Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation
Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation
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DOI：
10.1182/blood-2012-02-408419
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发表时间：
2013-01-31
期刊：
影响因子：
20.3
通讯作者：
Levesque, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Forristal, Catherine E.;Winkler, Ingrid G.;Levesque, Jean-Pierre
静止的造血干细胞（hsc）优先存在于可能相对缺氧的灌注不良的壁龛中。缺氧的大多数细胞效应是由o2不稳定的缺氧诱导转录因子（hif）介导的。为了研究缺氧对造血干细胞的影响，我们通过注射2种结构无关的脯氨酸羟化酶结构域（PHD）酶抑制剂：二甲基氧基酰甘氨酸和FG-4497，阻断了小鼠体内o -2依赖性HIF-1 α的降解。注射这两种PHD抑制剂中的任何一种都能稳定BM中HIF-1 α蛋白的表达。这些PHD抑制剂在体内稳定HIF-1 α增加了细胞周期G(0)期表型造血干细胞和未成熟造血祖细胞的比例，并通过5-溴-2' -脱氧尿苷掺入测量了它们的增殖。这种作用与促红细胞生成素无关，促红细胞生成素的表达在PHD抑制剂的作用下增加。最后，在严重的、亚致死的9.0 gy辐照前，用HIF-1 α稳定剂预处理小鼠，改善了血液恢复，并使受辐照小鼠BM中的HSC存活率提高了89倍。本研究的结果表明，HIF-1 α蛋白的水平可以在体内通过药理学方法来控制，以增加辐照后HSC的静止和恢复。(血。2013;121 (5):759 - 769)
Quiescent hematopoietic stem cells (HSCs) preferentially reside in poorly perfused niches that may be relatively hypoxic. Most of the cellular effects of hypoxia are mediated by O-2-labile hypoxia-inducible transcription factors (HIFs). To investigate the effects of hypoxia on HSCs, we blocked O-2-dependent HIF-1 alpha degradation in vivo in mice by injecting 2 structurally unrelated prolyl hydroxylase domain (PHD) enzyme inhibitors: dimethyloxalyl glycine and FG-4497. Injection of either of these 2 PHD inhibitors stabilized HIF-1 alpha protein expression in the BM. In vivo stabilization of HIF-1 alpha with these PHD inhibitors increased the proportion of phenotypic HSCs and immature hematopoietic progenitor cells in phase G(0) of the cell cycle and decreased their proliferation as measured by 5-bromo-2' -deoxyuridine incorporation. This effect was independent of erythropoietin, the expression of which was increased in response to PHD inhibitors. Finally, pretreatment of mice with a HIF-1 alpha stabilizer before severe, sublethal 9.0-Gy irradiation improved blood recovery and enhanced 89-fold HSC survival in the BM of irradiated mice as measured in long-term competitive repopulation assays. The results of the present study demonstrate that the levels of HIF-1 alpha protein can be manipulated pharmacologically in vivo to increase HSC quiescence and recovery from irradiation. (Blood. 2013;121(5):759-769)