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Cited by 891Hematopoietic Stem Cell TransplantationCancer, Hypoxia, and MetabolismMesenchymal stem cell research

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

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Takubo, Keiyo, Goda, Nobuhito, Yamada, Wakako, Iriuchishima, Hirono, Ikeda, Eiji, Kubota, Yoshiaki, Shima, Haruko, Johnson, Randall S. +3 more·2010·Cell Stem Cell
DOI 10.1016/j.stem.2010.06.020
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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-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.

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  • Cebpa-deficient MPPGM show nearly identical patterns of overexpression in genes like Bmi1, Foxo3 and Mycn.

    “Our previously published analysis (Higa et al., 2021) of Cebpa-deficient MPPGM shows nearly identical patterns of overexpression in genes like Bmi1, Foxo3 and Mycn (Tothova et al., 2007; Takubo et al., 2010; Merchant et al., 2011; Warr et al., 2013; Murakami et al., 2014; Scognamiglio et al., 2016).”

    From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Takubo et al., 2010

    The Results passages discuss Bmi1-mediated rescue in HIF-1α-deficient stem cells and Foxo3a as a marker of quiescent stem cells (page unavailable). A search for Cebpa-deficient MPPGM, Mycn, and the claimed overexpression pattern found no passage addressing that comparison. The citing sentence identifies the analysis as Higa et al.'s own; Takubo et al. does not verify its reported pattern in our copy. (LLM, conf=0.76)

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Authors
Takubo, K., Goda, N., Yamada, W., Iriuchishima, H., Ikeda, E., Kubota, Y., Shima, H., Johnson, R. S., Hirao, A., Suematsu, M., & Suda, T.
Affiliations
  • Keio University (JP)
  • Waseda University (JP)
  • Yamaguchi University (JP)
  • University of California San Diego (US)
  • Kanazawa University (JP)
Corresponding author
  • Takubo, Keiyo
  • Suda, Toshio
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2010-09
Volume
7
Issue
3
Pages
391-402
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2010.06.020
OpenAlex
W2068141056
Cited by
891
References
3
Citations by year
2026: 17 · 2025: 27 · 2024: 37 · 2023: 41 · 2022: 62 · 2021: 59 · 2020: 62 · 2019: 59 · 2018: 61 · 2017: 54 · 2016: 58 · 2015: 80 · 2014: 69 · 2013: 77 · 2012: 78
FWCI
40.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science (21390290)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
hematopoietic stem cells, HIF-1α, protein stabilization, hypoxia, endosteal niche, bone marrow, cell cycle quiescence, VHL E3 ubiquitin ligase, bone marrow transplantation, myelosuppression, aging, HSC maintenance
MeSH terms
Animals, Hypoxia, Bone Marrow, Cell Count, Cell Cycle, Hematopoietic Stem Cells, Homeostasis, Bone Marrow Transplantation, Mice, Knockout, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Stem Cell Niche

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