Cell Stem Cell
Volume 7, Issue 3, 3 September 2010, Pages 391-402
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Article
Regulation of the HIF-1α Level Is Essential for Hematopoietic Stem Cells

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Summary

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-1α (HIF-1α) protein. In HIF-1α-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-1α by biallelic loss of an E3 ubiquitin ligase for HIF-1α (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-1α levels.

Highlights

► Hematopoietic stem cells (HSCs) are highly hypoxic and stably express HIF-1α ► HIF-1αΔ/Δ mice show defective HSC function ► Overstabilizing HIF-1α through knockout of VHL also causes HSC defects ► Partial HIF-1α stabilization in VHL+/Δ heterozygotes improves HSC capacity

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