Cited by 66Hematopoietic Stem Cell TransplantationFOXO transcription factor regulationReproductive Biology and Fertility

Foxo3a is essential for maintenance of the hematopoietic stem cell pool.

Open access
Miyamoto, Kana, Araki, Kiyomi Y., Naka, Kazuhito, Arai, Fumio, Takubo, Keiyo, Yamazaki, Satoshi, Matsuoka, Sahoko, Miyamoto, Takeshi +11 more·2007·Cell stem cell

Abstract

Hematopoietic stem cells (HSCs) are maintained in an undifferentiated quiescent state within a bone marrow niche. Here we show that Foxo3a, a forkhead transcription factor that acts downstream of the PTEN/PI3K/Akt pathway, is critical for HSC self-renewal. We generated gene-targeted Foxo3a(-/-) mice and showed that, although the proliferation and differentiation of Foxo3a(-/-) hematopoietic progenitors were normal, the number of colony-forming cells present in long-term cocultures of Foxo3a(-/-) bone marrow cells and stromal cells was reduced. The ability of Foxo3a(-/-) HSCs to support long-term reconstitution of hematopoiesis in a competitive transplantation assay was also impaired. Foxo3a(-/-) HSCs also showed increased phosphorylation of p38MAPK, an elevation of ROS, defective maintenance of quiescence, and heightened sensitivity to cell-cycle-specific myelotoxic injury. Finally, HSC frequencies were significantly decreased in aged Foxo3a(-/-) mice compared to the littermate controls. Our results demonstrate that Foxo3a plays a pivotal role in maintaining the HSC pool.

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Crossref · 10.1016/j.stem.2007.02.001

Cites

37 of 37 references verified0 citation errors · 0 not checkable

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  • Age-dependent alterations in SOD2 regulation by FoxO3 and ATM contribute to loss of HSC function with aging.

    “age-dependent alterations in regulation of SOD2 by FoxO3 and the DNA damage sensing serine/threonine protein kinase ATM (ataxia-telangiectasia mutated) have been shown to contribute to loss of HSC function with aging11,16, 24.”
  • p38 plays an important role in regulating HSC self-renewal.

    “p38 plays an important role in regulating HSC self-renewal”
  • Activation of p38 by oxidative stress can mediate induction of HSC senescence in Atm mutants and FoxO3 KO mice via upregulation of p16.

    “activation of p38 by oxidative stress can mediate induction of HSC senescence in Atm mutants and FoxO3 KO mice via upregulation of p16.21,36”
  • FOXO transcription factors integrate growth factors and stress signal transduction pathways, and may represent a hub for the action of various systemic factors in stem cells in ageing brain, muscle, blood and intestine.

    “For example, FOXO transcription factors integrate growth factors and stress signal transduction pathways, and may represent a ‘hub’ for the action of various systemic factors in stem cells in ageing brain, muscle, blood and intestine32,85–90.”
  • Constitutive deletion of three of the FOXO genes (FOXO1, FOXO3 and FOXO4) in the MuSC lineage during development results in the impairment of postnatal establishment of the MuSC population and a more rapid MuSC depletion with age.

    “Consistent with previous reports of the role of FOXO factors in HSC, MuSC and NSC quiescence85–90, constitutive deletion of three of the FOXO genes (FOXO1, FOXO3 and FOXO4) in the MuSC lineage during development results in the impairment of postnatal establishment of the MuSC population and a more rapid MuSC depletion with age32.”

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Authors
Miyamoto, K., Araki, K. Y., Naka, K., Arai, F., Takubo, K., Yamazaki, S., Matsuoka, S., Miyamoto, T., Ito, K., Ohmura, M., Chen, C., Hosokawa, K., Nakauchi, H., Nakayama, K., Nakayama, K. I., Harada, M., Motoyama, N., Suda, T., & Hirao, A.
Affiliations
  • Kyushu University (JP)
  • National Center for Geriatrics and Gerontology (JP)
  • Kanazawa University (JP)
  • Keio University (JP)
  • Institute of Medical Science, The University of Tokyo (JP)
Corresponding author
  • Motoyama, Noboru
  • Suda, Toshio
  • Hirao, Atsushi
Venue
Cell stem cell
Publisher
Elsevier BV
Published
2007-06
Volume
1
Issue
1
Pages
101-112
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
OpenAlex
W1608717948
Cited by
41
References
38
Citations by year
2013: 8 · 2012: 14
FWCI
1.70
Type
journal article
Language
en
Open access
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology
  • Ministry of Health, Labour and Welfare
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
FOXO3, hematopoietic stem cells, HSC self-renewal, HSC quiescence, bone marrow microenvironment, PTEN/PI3K/AKT pathway, p38 MAPK phosphorylation, reactive oxygen species, myelosuppression, aging, long-term reconstitution, hematopoietic progenitor cells
MeSH terms
Forkhead Box Protein O3, Animals, Cell Differentiation, Enzyme Activation, Flow Cytometry, Hematopoietic Stem Cells, Apoptosis, p38 Mitogen-Activated Protein Kinases, Cell Proliferation, Mice, Forkhead Transcription Factors

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