Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model
Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model
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DOI：
10.1038/nature23664
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发表时间：
2017-08-31
期刊：
影响因子：
64.8
通讯作者：
Takahashi, Jun
中科院分区：
文献类型：
--
作者：
Kikuchi, Tetsuhiro;Morizane, Asuka;Takahashi, Jun
诱导多能干细胞 (iPS 细胞) 是治疗帕金森病 (PD) 的细胞疗法的一个有前途的来源，其中中脑多巴胺能神经元逐渐退化 (1,2)。然而，据我们所知，从未在灵长类 PD 模型中对人类 iPS 细胞衍生的多巴胺能神经元进行过长期分析。在这里，我们证明，在用神经毒素 MPTP 处理的 PD（食蟹猴）灵长类动物模型中，人类 iPS 细胞衍生的多巴胺能祖细胞能够存活并发挥中脑多巴胺能神经元的功能。基于评分和视频记录的分析显示，移植后猴子的自发运动有所增加。组织学研究表明，成熟的多巴胺能神经元将致密的神经突延伸到宿主纹状体中；无论细胞是来自帕金森病患者还是健康个体，这种效果都是一致的。通过底板标记 CORIN 分选的细胞至少两年内没有在大脑中形成任何肿瘤。最后，利用磁共振成像和正电子发射断层扫描来监测移植细胞的存活、扩增和功能以及宿主大脑的免疫反应。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祖细胞在临床上可用于治疗 PD 患者。
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(1,2). 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.