Generation of neural cells from DM1 induced pluripotent stem cells as cellular model for the study of central nervous system neuropathogenesis.
Generation of neural cells from DM1 induced pluripotent stem cells as cellular model for the study of central nervous system neuropathogenesis.
复制标题
DM1 诱导多能干细胞产生神经细胞，作为研究中枢神经系统神经发病机制的细胞模型。
DOI：
10.1089/cell.2012.0086
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发表时间：
2013
影响因子：
1.6
通讯作者：
Ashizawa,Tetsuo
中科院分区：
文献类型：
--
作者：
Xia,Guangbin;Santostefano,KatherineE;Goodwin,Marianne;Liu,Jilin;Subramony,SH;Swanson,MauriceS;Terada,Naohiro;Ashizawa,Tetsuo
肌强直性肌营养不良1型（DM 1）是一种常染色体显性遗传的多系统疾病。中枢神经系统（CNS）受累的发病机制知之甚少。疾病特异性诱导多能干细胞（iPSC）系将提供一种替代模型。在这项研究中，我们产生了两个DM 1线和一个正常的iPSC线从真皮成纤维细胞通过逆转录病毒转导Yamanaka的四个因素（hOct 4，hSox 2，hKlf 4，和hc-Myc）。DM 1和对照iPSC克隆均显示出典型的人胚胎干细胞（hESC）生长模式，具有高的核质比。iPSC集落在随后的传代中保持相同的生长模式。所有iPSC系均表达干细胞标志物并分化成源自三个胚胎胚层的细胞。所有iPSC系经历正常神经分化。在DM 1 iPSC、神经干细胞（NSC）和终末分化的神经元和星形胶质细胞中检测到核内RNA灶（DM 1的标志）。总之，我们已经成功地建立了疾病特异性人DM 1 iPSC系、NSC和具有特异性核内RNA病灶的神经元谱系，这为CNS机制研究提供了无限的细胞资源，并为治疗开发提供了转化平台。
Dystrophia myotonica type 1 (DM1) is an autosomal dominant multisystem disorder. The pathogenesis of central nervous system (CNS) involvement is poorly understood. Disease-specific induced pluripotent stem cell (iPSC) lines would provide an alternative model. In this study, we generated two DM1 lines and a normal iPSC line from dermal fibroblasts by retroviral transduction of Yamanaka's four factors (hOct4, hSox2, hKlf4, and hc-Myc). Both DM1 and control iPSC clones showed typical human embryonic stem cell (hESC) growth patterns with a high nuclear-to-cytoplasm ratio. The iPSC colonies maintained the same growth pattern through subsequent passages. All iPSC lines expressed stem cell markers and differentiated into cells derived from three embryonic germ layers. All iPSC lines underwent normal neural differentiation. Intranuclear RNA foci, a hallmark of DM1, were detected in DM1 iPSCs, neural stem cells (NSCs), and terminally differentiated neurons and astrocytes. In conclusion, we have successfully established disease-specific human DM1 iPSC lines, NSCs, and neuronal lineages with pathognomonic intranuclear RNA foci, which offer an unlimited cell resource for CNS mechanistic studies and a translational platform for therapeutic development.