Direct generation of functional dopaminergic neurons from mouse and human fibroblasts
Direct generation of functional dopaminergic neurons from mouse and human fibroblasts
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DOI：
10.1038/nature10284
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发表时间：
2011-08-11
期刊：
影响因子：
64.8
通讯作者：
Broccoli, Vania
中科院分区：
文献类型：
--
作者：
Caiazzo, Massimiliano;Dell'Anno, Maria Teresa;Broccoli, Vania
多巴胺能神经元移植可能会改善帕金森病的临床结果，帕金森病是一种由中脑多巴胺能神经元变性引起的神经系统疾病(1,2)。特别是，移植胚胎干细胞来源的多巴胺能神经元已被证明可有效恢复多巴胺缺乏情况下的运动症状(3,4)。然而，如果控制不当，多能来源细胞的使用可能会导致肿瘤的发生(5)。在这里，我们鉴定了一组最小的三个转录因子——Mash1（也称为 Ascl1）、Nurr1（也称为 Nr4a2）和 Lmx1a——能够从小鼠和人类成纤维细胞产生直接功能性多巴胺能神经元，而无需恢复到祖细胞阶段。诱导多巴胺能 (iDA) 细胞释放多巴胺，并显示出以规则尖峰组织的自发电活动，与大脑多巴胺能神经元的起搏器活动一致。这三个因素能够在健康供体和帕金森病患者的产前和成年成纤维细胞中引发多巴胺能神经元转化。从体细胞直接生成 iDA 细胞可能对理解神经元发育、体外疾病模型和细胞替代疗法的关键过程具有重要意义。
Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons(1,2). In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency(3,4). However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled(5). Here we identified a minimal set of three transcription factors-Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a-that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.