiosis was established between C57BL/6-TgN(ACTbEGFP)10sb/J transgenic mice (GFP+) and C57BL/6 wild-type mice (GFP−) to ensure blood cross-circulation between animals. Reparative dentinogenesis was stimulated by pulp exposures and capping on the first maxillary molar in the GFP− mice. Histologic sections of injured molars from GFP− mice were analyzed by epifluorescence microscopy to examine the contributions of GFP+ cells (nonresident progenitor cells and hematopoietic cells originating from GFP+ mice) to reparative dentinogenesis. Results GFP+ cells were detected in close association with reparative dentin formed at the site of pulp exposure in the maxillary first molars of the GFP− mice. Conclusions The present study suggests the participation of the nonresident progenitor cells and hematopoietic cells in reparative dentinogenesis. PMID:22892738

  20. Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic transplantation.

    PubMed

    Wolff, S N

    2002-04-01

    Failure to engraft after hematopoietic stem cell transplantation (graft dysfunction) or to sustain engraftment (graft rejection) is a formidable complication due to many possible factors. These include inadequate stem cell numbers, infections, graft-versus-host disease and immunological mediated processes. Fortunately, this complication is uncommon and can be overcome by additional hematopoietic stem cell infusions. Multiple treatment alternatives have been explored including hematopoietic growth factors, additional infusions of stem cells alone, with augmented immunosuppression or with additional cytotoxic therapy. Various sources of the additional stem cells are feasible including the original donor, using another donor, using stem cells collected from the marrow or after cytokine mobilization from the peripheral blood. This report will overview this complication and review the various studies that have attempted to define both cause and therapy. However, a lack of well-designed prospective studies has made definitive recommendations difficult although basic principles have been established. PMID:11979301

  1. Vascular precursors: origin, regulation and function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  2. 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. PMID:25526702

  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. 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. PMID:27037157

  5. 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

  6. Metastasis genetics, epigenetics, and the tumor microenvironment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  7. 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. PMID:26843326

  8. 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. PMID:27067726

  9. Proinflammatory signaling regulates hematopoietic stem cell emergence.

    PubMed

    Espín-Palazón, Raquel; Stachura, David L; Campbell, Clyde A; García-Moreno, Diana; Del Cid, Natasha; Kim, Albert D; Candel, Sergio; Meseguer, José; Mulero, Victoriano; Traver, David

    2014-11-20

    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 TNF? activates the Notch and NF-?B 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 TNF?, 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

  10. 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

  11. Immunoselection techniques in hematopoietic stem cell transplantation.

    PubMed

    Li Pira, Giuseppina; Biagini, Simone; Cicchetti, Elisabetta; Merli, Pietro; Brescia, Letizia Pomponia; Milano, Giuseppe Maria; Montanari, Mauro

    2016-06-01

    Hematopoietic Stem Cells Transplantation (HSCT) is an effective treatment for hematological and non-hematological diseases. The main challenge in autologous HSCT is purging of malignant cells to prevent relapse. In allogeneic HSCT graft-versus-host disease (GvHD) and opportunistic infections are frequent complications. Two types of graft manipulation have been introduced: the first one in the autologous context aimed at separating malignant cells from hematopoietic stem cells (HSC), and the second one in allogeneic HSCT aimed at reducing the incidence of GvHD and at accelerating immune reconstitution. Here we describe the manipulations used for cell purging in autologous HSCT or for T Cell Depletion (TCD) and T cell selection in allogeneic HSCT. More complex manipulations, requiring a Good Manufacturing Practice (GMP) facility, are briefly mentioned. PMID:27209628

  12. 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

  13. Exogenous endothelial cells as accelerators of hematopoietic reconstitution

    PubMed Central

    2012-01-01

    Despite the successes of recombinant hematopoietic-stimulatory factors at accelerating bone marrow reconstitution and shortening the neutropenic period post-transplantation, significant challenges remain such as cost, inability to reconstitute thrombocytic lineages, and lack of efficacy in conditions such as aplastic anemia. A possible means of accelerating hematopoietic reconstitution would be administration of cells capable of secreting hematopoietic growth factors. Advantages of this approach would include: a) ability to regulate secretion of cytokines based on biological need; b) long term, localized production of growth factors, alleviating need for systemic administration of factors that possess unintended adverse effects; and c) potential to actively repair the hematopoietic stem cell niche. Here we overview the field of hematopoietic growth factors, discuss previous experiences with mesenchymal stem cells (MSC) in accelerating hematopoiesis, and conclude by putting forth the rationale of utilizing exogenous endothelial cells as a novel cellular therapy for acceleration of hematopoietic recovery. PMID:23171397

