Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
Nature. 2017 Aug 30;548(7669):592-596. doi: 10.1038/nature23664.
Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson's disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.
诱导多能干细胞（iPS 细胞）是一种很有前途的细胞治疗来源，可以用来治疗帕金森病（PD），因为在这种疾病中，中脑多巴胺能神经元会逐渐退化。然而，据我们所知，从未有人对人类 iPS 细胞衍生的多巴胺能神经元在灵长类 PD 模型中的长期分析进行过研究。在这里，我们展示了人类 iPS 细胞衍生的多巴胺能祖细胞在使用神经毒素 MPTP 处理的 PD 灵长类模型（食蟹猴）中存活并作为中脑多巴胺能神经元发挥作用。基于评分的和视频记录分析显示，猴子在移植后的自发运动增加。组织学研究表明，成熟的多巴胺能神经元将密集的神经突延伸到宿主纹状体中；无论细胞是来自 PD 患者还是来自健康个体，这种效果都是一致的。通过地板板标记物 CORIN 分选的细胞在至少两年内没有在大脑中形成任何肿瘤。最后，磁共振成像和正电子发射断层扫描用于监测移植细胞的存活、扩增和功能以及宿主大脑中的免疫反应。因此，这项使用灵长类动物模型的临床前研究表明，人类 iPS 细胞衍生的多巴胺能前体细胞可用于治疗 PD 患者。
