多巴胺
神经元
诱导多能干细胞
生物
神经科学
体内
程序性细胞死亡
胚胎干细胞
细胞凋亡
生物化学
生物技术
基因
作者
Tae Wan Kim,So Yeon Koo,Markus Rießland,Hyunwoo Cho,Fayzan Chaudhry,Benjamin Kolisnyk,Marco Russo,Nathalie Saurat,Sanjoy Mehta,Ralph Garippa,Doron Betel,Lorenz Studer
标识
DOI:10.1101/2023.03.29.534819
摘要
Abstract Ongoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson’s disease (PD). However, a major unresolved challenge in the field is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo . We identified p53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. As a translationally applicable strategy to purify postmitotic dopamine neurons, we performed a cell surface marker screen that enabled purification without the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved and widely used TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic human PSC-derived dopamine neurons in PD. Highlights In vivo CRISPR-Cas9 screen identifies p53 limiting survival of grafted human dopamine neurons. TNFα-NFκB pathway mediates p53-dependent human dopamine neuron death Cell surface marker screen to enrich human dopamine neurons for translational use. FDA approved TNF-alpha inhibitor rescues in vivo dopamine neuron survival with in vivo function.
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