FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age.
Nat Cell Biol
; 22(11): 1307-1318, 2020 11.
Article
em En
| MEDLINE
| ID: mdl-33106654
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regeneração
/
Senescência Celular
/
Músculo Esquelético
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Antígenos CD34
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Células Satélites de Músculo Esquelético
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Proliferação de Células
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Fatores de Transcrição Forkhead
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Autorrenovação Celular
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Nat Cell Biol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Espanha