  14. 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. PMID:27143654

  15. The Tumor Microenvironment: A Pitch for Multiple Players

    PubMed Central

    Schiavoni, Giovanna; Gabriele, Lucia; Mattei, Fabrizio

    2013-01-01

    The cancer microenvironment may be conceptually regarded as a pitch where the main players are resident and non-resident cellular components, each covering a defined role and interconnected by a complex network of soluble mediators. The crosstalk between these cells and the tumor cells within this environment crucially determines the fate of tumor progression. Immune cells that infiltrate the tumor bed are transported there by blood circulation and exert a variety of effects, either counteracting or favoring tumor outgrowth. Here, we review and discuss the multiple populations composing the tumor bed, with special focus on immune cells subsets that positively or negatively dictate neoplastic progression. In this scenario, the contribution of cancer stem cells within the tumor microenvironment will also be discussed. Finally, we illustrate recent advances on new integrated approaches to investigate the tumor microenvironment in vitro. PMID:23616948

  16. Genotoxic sensitivity of the developing hematopoietic system.

    PubMed

    Udroiu, Ion; Sgura, Antonella

    2016-01-01

    Genotoxic sensitivity seems to vary during ontogenetic development. Animal studies have shown that the spontaneous mutation rate is higher during pregnancy and infancy than in adulthood. Human and animal studies have found higher levels of DNA damage and mutations induced by mutagens in fetuses/newborns than in adults. This greater susceptibility could be due to reduced DNA repair capacity. In fact, several studies indicated that some DNA repair pathways seem to be deficient during ontogenesis. This has been demonstrated also in murine hematopoietic stem cells. Genotoxicity in the hematopoietic system has been widely studied for several reasons: it is easy to assess, deals with populations cycling also in the adults and may be relevant for leukemogenesis. Reviewing the literature concerning the application of the micronucleus test (a validated assay to assess genotoxicity) in fetus/newborns and adults, we found that the former show almost always higher values than the latter, both in animals treated with genotoxic substances and in those untreated. Therefore, we draw the conclusion that the genotoxic sensitivity of the hematopoietic system is more pronounced during fetal life and decreases during ontogenic development. PMID:27036061

  17. Chronic variable stress activates hematopoietic stem cells

    PubMed Central

    Courties, Gabriel; Dutta, Partha; Iwamoto, Yoshiko; Zaltsman, Alex; von zur Muhlen, Constantin; Bode, Christoph; Fricchione, Gregory L.; Denninger, John; Lin, Charles P.; Vinegoni, Claudio; Libby, Peter; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias

    2014-01-01

    Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis1,2. While incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known crosstalk between the brain and immune system includes the hypothalamic–pituitary–adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic–adrenal–medullary axis, which controls stress–induced catecholamine release in support of the fight–or–flight reflex3,4. It remains unknown however if chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive progenitors, giving rise to higher levels of disease–promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Sympathetic nerve fibers release surplus noradrenaline, which uses the β3 adrenergic receptor to signal bone marrow niche cells to decrease CXCL12 levels. Consequently, elevated hematopoietic stem cell proliferation increases output of neutrophils and inflammatory monocytes. When atherosclerosis–prone ApoE−/− mice encounter chronic stress, accelerated hematopoiesis promotes plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans. PMID:24952646

  18. Modification of the tumor microenvironment to enhance immunity.

    PubMed

    Liao, Yu-Pei; Schaue, Dorthe; McBride, William H

    2007-01-01

    The growth and spread of cancer depends as much on the host response to tumor as on the biological characteristics of the tumor itself. This interaction is at its most intimate and dynamic within the tumor microenvironment. It is here that the battle is fought that leads to mutual evolution of tumor and host cell phenotypes. Contributing to this evolutionary process are physiological changes distinctive for the tumor microenvironment, such as hypoxia, low nutrient levels, low extracellular pH, and high interstitial fluid pressure. These largely result from the chaotic intratumoral vasculature but are impacted by the nature of the tumor and the inflammatory and wound healing responses that are generated. Numerous infiltrating immune cells, including macrophages, lymphocytes, natural killer cells and dendritic cells infiltrate the tumor, contributing to high levels of growth factors, hormones, and cytokines. We suggest that the integrated interplay between host and tumor factors results in distinct phenotypes that determine the response to therapy as well as tumor behavior. Targeting the tumor microenvironment to awaken or reawaken immune cells, or to redirect it from a pro-tumor to an anti-tumor state, will require understanding of this phenotype. Current conventional therapies target tumors not tumor cells and clearly affect the host infiltrate and the physiological characteristics of the tumor microenvironment. This may an advantage that has yet to be effectively exploited due to lack of knowledge of existing phenotypes resulting from the tumor-host interactions. The same lack of knowledge impacts outcomes of clinical immunotherapy (IT) trials that have so far not broken through the ceiling of 10% success rate that seems to exist even in melanoma. It seems obvious that more could be achieved by combining therapies that tackle malignancies from multiple angles, with the tumor microenvironment conditioned to support a powerful effector arm generated by IT. The

  19. 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

  20. Leukemia Stem Cells and Microenvironment: Biology and Therapeutic Targeting

    PubMed Central

    Konopleva, Marina Y.; Jordan, Craig T.

    2011-01-01

    Acute myelogenous leukemia is propagated by a subpopulation of leukemia stem cells (LSCs). In this article, we review both the intrinsic and extrinsic components that are known to influence the survival of human LSCs. The intrinsic factors encompass regulators of cell cycle and prosurvival pathways (such as nuclear factor kappa B [NF-κB], AKT), pathways regulating oxidative stress, and specific molecular components promoting self-renewal. The extrinsic components are generated by the bone marrow microenvironment and include chemokine receptors (CXCR4), adhesion molecules (VLA-4 and CD44), and hypoxia-related proteins. New strategies that exploit potentially unique properties of the LSCs and their microenvironment are discussed. PMID:21220598

  1. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence.

    PubMed

    Barker, Holly E; Paget, James T E; Khan, Aadil A; Harrington, Kevin J

    2015-07-01

    Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused 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 that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy. PMID:26105538

  2. Intravital Microscopy for Imaging the Tumor Microenvironment in Live Mice.

    PubMed

    Naumenko, Victor; Jenne, Craig; Mahoney, Douglas J

    2016-01-01

    The development of intravital microscopy has provided unprecedented capacity to study the tumor microenvironment in live mice. The dynamic behavior of cancer, stromal, vascular, and immune cells can be monitored in real time, in situ, in both primary tumors and metastatic lesions, allowing treatment responses to be observed at single cell resolution and therapies tracked in vivo. These features provide a unique opportunity to elucidate the cellular mechanisms underlying the biology and treatment of cancer. We describe here a method for imaging the microenvironment of subcutaneous tumors grown in mice using intravital microscopy. PMID:27581025

  3. The Bone Microenvironment: a Fertile Soil for Tumor Growth.

    PubMed

    Buenrostro, Denise; Mulcrone, Patrick L; Owens, Philip; Sterling, Julie A

    2016-08-01

    Bone metastatic disease remains a significant and frequent problem for cancer patients that can lead to increased morbidity and mortality. Unfortunately, despite decades of research, bone metastases remain incurable. Current studies have demonstrated that many properties and cell types within the bone and bone marrow microenvironment contribute to tumor-induced bone disease. Furthermore, they have pointed to the importance of understanding how tumor cells interact with their microenvironment in order to help improve both the development of new therapeutics and the prediction of response to therapy. PMID:27255469

  4. 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

  5. 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

  6. Exosomic microRNAs in the Tumor Microenvironment

    PubMed Central

    Neviani, Paolo; Fabbri, Muller

    2015-01-01

    Dissecting the crosstalk between tumor cells and tumor microenvironment is quickly becoming the new frontier in cancer research. It is now widely accepted that cancer cells can exert a profound influence over their surroundings, by changing the microenvironment from a normal to a tumor-supportive state that allows for sustained tumor growth, invasion, and drug resistance. Extracellular vesicles, especially exosomes, are recognized as a new category of intercellular communicator, and they are emerging as of primary importance in controlling the interplay between the tumor and its environment. Exosomes derived from cancer cells or from cells of the tumor microenvironment allow for the horizontal transfer of information by virtue of their cargo, made of functional proteins and nucleic acids that are specifically sorted and loaded in exosomes during their biogenesis. In this review, we will discuss the current knowledge regarding the role invested by microRNAs, a family of short non-coding RNAs frequently deregulated in malignancies and present in exosomes, in shaping the microenvironment in a cancer-dependent manner. PMID:26258125

  7. Parallel Aspects of the Microenvironment in Cancer and Autoimmune Disease.

    PubMed

    Rahat, Michal A; Shakya, Jivan

    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

  8. 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.

  9. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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. 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