Osteolineage niche cells initiate hematopoietic stem cell mobilization (Retracted article. See vol. 119, pg. 1793, 2012)

Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Department of Stem Cell and Regenerative Biology, Harvard University, and Harvard Stem Cell Institute, Boston, MA 02215, USA.
Blood (Impact Factor: 10.45). 06/2008; 112(3):519-31. DOI: 10.1182/blood-2008-01-133710
Source: PubMed


Recent studies have implicated bone-lining osteoblasts as important regulators of hematopoietic stem cell (HSC) self-renewal and differentiation; however, because much of the evidence supporting this notion derives from indirect in vivo experiments, which are unavoidably complicated by the presence of other cell types within the complex bone marrow milieu, the sufficiency of osteoblasts in modulating HSC activity has remained controversial. To address this, we prospectively isolated mouse osteoblasts, using a novel flow cytometry-based approach, and directly tested their activity as HSC niche cells and their role in cyclophosphamide/granulocyte colony-stimulating factor (G-CSF)-induced HSC proliferation and mobilization. We found that osteoblasts expand rapidly after cyclophosphamide/G-CSF treatment and exhibit phenotypic and functional changes that directly influence HSC proliferation and maintenance of reconstituting potential. Effects of mobilization on osteoblast number and function depend on the function of ataxia telangiectasia mutated (ATM), the product of the Atm gene, demonstrating a new role for ATM in stem cell niche activity. These studies demonstrate that signals from osteoblasts can directly initiate and modulate HSC proliferation in the context of mobilization. This work also establishes that direct interaction with osteolineage niche cells, in the absence of additional environmental inputs, is sufficient to modulate stem cell activity.

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    • "By integrating data from numerous systems, we can generate a hypothetical “parts list” for HSC niches, including the HSC itself; stromal cells; ECM proteins; blood vessels; neural inputs; and endothelial cells (ECs) (Figure 1). The interactions of HSC-niche influence the self-renewal [7, 13], quiescence [18–20], or mobilization of HSCs [21], depending on multiple intrinsic and extrinsic factors. "
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    ABSTRACT: Though discovered later than osteoblastic niche, vascular niche has been regarded as an alternative indispensable niche operating regulation on hematopoietic stem cells (HSCs). As significant progresses gained on this type niche, it is gradually clear that the main work of vascular niche is undertaking to support hematopoiesis. However, compared to what have been defined in the mechanisms through which the osteoblastic niche regulates hematopoiesis, we know less in vascular niche. In this review, based on research data hitherto we will focus on component foundation and various functions of vascular niche that guarantee the normal hematopoiesis process within bone marrow microenvironments. And the possible pathways raised by various research results through which this environment undergoes its function will be discussed as well.
    Full-text · Article · Apr 2014
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    • "Osteocytes and their role are under investigation. For instance, the CD45−/Ter119−/OPN+ osteoblasts were shown to rapidly expand in vivo, following cyclophosphamide/G-CSF treatment, correlating to HSC proliferation and mobilization, and treated isolated OPN+ cells improved their in vitro haemopoietic supportive ability [20]. The maturation state of osteoblasts appears to be related to the haemopoietic supportive functions, with immature osteoblasts being more efficient in HSC support [21]. "
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    ABSTRACT: Immune-mediated bone marrow failure syndromes (BMFS) are characterized by ineffective marrow haemopoiesis and subsequent peripheral cytopenias. Ineffective haemopoiesis is the result of a complex marrow deregulation including genetic, epigenetic, and immune-mediated alterations in haemopoietic stem/progenitor cells, as well as abnormal haemopoietic-to-stromal cell interactions, with abnormal release of haemopoietic growth factors, chemokines, and inhibitors. Mesenchymal stem/stromal cells (MSCs) and their progeny (i.e., osteoblasts, adipocytes, and reticular cells) are considered as key cellular components of the bone marrow haemopoietic niche. MSCs may interfere with haemopoietic as well as immune regulation. Evidence suggests that bone marrow MSCs may be involved in immune-mediated BMFS underlying pathophysiology, harboring either native abnormalities and/or secondary defects, caused by exposure to activated marrow components. This review summarizes previous as well as more recent information related to the biologic/functional characteristics of bone marrow MSCs in myelodysplastic syndromes, acquired aplastic anemia, and chronic idiopathic neutropenia.
    Full-text · Article · Dec 2013 · Clinical and Developmental Immunology
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    • "Proliferation of normal haematopoietic precursors was greatly enhanced in co-cultures with CFU-Fs obtained from mice sacrificed 3 days after irradiation as compared to cultures with CFU-Fs from normal bone marrow. Previous observations have also underlined the importance of (pre)osteoblastic cells in hematopoietic stem cell proliferation and mobilization [44]. CFU-Fs from normal and irradiated mice were unable to maintain immature haematopoietic cells (ckit+lin-) in their precursor stage of differentiation as tested by their capacities to form hematopoietic colonies in vitro. "
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    ABSTRACT: Many studies have already examined the hematopoietic recovery after irradiation but paid with very little attention to the bone marrow microenvironment. Nonetheless previous studies in a murine model of reversible radio-induced bone marrow aplasia have shown a significant increase in alkaline phosphatase activity (ALP) prior to hematopoietic regeneration. This increase in ALP activity was not due to cell proliferation but could be attributed to modifications of the properties of mesenchymal stem cells (MSC). We thus undertook a study to assess the kinetics of the evolution of MSC correlated to their hematopoietic supportive capacities in mice treated with sub lethal total body irradiation. In our study, colony-forming units-fibroblasts (CFU-Fs) assay showed a significant MSC rate increase in irradiated bone marrows. CFU-Fs colonies still possessed differentiation capacities of MSC but colonies from mice sacrificed 3 days after irradiation displayed high rates of ALP activity and a transient increase in osteoblastic markers expression while pparγ and neuropilin-1 decreased. Hematopoietic supportive capacities of CFU-Fs were also modified: as compared to controls, irradiated CFU-Fs significantly increased the proliferation rate of hematopoietic precursors and accelerated the differentiation toward the granulocytic lineage. Our data provide the first evidence of the key role exerted by the balance between osteoblasts and adipocytes in spontaneous bone marrow regeneration. First, (pre)osteoblast differentiation from MSC stimulated hematopoietic precursor's proliferation and granulopoietic regeneration. Then, in a second time (pre)osteoblasts progressively disappeared in favour of adipocytic cells which down regulated the proliferation and granulocytic differentiation and then contributed to a return to pre-irradiation conditions.
    Full-text · Article · Feb 2012 · PLoS ONE
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