Foxo3a is essential for maintenance of the hematopoietic stem cell pool.
Open accessAbstract
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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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.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [16]
p38 plays an important role in regulating HSC self-renewal.
“p38 plays an important role in regulating HSC self-renewal”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [36]
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”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [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.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [89]
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.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [89]
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“(B) Relative expression of selfrenewal genes (Bmi1, Foxo3, Mpl, and Mycn) calculated by first normalizing to Gusb within each group, then normalizing to Cebpa+/+ vehicle group from MPP3 cell culture at 12 h. (C)MPP3 CFU assay (data are representative of two experiments with n = 3 or 6 per group): third and fourth plat…”
BackgroundResultInfluentialBlood on the tracks: hematopoietic stem cell-endothelial cell interactions in homing and engraftment
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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
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2238 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- 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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