Molecular aging and rejuvenation of human muscle stem cells.
Molecular aging and rejuvenation of human muscle stem cells.
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DOI：
10.1002/emmm.200900045
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发表时间：
2009-11
影响因子：
11.1
通讯作者：
Conboy, Irina
中科院分区：
文献类型：
--
作者：
Carlson, Morgan E.;Suetta, Charlotte;Conboy, Michael J.;Aagaard, Per;Mackey, Abigail;Kjaer, Michael;Conboy, Irina
关于人类器官干细胞的调节（一般来说，以及在衰老过程中），我们所知甚少，而且以前的大多数数据都是在短命的啮齿动物中收集的。我们研究了啮齿类动物的干细胞衰老是否可以外推到遗传和环境可变的人类。我们的发现建立了人类干细胞衰老的关键进化保守机制。我们发现，卫星细胞维持在老年人骨骼肌中，但由于Notch的活化减少以及转化生长因子β（TGF-β）/磷酸化Smad 3（pSmad 3）的升高而不能响应于肌肉磨损而活化。此外，这项工作表明，丝裂原活化蛋白激酶（MAPK）/磷酸细胞外信号调节激酶（pERK）信号在人类肌肉中随着年龄的增长而下降，并且对于激活人类肌肉干细胞中的Notch很重要。这种分子理解，结合人类卫星细胞本质上保持年轻的数据，引入了新的治疗靶点。事实上，MAPK/Notch的激活恢复了对70岁人类卫星细胞的“年轻”肌原性反应，使它们与20岁人类的细胞相似。这些发现有力地表明，人类肌肉维护和修复的老化可以通过特定分子途径的“年轻”校准来逆转。
Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-β)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intrinsically young, introduced novel therapeutic targets. Indeed, activation of MAPK/Notch restored ‘youthful’ myogenic responses to satellite cells from 70-year-old humans, rendering them similar to cells from 20-year-old humans. These findings strongly suggest that aging of human muscle maintenance and repair can be reversed by ‘youthful’ calibration of specific molecular pathways.
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影响因子：
5.5
作者：
Pistilli, Emidio E.;Siu, Parco M.;Alway, Stephen E.
通讯作者：
Alway, Stephen E.
影响因子：
5.5
作者：
Crameri, R. M.;Aagaard, P.;Kjaer, M.
通讯作者：
Kjaer, M.
影响因子：
5.2
作者：
Collins, Charlotte A.;Zammit, Peter S.;Partridge, Terence A.
通讯作者：
Partridge, Terence A.
影响因子：
11.8
作者：
Conboy, IM;Rando, TA
通讯作者：
Rando, TA
影响因子：
2.7
作者：
Carmena, A;Buff, E;Michelson, AM
通讯作者：
Michelson, AM