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

    Research output: Contribution to journalArticle

    487 Citations (Scopus)

    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-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.

    Original languageEnglish
    Pages (from-to)391-402
    Number of pages12
    JournalCell Stem Cell
    Volume7
    Issue number3
    DOIs
    Publication statusPublished - 2010 Sep 3

    Fingerprint

    Hypoxia-Inducible Factor 1
    Hematopoietic Stem Cells
    Cell Cycle
    Bone Marrow Transplantation
    Bone Marrow
    Stem Cell Niche
    Ubiquitin-Protein Ligases
    Cell Count
    Transplantation

    ASJC Scopus subject areas

    • Cell Biology
    • Molecular Medicine
    • Genetics

    Cite this

    Takubo, K., Goda, N., Yamada, W., Iriuchishima, H., Ikeda, E., Kubota, Y., ... Suda, T. (2010). Regulation of the HIF-1α level is essential for hematopoietic stem cells. Cell Stem Cell, 7(3), 391-402. https://doi.org/10.1016/j.stem.2010.06.020

    Regulation of the HIF-1α level is essential for hematopoietic stem cells. / Takubo, Keiyo; Goda, Nobuhito; Yamada, Wakako; Iriuchishima, Hirono; Ikeda, Eiji; Kubota, Yoshiaki; Shima, Haruko; Johnson, Randall S.; Hirao, Atsushi; Suematsu, Makoto; Suda, Toshio.

    In: Cell Stem Cell, Vol. 7, No. 3, 03.09.2010, p. 391-402.

    Research output: Contribution to journalArticle

    Takubo, K, Goda, N, Yamada, W, Iriuchishima, H, Ikeda, E, Kubota, Y, Shima, H, Johnson, RS, Hirao, A, Suematsu, M & Suda, T 2010, 'Regulation of the HIF-1α level is essential for hematopoietic stem cells', Cell Stem Cell, vol. 7, no. 3, pp. 391-402. https://doi.org/10.1016/j.stem.2010.06.020
    Takubo, Keiyo ; Goda, Nobuhito ; Yamada, Wakako ; Iriuchishima, Hirono ; Ikeda, Eiji ; Kubota, Yoshiaki ; Shima, Haruko ; Johnson, Randall S. ; Hirao, Atsushi ; Suematsu, Makoto ; Suda, Toshio. / Regulation of the HIF-1α level is essential for hematopoietic stem cells. In: Cell Stem Cell. 2010 ; Vol. 7, No. 3. pp. 391-402.
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