CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Journal of Experimental Medicine (Impact Factor: 12.52). 10/2008; 205(10):2381-95. DOI: 10.1084/jem.20080072
Source: PubMed


The CD45 phosphatase is uniquely expressed by all leukocytes, but its role in regulating hematopoietic progenitors is poorly understood. We show that enhanced CD45 expression on bone marrow (BM) leukocytes correlates with increased cell motility in response to stress signals. Moreover, immature CD45 knockout (KO) cells showed defective motility, including reduced homing (both steady state and in response to stromal-derived factor 1) and reduced granulocyte colony-stimulating factor mobilization. These defects were associated with increased cell adhesion mediated by reduced matrix metalloproteinase 9 secretion and imbalanced Src kinase activity. Poor mobilization of CD45KO progenitors by the receptor activator of nuclear factor kappaB ligand, and impaired modulation of the endosteal components osteopontin and stem cell factor, suggested defective osteoclast function. Indeed, CD45KO osteoclasts exhibited impaired bone remodeling and abnormal morphology, which we attributed to defective cell fusion and Src function. This led to irregular distribution of metaphyseal bone trabecules, a region enriched with stem cell niches. Consequently, CD45KO mice had less primitive cells in the BM and increased numbers of these cells in the spleen, yet with reduced homing and repopulation potential. Uncoupling environmental and intrinsic defects in chimeric mice, we demonstrated that CD45 regulates progenitor movement and retention by influencing both the hematopoietic and nonhematopoietic compartments.

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    • "CD45 negative osteoclasts display a reduced response to RANKL resulting in poor HSC mobilization. Thus CD45 is a paradigm of the concurrent regulation of hematopoiesis and the microenvironment [68, 69]. "
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    ABSTRACT: Following chemotherapy and/or the administration of growth factors, such as granulocyte-colony stimulated factor (G-CSF), hematopoietic stem cells (HSC) mobilize from bone marrow to peripheral blood. This review aims to systematically present the structure of the HSC "niche" and elucidate the mechanisms of their mobilization. However, this field is constantly evolving and new pathways and molecules have been shown to contribute to the mobilization process. Understanding the importance and the possible primary pathophysiologic role of each pathway is rather difficult, since they share various overlapping components. The primary initiating event for the mobilization of HSC is chemotherapy-induced endogenous G-CSF production or exogenous G-CSF administration. G-CSF induces proliferation and expansion of the myelomonocytic series, which leads to proteolytic enzyme activation. These enzymes result in disruption of various receptor-ligand bonds, which leads to the disanchorage of HSC from the bone marrow stroma. In everyday clinical practice, CXC chemokine receptor-4 (CXCR4) antagonists are now being used as mobilization agents in order to improve HSC collection. Furthermore, based on the proposed mechanisms of HSC mobilization, novel mobilizing agents have been developed and are currently evaluated in preclinical and clinical studies.
    BioMed Research International 08/2014; 2014:835138. DOI:10.1155/2014/835138 · 3.17 Impact Factor
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    • "CD34, the marker of hematopoietic stem cells, is highly expressed on the progenitor cells, decreases with cell maturation, and is lost fully on mature cells (10). CD45 is also expressed on hematopoietic cells and assists in bone marrow egress and tissue migration (11, 12). "
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    ABSTRACT: Hematopoietic stem and progenitor cells contribute to allergic inflammation. Pro-inflammatory cytokines that are generated following allergen challenge can impact the differentiation of hematopoietic progenitor cells leading to increased production of effector cells such as eosinophils and basophils, which are key cells involved in the pathogenesis of allergic airway inflammation. Homing of stem cells to the lungs is associated with inflammatory and remodeling changes in asthmatics. Factors that modulate the differentiation and increased migration of stem cells to the site of inflammation in asthma remain to be defined. Stem cells can mature at the site of inflammation in response to inflammatory mediators and other components in the milieu. While the available data suggest that hematopoietic cells traffic to target tissues, the molecular factors underlying in situ differentiation have yet to be specified. Here, we critically evaluate the potential role of hematopoietic progenitors in contributing to the increased immune cell infiltrate in allergic asthma and the factors that drive their differentiation.
    Frontiers in Immunology 12/2013; 4:428. DOI:10.3389/fimmu.2013.00428
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    • "However; CD45 has a likely role in adult stem cell function. In CD45 deficient (−/−) mice, the most primitive hematopoietic stem cells (HSCs) are reduced in number and CD45 (−/−) bone marrow transplantation recipients show deficient engraftment of normal HSCs, suggesting a role for CD45 in the stem cell niche [31]. Interestingly, HSCs in CD45 (−/−) mice had a deficiency in SDF-1 mediated homing, which is recognized as an important factor in CPC migration [32]. "
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    ABSTRACT: There is strong evidence supporting the claim that endogenous cardiac progenitor cells (CPCs) are key players in cardiac regeneration, but the anatomic source and phenotype of the master cardiac progenitors remains uncertain. Our aim was to investigate the different cardiac stem cell populations in the left atrial appendage (LAA) and their fates. We investigated the CPC content and profile of adult murine LAAs using immunohistochemistry and flow cytometry. We demonstrate that the LAA contains a large number of CPCs relative to other areas of the heart, representing over 20% of the total cell number. We grew two distinct CPC populations from the LAA by varying the degree of proteolysis. These differed by their histological location, surface marker profiles and growth dynamics. Specifically, CD45(pos) cells grew with milder proteolysis, while CD45(neg) cells grew mainly with more intense proteolysis. Both cell types could be induced to differentiate into cells with cardiomyocyte markers and organelles, albeit by different protocols. Many CD45(pos) cells expressed CD45 initially and rapidly lost its expression while differentiating. Our results demonstrate that the left atrial appendage plays a role as a reservoir of multiple types of progenitor cells in murine adult hearts. Two different types of CPCs were isolated, differing in their epicardial-myocardial localization. Considering studies demonstrating layer-specific origins of different cardiac progenitor cells, our findings may shed light on possible pathways to study and utilize the diversity of endogenous progenitor cells in the adult heart.
    PLoS ONE 03/2013; 8(3):e59228. DOI:10.1371/journal.pone.0059228 · 3.23 Impact Factor
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