Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells
Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells
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DOI：
10.1002/stem.2743
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发表时间：
2018-02-01
期刊：
影响因子：
5.2
通讯作者：
Ono, Yusuke
中科院分区：
文献类型：
--
作者：
Fujimaki, Shin;Seko, Daiki;Ono, Yusuke
卫星细胞是肌肉组织干细胞，表达三种Notch受体(Notch1-3)。Notch1和Notch2在卫星细胞中的功能到目前为止还没有得到充分的评价。我们利用三苯氧胺诱导的卫星细胞特异性条件基因敲除小鼠的Notch1(N1-scKO)、Notch2(N2-scKO)和Notch1/Notch2(ScDKO)基因，研究了Notch1和Notch2在成年骨骼肌成肌进展中的作用。在静止状态下，n2-scKO小鼠的卫星细胞数略有减少，而n1-scKO小鼠的卫星细胞数不明显，而scDKO小鼠的卫星细胞数几乎完全耗尽。N1-scKO和N2-scKO小鼠均表现出心脏毒素注射诱导的肌肉再生缺陷，而scDKO小鼠肌肉再生严重受损，并出现明显的纤维化。在激活状态下，单独消融卫星细胞中的Notch1或Notch2阻止了群体扩张和自我更新，但诱导了过早的肌肉生成。因此，我们的结果表明，Notch1和Notch2通过阻止激活来协调维持静止期的干细胞库，并在激活状态下调节干细胞命运的决定，从而控制成年肌肉的再生。
Satellite cells, the muscle tissue stem cells, express three Notch receptors (Notch1-3). The function of Notch1 and Notch2 in satellite cells has to date not been fully evaluated. We investigated the role of Notch1 and Notch2 in myogenic progression in adult skeletal muscle using tamoxifen-inducible satellite cell-specific conditional knockout mice for Notch1 (N1-scKO), Notch2 (N2-scKO), and Notch1/Notch2 (scDKO). In the quiescent state, the number of satellite cells was slightly reduced in N2-scKO, but not significantly in N1-scKO, and almost completely depleted in scDKO mice. N1-scKO and N2-scKO mice both exhibited a defect in muscle regeneration induced by cardiotoxin injection, while muscle regeneration was severely compromised with marked fibrosis in scDKO mice. In the activated state, ablation of either Notch1 or Notch2 alone in satellite cells prevented population expansion and self-renewal but induced premature myogenesis. Therefore, our results indicate that Notch1 and Notch2 coordinately maintain the stem-cell pool in the quiescent state by preventing activation and regulate stem-cell-fate decision in the activated state, governing adult muscle regeneration.