Regulation of the HIF-1alpha level is essential for hematopoietic stem cells - PubMed (original) (raw)
. 2010 Sep 3;7(3):391-402.
doi: 10.1016/j.stem.2010.06.020.
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- PMID: 20804974
- DOI: 10.1016/j.stem.2010.06.020
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Regulation of the HIF-1alpha level is essential for hematopoietic stem cells
Keiyo Takubo et al. Cell Stem Cell. 2010.
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Abstract
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-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 p16(Ink4a)/p19(Arf)-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.
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Comment in
- Hypoxia signaling in hematopoietic stem cells: a double-edged sword.
Pollard PJ, Kranc KR. Pollard PJ, et al. Cell Stem Cell. 2010 Sep 3;7(3):276-8. doi: 10.1016/j.stem.2010.08.006. Cell Stem Cell. 2010. PMID: 20804963 No abstract available. - Metabolic makeover for HSCs.
Warr MR, Passegué E. Warr MR, et al. Cell Stem Cell. 2013 Jan 3;12(1):1-3. doi: 10.1016/j.stem.2012.12.005. Cell Stem Cell. 2013. PMID: 23290130
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