Bone marrow endosteal mesenchymal progenitors depend on HIF factors for maintenance and regulation of hematopoiesis.
Bone marrow endosteal mesenchymal progenitors depend on HIF factors for maintenance and regulation of hematopoiesis.
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骨髓内骨间充质祖细胞取决于HIF因子维持和调节造血的因素。
DOI：
10.1016/j.stemcr.2014.04.002
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发表时间：
2014-06-03
影响因子：
5.9
通讯作者：
Bernardi, Rosa
中科院分区：
文献类型：
--
作者：
Guarnerio, Jlenia;Coltella, Nadia;Ala, Ugo;Tonon, Giovanni;Pandolfi, Pier Paolo;Bernardi, Rosa
造血干细胞（HSC）的维持和分化是通过细胞自主和非细胞自主机制在特定的骨髓微环境中调节的。最近的证据表明，HIF-1α的信号转导有助于细胞自主调节HSC的维持。通过研究HIF因子在骨髓间充质祖细胞中的作用，我们发现小鼠骨髓间充质祖细胞表达高水平的HIF-1α和HIF-2α，并且在体外低氧条件下优先增殖。HIF-1α或HIF-2α的失活显著影响它们的表型、增殖和分化。此外，HIF因子的下调引起干扰素应答基因的增加，并通过STAT 1介导的机制触发造血祖细胞的扩增和分化。有趣的是，在需求驱动的造血条件下，HIF因子在体内间充质祖细胞中特异性下调。总之，我们的研究结果表明，HIF因子也调节造血非细胞自主防止激活的间充质祖细胞，促进造血的潜在计划。骨内膜间充质祖细胞表现出低氧状态HIF因子细胞自主调节间充质祖细胞的生物学HIF因子抑制间充质祖细胞中的干扰素应答程序HIF因子通过非细胞自主机制调节造血通过低氧诱导因子（HIF）的信号传导促进造血干细胞的自我更新。Bernardi及其同事发现，HIFs也非细胞自主地调节来自骨髓骨内膜表面的间充质祖细胞的造血。在间充质祖细胞内，HIF抑制干扰素诱导的信号，这反过来导致造血祖细胞在需求驱动的造血条件下扩增和分化。
Maintenance and differentiation of hematopoietic stem cells (HSCs) is regulated through cell-autonomous and non-cell-autonomous mechanisms within specialized bone marrow microenvironments. Recent evidence demonstrates that signaling by HIF-1α contributes to cell-autonomous regulation of HSC maintenance. By investigating the role of HIF factors in bone marrow mesenchymal progenitors, we found that murine endosteal mesenchymal progenitors express high levels of HIF-1α and HIF-2α and proliferate preferentially in hypoxic conditions ex vivo. Inactivation of either HIF-1α or HIF-2α dramatically affects their phenotype, propagation, and differentiation. Also, downregulation of HIF factors provokes an increase in interferon-responsive genes and triggers expansion and differentiation of hematopoietic progenitors by a STAT1-mediated mechanism. Interestingly, in conditions of demand-driven hematopoiesis HIF factors are specifically downregulated in mesenchymal progenitors in vivo. In conclusion, our findings indicate that HIF factors also regulate hematopoiesis non-cell-autonomously by preventing activation of a latent program in mesenchymal progenitors that promotes hematopoiesis. Endosteal mesenchymal progenitors exhibit a hypoxic state HIF factors cell autonomously regulate the biology of mesenchymal progenitors HIF factors repress interferon-responsive programs in mesenchymal progenitors HIF factors regulate hematopoiesis through non-cell-autonomous mechanisms Signaling through hypoxia-inducible factors (HIFs) promotes self-renewal of hematopoietic stem cells. Here, Bernardi and colleagues found that HIFs also regulate hematopoiesis non-cell-autonomously from mesenchymal progenitors residing at the endosteal surface of the bone marrow. Within mesenchymal progenitors, HIFs suppress interferon-induced signals that, in turn, lead to expansion and differentiation of hematopoietic progenitors in conditions of demand-driven hematopoiesis.
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DOI：
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