Activated G(s) signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA
Blood (Impact Factor: 10.45). 08/2012; 120(17):3425-35. DOI: 10.1182/blood-2011-11-395418
Source: PubMed


Adult hematopoiesis occurs primarily in the BM space where hematopoietic cells interact with stromal niche cells. Despite this close association, little is known about the specific roles of osteoblastic lineage cells (OBCs) in maintaining hematopoietic stem cells (HSCs), and how conditions affecting bone formation influence HSC function. Here we use a transgenic mouse model with the ColI(2.3) promoter driving a ligand-independent, constitutively active 5HT4 serotonin receptor (Rs1) to address how the massive increase in trabecular bone formation resulting from increased G(s) signaling in OBCs impacts HSC function and blood production. Rs1 mice display fibrous dysplasia, BM aplasia, progressive loss of HSC numbers, and impaired megakaryocyte/erythrocyte development with defective recovery after hematopoietic injury. These hematopoietic defects develop without compensatory extramedullary hematopoiesis, and the loss of HSCs occurs despite a paradoxical expansion of stromal niche cells with putative HSC-supportive activity (ie, endothelial, mesenchymal, and osteoblastic cells). However, Rs1-expressing OBCs show decreased expression of key HSC-supportive factors and impaired ability to maintain HSCs. Our findings indicate that long-term activation of G(s) signaling in OBCs leads to contextual changes in the BM niche that adversely affect HSC maintenance and blood homeostasis.

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Available from: Koen Schepers, Aug 19, 2014
    • "For instance, Rac GTPases in nestin+ perivascular BMSCs have been recently involved in HSC regulation [32] [33]. Other studies suggest that long-term activation of Gs signaling in osteoblastic cells negatively affect HSC maintenance [34] [35]. Also, Wnt signaling regulates the survival, self-renewal and differentiation of HSPCs [36,37]. "
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    • "During hematopoiesis, HSCs are mobilized from dormant style [32, 41], migrate to bloodstream by penetrating the sinusoidal wall [35], and at last differentiate into several kinds of blood cells [42]. Once the BM was under stress, extramedullary hematopoiesis within vascular niche occurs in the spleen or liver to supplement the function in abnormal BM [43]. Along the process, there are various factors involved, which will be discussed as follows. "
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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.
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    • "Under certain circumstances, including myelofibrosis, circulating HSCs from the peripheral blood filter into the tissues. Colonization of filtered HSCs are considered to reside in specific niches, which are specialized microenvironments, such as osteoblastic cells, vascular endothelial cells, liver sinusoidal cells and reticular cells (14–16). With the collaboration of several other molecular findings (17) fetal hematopoiesis as well as EMH occurs mainly in the liver (5). "
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