Geriatric muscle stem cells switch reversible quiescence into senescence
Geriatric muscle stem cells switch reversible quiescence into senescence
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DOI：
10.1038/nature13013
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发表时间：
2014-02-20
期刊：
影响因子：
64.8
通讯作者：
Munoz-Canoves, Pura
中科院分区：
文献类型：
--
作者：
Sousa-Victor, Pedro;Gutarra, Susana;Munoz-Canoves, Pura
骨骼肌的再生依赖于成体干细胞(卫星细胞)的数量，这些细胞在一生中保持静止。卫星细胞的再生功能随着年龄的增长而下降。在此，我们报道了老年卫星细胞在肌肉动态平衡条件下不能维持其正常的静止状态，这不可逆转地影响其固有的再生和自我更新能力。在老年小鼠中，静止的卫星细胞通过转换到不可逆的预衰老状态而失去可逆的静止，这种状态是由p16(INK4a)(也称为CDKN2a)的去抑制引起的。在受伤时，这些细胞无法激活和扩张，即使在年轻的环境中也会加速进入完全衰老状态(GERO转换)。老年卫星细胞中p16(INK4a)的沉默可以恢复静止和肌肉再生功能。我们的结果表明，成年生命中保持平静依赖于对衰老途径的主动抑制。由于p16(INK4a)在人类老年卫星细胞中调节失调，这些发现为骨骼肌干细胞再生提供了基础。
Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16(INK4a) (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16(INK4a) silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16(INK4a) is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.