Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.
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.
Takubo
Keiyo
K
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan. keiyot@gmail.com
Goda
Nobuhito
N
Yamada
Wakako
W
Iriuchishima
Hirono
H
Ikeda
Eiji
E
Kubota
Yoshiaki
Y
Shima
Haruko
H
Johnson
Randall S
RS
Hirao
Atsushi
A
Suematsu
Makoto
M
Suda
Toshio
T
D000818:Animals; D001853:Bone Marrow; D016026:Bone Marrow Transplantation; D002452:Cell Count; D002453:Cell Cycle; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D006706:Homeostasis; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055153:Stem Cell Niche / Q000166:cytology / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit