澳大利亚弗洛雷神经科学与心理健康研究所Clare L. Parish发现病毒传送的神经胶质细胞系来源的的神经营养因子（GDNF）促进帕金森氏病（PD）中人多能干细胞（hPSC）移植的功能整合。2020年2月13日，《细胞—干细胞》在线发表了这项成果。

他们检查了是否提供发育关键蛋白GDNF可以改善移植预后。他们追踪了植入到富含GDNF的环境或延迟接触后Dans应答。早期GDNF促进非多巴胺能神经元（DAns）的存活和可塑性，从而导致PD大鼠增强的运动恢复。延迟接触GDNF可通过增加Dan特异性、DAn可塑性和DA代谢来促进功能恢复。转录谱分析揭示了有丝分裂原激活蛋白激酶（MAPK）信号在GDNF下游的作用。总之，这些结果证明了神经营养性基因治疗策略改善hPSC移植预后的潜力。

据了解，由hPSC产生的DAns在移植后能够功能整合，最近已进入PD的临床试验。然而，临床前研究强调了与胎儿组织相比，hPSC来源的移植物中DAns的比例较低，并且可塑性较差。

附：英文原文

Title: Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson’s Disease

Author: Carlos W. Gantner, Isabelle R. de Luzy, Jessica A. Kauhausen, Niamh Moriarty, Jonathan C. Niclis, Christopher R. Bye, Vanessa Penna, Cameron P.J. Hunt, Charlotte M. Ermine, Colin W. Pouton, Deniz Kirik, Lachlan H. Thompson, Clare L. Parish

Issue&Volume: February 13, 2020

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

DOI: 10.1016/j.stem.2020.01.010

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30010-2