Regulation of the HIF-1α Level Is Essential for Hematopoietic Stem Cells
Regulation of the HIF-1α Level Is Essential for Hematopoietic Stem Cells
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DOI：
10.1016/j.stem.2010.06.020
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发表时间：
2010-09-03
期刊：
影响因子：
23.9
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Takubo, Keiyo;Goda, Nobuhito;Suda, Toshio
造血干细胞（hsc）维持在一个特定的微环境称为干细胞生态位。哺乳动物造血干细胞在骨髓的缺氧区（BM）内皮生态位中保持静止。在这项研究中，我们发现正常造血干细胞维持细胞内缺氧并稳定缺氧诱导因子-1 α (HIF-1 α)蛋白。在HIF-1 α缺陷小鼠中，HSC在各种应激环境下（包括骨髓移植、骨髓抑制或衰老）以p16(Ink4a)/p19（Arf）依赖的方式失去细胞周期静止，HSC数量减少。HIF-1 α (VHL)的E3泛素连接酶双等位基因缺失导致的HIF-1 α过度稳定诱导造血干细胞及其祖细胞的细胞周期静止，但导致移植能力受损。相比之下，在骨髓移植过程中，VHL的单等位基因缺失诱导细胞周期静止并改善骨髓移植。这些数据表明造血干细胞通过精确调节HIF-1 α水平维持细胞周期静止。
Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Mammalian HSCs are kept quiescent in the endosteal niche, a hypoxic zone of the bone marrow (BM). In this study, we show that normal HSCs maintain intracellular hypoxia and stabilize hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein. In HIF-1 alpha-deficient mice, the HSCs lost their cell cycle quiescence and HSC numbers decreased during various stress settings including bone marrow transplantation, myelosuppression, or aging, in a p16(Ink4a)/p19(Arf)-dependent manner. Overstabilization of HIF-1 alpha by biallelic loss of an E3 ubiquitin ligase for HIF-1 alpha (VHL) induced cell cycle quiescence in HSCs and their progenitors but resulted in an impairment in transplantation capacity. In contrast, monoallelic loss of VHL induced cell cycle quiescence and improved BM engraftment during bone marrow transplantation. These data indicate that HSCs maintain cell cycle quiescence through the precise regulation of HIF-1 alpha levels.