The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age
Abstract
Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent stem-cell states distinguished by relative CD34 expression: CD34 High, with stemness properties (genuine state), and CD34 Low, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle.
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In the citing paper
“In muscle, MuSCs also exist as a heterogeneous quiescent population in adult mice30–33, with changes in heterogeneity with ageing32,34,35.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [32]
In the citing paper
“For example, subpopulations of MuSCs become more ‘primed’ (that is, poised towards a myogenic fate) with ageing32, whereas others adopt a more fibrogenic state16.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [32]
In the citing paper
“A subpopulation of MuSCs (identified by higher levels of CD34) appears to be preserved during ageing32.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [32]
In the citing paper
“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 [32]
In the citing paper
“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 [32]
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Metadata
- Authors
- García-Prat, L., Perdiguero, E., Alonso-Martín, S., Dell’Orso, S., Ravichandran, S., Brooks, S. R., Juan, A. H., Campanario, S., Jiang, K., Hong, X., Ortet, L., Ruiz-Bonilla, V., Flández, M., Moiseeva, V., Rebollo, E., Jardí, M., Sun, H.-W., Musarò, A., Sandri, M., del Sol, A., Sartorelli, V., & Muñoz-Cánoves, P.
- Affiliations
- Universitat Pompeu Fabra (ES)
- National Institutes of Health (US)
- University of Luxembourg (LU)
- Spanish National Centre for Cardiovascular Research (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Istituto Pasteur (IT)
- University of Padua (IT)
- Corresponding author
- Ravichandran, Srikanth
- Sartorelli, Vittorio
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2020-10-26
- Volume
- 22
- Issue
- 11
- Pages
- 1307-1318
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W3094513505
- Cited by
- 161
- References
- 65
- Citations by year
- 2026: 20 · 2025: 22 · 2024: 28 · 2023: 29 · 2022: 38 · 2021: 23 · 2020: 1
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- FOXO, skeletal muscle stem cells, stem cell quiescence, aging, CD34, stem cell heterogeneity, insulin-like growth factor I, Akt signaling, myogenesis, muscle regeneration
- MeSH terms
- Cell Self Renewal, Forkhead Box Protein O1, Forkhead Box Protein O3, Age Factors, Animals, Cells, Cultured, Gene Expression Regulation, Male, Mice, Inbred C57BL, Phenotype, Regeneration, Signal Transduction, Mice, SCID, Cellular Senescence, Mice, Knockout, Muscle, Skeletal, Cell Cycle Proteins, Antigens, CD34, Satellite Cells, Skeletal Muscle, Cell Proliferation, Proto-Oncogene Proteins c-akt, Forkhead Transcription Factors, Cardiotoxins, Stem Cell Niche
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