Brief Report: Blockade of Notch Signaling in Muscle Stem Cells Causes Muscular Dystrophic Phenotype and Impaired Muscle Regeneration
Brief Report: Blockade of Notch Signaling in Muscle Stem Cells Causes Muscular Dystrophic Phenotype and Impaired Muscle Regeneration
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DOI：
10.1002/stem.1319
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发表时间：
2013-04-01
期刊：
影响因子：
5.2
通讯作者：
Wu, Lizi
中科院分区：
文献类型：
--
作者：
Lin, Shuibin;Shen, Huangxuan;Wu, Lizi
肌肉萎缩症是一组以进行性肌肉无力和变性为特征的毁灭性疾病，其病因包括肌肉基因突变和肌肉干细胞再生缺陷。Notch信号对于骨骼肌的形成至关重要，在维持肌肉干细胞库和防止肌肉过早分化方面发挥着重要作用。为了研究Notch信号阻断对肌肉干细胞的功能影响，我们建立了一个条件敲入小鼠模型，在该模型中，内源性Notch信号在肌肉干细胞区室中被特异性阻断。肌肉干细胞Notch信号抑制小鼠表现出几种肌肉营养不良特征和肌肉再生受损。对卫星细胞和分离的原代成肌细胞的分析表明，肌肉干细胞中的Notch信号阻断导致卫星细胞的激活和增殖减少，但增强了成肌细胞的分化。因此，我们的数据表明，Notch信号控制着对肌肉萎缩症再生至关重要的过程，这表明Notch抑制剂治疗可能对肌肉功能有潜在的副作用。干细胞2013；31:823828
Muscular dystrophies are a group of devastating diseases characterized by progressive muscle weakness and degeneration, with etiologies including muscle gene mutations and regenerative defects of muscle stem cells. Notch signaling is critical for skeletal myogenesis and has important roles in maintaining the muscle stem cell pool and preventing premature muscle differentiation. To investigate the functional impact of Notch signaling blockade in muscle stem cells, we developed a conditional knock-in mouse model in which endogenous Notch signaling is specifically blocked in muscle stem cell compartment. Mice with Notch signaling inhibition in muscle stem cells showed several muscular dystrophic features and impaired muscle regeneration. Analyses of satellite cells and isolated primary myoblasts revealed that Notch signaling blockade in muscle stem cells caused reduced activation and proliferation of satellite cells but enhanced differentiation of myoblasts. Our data thus indicate that Notch signaling controls processes that are critical to regeneration in muscular dystrophy, suggesting that Notch inhibitor therapies could have potential side effects on muscle functions. STEM CELLS 2013;31:823828