Molecular mechanisms for hematopoietic stem cells by HIF-1/VHL regulatory system

造血干细胞(HSCs)维持在一个特定的微环境中，称为干细胞生态位。哺乳动物的HSCs在骨内壁龛中保持静止，这是骨髓(BM)的缺氧区。我们发现，正常的HSC维持细胞内的低氧，并稳定低氧诱导因子-1α(HIF-1α)蛋白。在HIF-1α缺陷小鼠中，HSC在包括骨髓移植、骨髓抑制或衰老在内的各种应激条件下，以p16INK4a/p19Arf依赖的方式失去了细胞周期停滞，HSC数量减少。HIF-1α的E3泛素连接酶双等位基因缺失(VHL)导致HIF-1α过度稳定，导致HSCs及其前体细胞周期停滞，但导致移植能力受损。相反，在骨髓移植过程中，VHL的单等位基因丢失导致细胞周期停滞，并改善了骨髓植入。这些数据表明，HSCs通过精确调节HIF-1α水平来维持细胞周期的静止。

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). We found that normal HSCs maintain intracellular hypoxia and stabilize hypoxia-inducible factor-1alpha (HIF-1alpha) protein. In HIF-1alpha-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 p16Ink4a/p19Arf-dependent manner. Overstabilization of HIF-1alpha by biallelic loss of an E3 ubiquitin ligase for HIF-1alpha (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-1alpha levels.