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: CD34High, with stemness properties (genuine state), and CD34Low, 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.

FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age / Garcia-Prat, L.; Perdiguero, E.; Alonso-Martin, S.; Dell'Orso, S.; Ravichandran, S.; Brooks, S. R.; Juan, A. H.; Campanario, S.; Jiang, K.; Hong, X.; Ortet, L.; Ruiz-Bonilla, V.; Flandez, M.; Moiseeva, V.; Rebollo, E.; Jardi, M.; Sun, H. -W.; Musaro', A.; Sandri, M.; Sol, A.; Sartorelli, V.; Munoz-Canoves, P.. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 22:11(2020), pp. 1307-1318. [10.1038/s41556-020-00593-7]

FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age

MUSARO' A.;
2020

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: CD34High, with stemness properties (genuine state), and CD34Low, 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.
2020
aging; satellite cells; foxO; stem-cell
01 Pubblicazione su rivista::01a Articolo in rivista
FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age / Garcia-Prat, L.; Perdiguero, E.; Alonso-Martin, S.; Dell'Orso, S.; Ravichandran, S.; Brooks, S. R.; Juan, A. H.; Campanario, S.; Jiang, K.; Hong, X.; Ortet, L.; Ruiz-Bonilla, V.; Flandez, M.; Moiseeva, V.; Rebollo, E.; Jardi, M.; Sun, H. -W.; Musaro', A.; Sandri, M.; Sol, A.; Sartorelli, V.; Munoz-Canoves, P.. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 22:11(2020), pp. 1307-1318. [10.1038/s41556-020-00593-7]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1469084
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