Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia.
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Cell Stem Cell. 2020 Apr 2;26(4):511-526.e5. doi: 10.1016/j.stem.2020.01.010. Epub 2020 Feb 13.
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.
多巴胺能神经元（DAns）可由人多能干细胞（hPSCs）产生，在移植后能够发挥功能整合作用，并且最近已推进到帕金森病（PD）的临床试验中。然而，临床前研究强调了 hPSC 衍生移植物中 DAns 的比例较低，以及它们与胎儿组织相比的可塑性较差。在这里，我们研究了递送人神经胶质细胞源性神经营养因子（GDNF）这一发育关键蛋白是否可以改善移植物的结果。我们追踪了植入富含 GDNF 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，从而使 PD 大鼠的运动功能恢复得到增强。延迟暴露于 GDNF 通过增加 DAn 特化、DAn 可塑性和 DA 代谢来促进功能恢复。转录谱分析揭示了 GDNF 下游丝裂原活化蛋白激酶（MAPK）信号的作用。总的来说，这些结果表明神经营养基因治疗策略具有改善 hPSC 移植物结果的潜力。
