Human glial progenitor cells (hGPCs) are promising cellular substrates to explore for the in situ production of new neurons for brain repair. Proof of concept for direct neuronal reprogramming of glial progenitors has been obtained in mouse models in vivo, but conversion using human cells has not yet been demonstrated. Such studies have been difficult to perform since hGPCs are born late during human fetal development, with limited accessibility for in vitro culture. In this study, we show proof of concept of hGPC conversion using fetal cells and also establish a renewable and reproducible stem cell-based hGPC system for direct neural conversion in vitro. Using this system, we have identified optimal combinations of fate determinants for the efficient dopaminergic (DA) conversion of hGPCs, thereby yielding a therapeutically relevant cell type that selectively degenerates in Parkinson's disease. The induced DA neurons show a progressive, subtype-specific phenotypic maturation and acquire functional electrophysiological properties indicative of DA phenotype.

人类神经胶质祖细胞（hGPCs）是有前途的细胞底物，以探索用于大脑修复的新神经元的原位产生。已经在体内小鼠模型中获得了神经胶质祖细胞直接神经元重编程的概念证明，但是尚未证明使用人细胞的转化。由于hGPCs在人类胎儿发育过程中出生较晚，并且体外培养的可及性有限，因此这类研究一直很难进行。在这项研究中，我们展示了使用胎儿细胞进行hGPC转化的概念证明，并且还建立了可再生和可再现的基于干细胞的hGPC系统，用于体外直接神经转化。使用该系统，我们已经确定了hGPCs有效多巴胺能（DA）转化的命运决定因素的最佳组合，从而产生了在帕金森氏病中选择性退化的治疗相关细胞类型。诱导的DA神经元表现出进行性亚型特异性表型成熟，并获得指示DA表型的功能性电生理特性。