Regulation of the HIF-1α Level Is Essential for Hematopoietic Stem Cells

• Published in: Cell stem cell 2010-09, Vol.7 (3), p.391-402
• Main Authors: Takubo, Keiyo, Goda, Nobuhito, Yamada, Wakako, Iriuchishima, Hirono, Ikeda, Eiji, Kubota, Yoshiaki, Shima, Haruko, Johnson, Randall S., Hirao, Atsushi, Suematsu, Makoto, Suda, Toshio
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; STEMCELL
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2010.06.020

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 p16 Ink4a/p19 Arf-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. ► Hematopoietic stem cells (HSCs) are highly hypoxic and stably express HIF-1α ► HIF-1α Δ/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