Modeling Duchenne muscular dystrophy using patient-derived iPS cells

在这项研究中，我们使用患者来源的iPS细胞证明了Duchenne肌营养不良症(DMD)的早期发病机制。从DMD-iPSCs分化而来的DMD-肌肉表现出与对照IPSC来源的肌肉相似的基因表达谱和相似的成熟度，并且没有观察到DMD-肌肉的分化延迟。当DMD肌肉受到电刺激时，DMD肌肉的细胞内钙内流高于对照肌肉。离子霉素引起的钙超载对DMD肌的细胞损伤较对照肌大。由于这些表型可以通过外显子跳跃技术恢复dystrophin的表达而得到改善，我们得出结论，过量的钙内流是由dystrophin缺失引起的DMD早期发病的触发因素。根据我们的研究结果，我们将通过分析Dystrophin缺失引起的机制来开发针对过度钙内流的新药。

In this study, we demonstrated the early pathogenesis of Duchenne muscular dystrophy (DMD) using patient-derived iPS cells. DMD-muscles differentiated from DMD-iPSCs exhibited similar gene expression profile and similar maturity as control iPSC-derived muscles, and no differentiation delay was observed in DMD-muscles. When DMD-muscles were exposed to electric stimulation, higher intracellular Ca2+ influx was observed in DMD-muscles than control-muscles. Larger cell damage was observed in DMD-muscles than control-muscles through overloading Ca2+ by ionomycin. Since these phenotype could be ameliorated by restored dystrophin expression by exon skip technics, we conclude that excessive Ca2+ influx is the trigger for the early pathogenesis of DMD caused by absence of dystrophin. According to our findings, we are going to develop new drugs targeting excessive Ca2+ influx by analyzing the mechanism which is caused by absence of dystrophin.