mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert
Open accessAbstract
A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term G(Alert). Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into G(Alert) and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-G(Alert) transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G(Alert) possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into G(Alert) functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.
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Inflammatory initiation of a cell cycle-primed Galert state in HSCs and other cells requires activation of mammalian target of rapamycin.
“inflammatory initiation of a cell cycle–primed Galert state in HSCs and other cells requires activation of mammalian target of rapamycin (Rodgers et al., 2014).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Rodgers et al., 2014
The Abstract states that injury-induced systemic signals produce GAlert and that mTORC1 is necessary for this transition in muscle satellite cells. The passage on long-term HSCs reports mTORC1 activation after muscle injury, but does not establish that mTORC1 is required for their transition or that inflammation initiates it. No page numbers are supplied in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPriming of activation by systemic signaling factors improves regeneration.
“Likewise, ‘priming’ of activation by systemic signaling factors has been reported to improve regeneration (Rodgers et al., 2014, 2017).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Rodgers et al., 2014
Across all clusters, there were no distinct cell-cycle states observed.
“Across all clusters, there were no distinct cell-cycle states observed, consistent with reports of the first division occurring ≥24 hours after our 18 h time point (Gilbert et al., 2010; Rodgers et al., 2014) (Fig. S2D).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Rodgers et al., 2014
Stable intermediary activation states might exist in vivo.
“For instance, although we do not observe bistable transcriptional states between the most-quiescent and most-activated cells in our experiments, stable intermediary activation states might exist in vivo (Rodgers et al., 2014).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Rodgers et al., 2014
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- Authors
- Rodgers, J. T., King, K. Y., Brett, J. O., Cromie, M. J., Charville, G. W., Maguire, K. K., Brunson, C., Mastey, N., Liu, L., Tsai, C.-R., Goodell, M. A., & Rando, T. A.
- Affiliations
- Stanford Medicine (US)
- Baylor College of Medicine (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Rando, Thomas A.
- ORCID
- Venue
- Nature
- Published
- 2014-05-25
- Volume
- 510
- Issue
- 7505
- Pages
- 393-396
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4065227
- OpenAlex
- W1964204876
- Cited by
- 776
- References
- 35
- Citations by year
- 2026: 48 · 2025: 51 · 2024: 65 · 2023: 93 · 2022: 71 · 2021: 72 · 2020: 64 · 2019: 63 · 2018: 59 · 2017: 80 · 2016: 43 · 2015: 53 · 2014: 14
- FWCI
- 25.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002324)
- China Scholarship Council
- National Institute on Aging (R37AG023806, K99AG041764, R01AG023806, F30AG035521, R01AG047820, P01AG036695)
- National Heart, Lung, and Blood Institute (K08HL098898)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK092883)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR062185)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- stem cell quiescence, mTORC1, muscle stem cells, satellite cells, hepatocyte growth factor, tissue regeneration, injury response, cell cycle entry
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Cell Cycle, Cells, Cultured, Gene Expression Regulation, Male, Mice, Inbred C57BL, Regeneration, Resting Phase, Cell Cycle, Muscle, Skeletal, Gene Expression Profiling, Satellite Cells, Skeletal Muscle, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases
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