Modeling the Pathogenesis of Charcot-Marie-Tooth Disease Type 1A Using Patient-Specific iPSCs.
Modeling the Pathogenesis of Charcot-Marie-Tooth Disease Type 1A Using Patient-Specific iPSCs.
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使用患者特异性 iPSC 模拟 1A 型腓骨肌萎缩症的发病机制
DOI：
10.1016/j.stemcr.2017.11.013
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发表时间：
2018-01-09
影响因子：
5.9
通讯作者：
Yao X
中科院分区：
文献类型：
--
作者：
Shi L;Huang L;He R;Huang W;Wang H;Lai X;Zou Z;Sun J;Ke Q;Zheng M;Lu X;Pei Z;Su H;Xiang AP;Li W;Yao X
腓骨肌萎缩症1A型（Charcot-Marie-Tooth disease type 1A，CMT 1A）是最常见的遗传性周围神经病之一，与PMP 22基因重复有关。以前对CMT 1A的研究主要依赖于啮齿动物模型，目前尚不清楚PMP 22过表达如何导致患者的表型。在这里，我们从两名CMT 1A患者中产生了人诱导多能干细胞（hiPSC）系作为体外细胞模型。我们发现，与正常对照细胞不同，CMT 1A hiPSCs很少通过神经嵴干细胞（NCSC）产生许旺细胞。相反，CMT 1A NCSC在Schwann细胞分化系统中产生了许多神经内膜成纤维细胞样细胞，并且在PMP 22过表达的iPSC模型中获得了类似的结果。因此，尽管CMT 1A的发病机理是脱髓鞘-髓鞘再生和/或髓鞘形成障碍理论，但许旺细胞的发育障碍可能被认为是CMT 1A的根本原因。我们的研究结果可能具有重要的意义，揭示了潜在的机制和发展的一个有前途的治疗策略CMT 1A神经病变。使用hiPSC衍生的NCSC对具有PMP 22复制的CMT 1A疾病进行建模，PMP 22复制可能导致NCSC的施旺细胞发育缺陷，PMP 22过表达的NCSC概括了CMT 1A NCSC的表型，PMP 22复制如何导致CMT 1A神经病仍有待阐明。在这篇文章中，Yao，Li及其同事表明，来自CMT 1A hiPSC的神经嵴干细胞（NCSC）具有许旺细胞的发育障碍;相比之下，CMT 1A NCSC在许旺细胞分化系统中产生许多神经内膜成纤维细胞样细胞。
Charcot-Marie-Tooth disease type 1A (CMT1A), one of the most frequent inherited peripheral neuropathies, is associated with PMP22 gene duplication. Previous studies of CMT1A mainly relied on rodent models, and it is not yet clear how PMP22 overexpression leads to the phenotype in patients. Here, we generated the human induced pluripotent stem cell (hiPSC) lines from two CMT1A patients as an in vitro cell model. We found that, unlike the normal control cells, CMT1A hiPSCs rarely generated Schwann cells through neural crest stem cells (NCSCs). Instead, CMT1A NCSCs produced numerous endoneurial fibroblast-like cells in the Schwann cell differentiation system, and similar results were obtained in a PMP22-overexpressing iPSC model. Therefore, despite the demyelination-remyelination and/or dysmyelination theory for CMT1A pathogenesis, developmental disabilities of Schwann cells may be considered as an underlying cause of CMT1A. Our results may have important implications for the uncovering of the underlying mechanism and the development of a promising therapeutic strategy for CMT1A neuropathy. Modeling CMT1A disease with PMP22 duplication using hiPSC-derived NCSCs PMP22 duplication may lead to Schwann cell developmental defect of NCSCs PMP22-overexpressing NCSCs recapitulate the phenotype of CMT1A NCSCs How PMP22 duplication leads to CMT1A neuropathy remains to be elucidated. In this article, Yao, Li, and colleagues show that neural crest stem cells (NCSCs) derived from CMT1A hiPSCs have developmental disabilities of Schwann cells; in contrast, CMT1A NCSCs generate numerous endoneurial fibroblast-like cells in the Schwann cell differentiation system.
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