A Disintegrin and Metalloprotease 10 (ADAM10) Is Indispensable for Maintenance of the Muscle Satellite Cell Pool
A Disintegrin and Metalloprotease 10 (ADAM10) Is Indispensable for Maintenance of the Muscle Satellite Cell Pool
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DOI：
10.1074/jbc.m115.653477
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发表时间：
2015-11-20
影响因子：
4.8
通讯作者：
Horiuchi, Keisuke
中科院分区：
文献类型：
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作者：
Mizuno, Sakiko;Yoda, Masaki;Horiuchi, Keisuke
卫星细胞（SC）是肌肉特异性干细胞，对受损肌肉的再生至关重要。虽然SC具有强大的再生肌纤维的能力，但SC的数量随着衰老而减少，导致肌肉损伤后恢复不足。我们在此表明，ADAM10（一种去整合素和金属蛋白酶10），一种膜结合蛋白水解酶，在Notch加工（S2切割）中具有关键作用，对于维持SC静止是必不可少的。我们产生了突变小鼠，其中干细胞中的ADAM10可以通过他莫昔芬注射有条件地消除。他莫昔芬处理的突变小鼠没有表现出任何明显的缺陷，并在未经挑战的条件下正常生长。然而，这些小鼠在化学诱导的肌肉损伤后显示出几乎完全丧失肌肉再生，原位杂交和流式细胞术分析显示，与野生型对照相比，突变小鼠具有显著更少的SC。值得注意的是，我们发现在SC中ADAM10的失活严重损害Notch信号传导，并导致肌源性分化失调，最终导致体内SC池的剥夺。总之，本研究结果强调了ADAM 10作为SC中Notch信号传导和维持SC池的不可或缺的组分的作用。
Satellite cells (SCs) are muscle-specific stem cells that are essential for the regeneration of damaged muscles. Although SCs have a robust capacity to regenerate myofibers, the number of SCs decreases with aging, leading to insufficient recovery after muscle injury. We herein show that ADAM10 (a disintegrin and metalloprotease 10), a membrane-bound proteolytic enzyme with a critical role in Notch processing (S2 cleavage), is essential for the maintenance of SC quiescence. We generated mutant mice in which ADAM10 in SCs can be conditionally abrogated by tamoxifen injection. Tamoxifen-treated mutant mice did not show any apparent defects and grew normally under unchallenged conditions. However, these mice showed a nearly complete loss of muscle regeneration after chemically induced muscle injury, in situ hybridization and flow cytometric analyses revealed that the mutant mice had significantly less SCs compared with wild type controls. Of note, we found that inactivation of ADAM10 in SCs severely compromised Notch signaling and led to dysregulated myogenic differentiation, ultimately resulting in deprivation of the SC pool in vivo. Taken together, the present findings underscore the role of ADAM 10 as an indispensable component of Notch signaling in SCs and for maintaining the SC pool.