Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.

中文翻译：

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GDNF 的病毒递送促进人类干细胞移植物在帕金森病中的功能整合。

由人类多能干细胞 (hPSC) 产生的多巴胺能神经元 (DAns) 能够在移植后进行功能整合，并且最近已进入帕金森病 (PD) 的临床试验。然而，临床前研究强调了 hPSC 衍生移植物中 DAns 的比例较低，并且与胎儿组织相比，它们的可塑性较差。在这里，我们检查了发育关键蛋白——神经胶质细胞系衍生神经营养因子 (GDNF) 的传递是否可以改善移植结果。我们跟踪了植入 GDNF 丰富环境或延迟暴露后的 DAns 的反应。早期 GDNF 促进了非 DAns 的存活和可塑性，导致 PD 大鼠的运动恢复增强。延迟暴露于 GDNF 通过增加 DAn 规格促进功能恢复，DA的可塑性和DA的代谢。转录分析揭示了丝裂原活化蛋白激酶 (MAPK) 信号传导下游 GDNF 的作用。总的来说，这些结果证明了神经营养基因治疗策略在改善 hPSC 移植结果方面的潜力。