Regulation of the HIF-1α level is essential for hematopoietic stem cells

Keiyo Takubo*, Nobuhito Goda, Wakako Yamada, Hirono Iriuchishima, Eiji Ikeda, Yoshiaki Kubota, Haruko Shima, Randall S. Johnson, Atsushi Hirao, Makoto Suematsu, Toshio Suda

*この研究の対応する著者

研究成果: Article査読

604 被引用数 (Scopus)

抄録

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/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.

本文言語English
ページ(範囲)391-402
ページ数12
ジャーナルCell Stem Cell
7
3
DOI
出版ステータスPublished - 2010 9 3

ASJC Scopus subject areas

  • 分子医療
  • 遺伝学
  • 細胞生物学

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