Chan Anthony W S, Cheng Pei-Hsun, Neumann Adam, Yang Jin-Jing
Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
Cell Reprogram. 2010 Oct;12(5):509-17. doi: 10.1089/cell.2010.0019.
Induced pluripotent Huntington's disease monkey stem cells (rHD-iPSCs) were established by the overexpression of rhesus macaque transcription factors (Oct4, Sox2, and Klf4) in transgenic Huntington's monkey skin fibroblasts. The rHD-iPSCs were pluripotent and capable of differentiating into neuronal cell types in vitro and developed teratoma in immune compromised mice. We also demonstrated the upregulation of endogenous Oct4 and Sox2 after successful reprogramming to pluripotency in rHD-iPSCs, which was not expressed in skin fibroblasts. rHD-iPSCs also developed cellular features comparable to Huntington's disease (HD), including the accumulation of mutant huntingtin (htt) aggregate and the formation of intranuclear inclusions (NIs) paralleling neural differentiation in vitro. Induced pluripotent stem cells from transgenic HD monkeys open a new era of nonhuman primate modeling of human diseases. rHD-iPSCs that develop key HD cellular features and parallel neural differentiation can be a powerful platform for investigating the developmental impact on HD pathogenesis and developing new therapies, which can be evaluated in HD monkeys from whom the rHD-iPSCs were derived.
通过在转基因亨廷顿病猴皮肤成纤维细胞中过表达恒河猴转录因子（Oct4、Sox2和Klf4），建立了诱导多能性亨廷顿病猴干细胞（rHD-iPSCs）。rHD-iPSCs具有多能性，能够在体外分化为神经元细胞类型，并在免疫缺陷小鼠中形成畸胎瘤。我们还证明，在成功重编程为rHD-iPSCs的多能性后，内源性Oct4和Sox2上调，而在皮肤成纤维细胞中不表达。rHD-iPSCs还表现出与亨廷顿病（HD）相当的细胞特征，包括突变型亨廷顿蛋白（htt）聚集体的积累以及与体外神经分化平行的核内包涵体（NIs）的形成。转基因HD猴诱导多能干细胞开启了人类疾病非人灵长类动物模型的新时代。具有关键HD细胞特征并平行神经分化的rHD-iPSCs可以成为一个强大的平台，用于研究对HD发病机制的发育影响并开发新疗法，这些疗法可以在源自其rHD-iPSCs的HD猴中进行评估。
