TY - JOUR
T1 - Regulation of the HIF-1α level is essential for hematopoietic stem cells
AU - Takubo, Keiyo
AU - Goda, Nobuhito
AU - Yamada, Wakako
AU - Iriuchishima, Hirono
AU - Ikeda, Eiji
AU - Kubota, Yoshiaki
AU - Shima, Haruko
AU - Johnson, Randall S.
AU - Hirao, Atsushi
AU - Suematsu, Makoto
AU - Suda, Toshio
N1 - Funding Information:
We thank T. Kitamura for providing Plat E packaging cells; A. Iwama for providing Bmi1 retroviral vector; K. Rajewsky for providing Mx1-Cre mice; V. Haase for providing VHL flox/flox mice; H. Saya and M.C. Simon for fruitful suggestions; T. Muraki, A. Kumakubo, and T. Hirose for essential support; and F. Arai, T. Naito, N. Tago, and A. Ono for FACS operation. K.T. was a research fellow of JSPS supported by the Global COE Programs for Human Metabolomic Systems Biology and for Stem Cell Medicine and also in part by a MEXT Grant-in-Aid for Young Scientists (B) and a Grant-in-Aid for Scientific Research on Priority Areas. A.H. and M.S. were supported in part by a MEXT Grant-in-Aid for Creative Scientific Research 17GS0419. M.S. supported FACS analysis as the Leader of ERATO, JST, Suematsu Gas Biology Project. T.S. was supported by a MEXT Grant-in-Aid for Specially Promoted Research.
PY - 2010/9/3
Y1 - 2010/9/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stem.2010.06.020
DO - 10.1016/j.stem.2010.06.020
M3 - Article
C2 - 20804974
AN - SCOPUS:77956217067
SN - 1934-5909
VL - 7
SP - 391
EP - 402
JO - Cell stem cell
JF - Cell stem cell
IS - 3
ER -