细胞生物学
骨骼肌
衰老
干细胞
再生(生物学)
老化
心肌细胞
肌萎缩
生物
内分泌学
遗传学
作者
Laura García‐Prat,Eusebio Perdiguero,Sonia Alonso-Martín,Stefania Dell’Orso,Srikanth Ravichandran,Stephen R. Brooks,Aster H. Juan,Silvia Campanario,Kan Jiang,Xiaotong Hong,Laura Ortet,Vanessa Ruiz‐Bonilla,Marta Flández,Victoria Moiseeva,Elena Rebollo,Mercè Jardı́,Hong‐Wei Sun,Antonio Musarò,Marco Sandri,Antonio del Sol,Vittorio Sartorelli,Pura Muñoz‐Cánoves
标识
DOI:10.1038/s41556-020-00593-7
摘要
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. García-Prat, Perdiguero, Alonso-Martín et al. show that skeletal muscle contains a subpopulation of quiescent stem cells, maintained by FoxO signalling, that is preserved into late life but declines in advanced geriatric age.
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