美国斯隆-凯特琳癌症研究所Lorenz Studer等研究人员合作发现，TNF-NF-κB-p53轴限制hPSC衍生多巴胺神经元的体内存活。相关论文于2024年6月11日在线发表于国际学术期刊《细胞》。

研究人员进行了一次集中的CRISPR-Cas9筛选，以提高有丝分裂后多巴胺神经元在体内的存活率。研究人员发现p53介导的细胞凋亡是多巴胺神经元丢失的主要原因，并发现肿瘤坏死因子α（TNF-α）-核因子κB（NF-κB）信号传导在限制细胞存活方面的因果关系。作为一种纯化凋亡后多巴胺神经元的转化相关策略，研究人员确定了无需基因报告即可纯化的细胞表面标记物。

将细胞分拣与临床批准的TNF-α抑制剂阿达木单抗（adalimumab）治疗相结合，能在临床前帕金森病（PD）小鼠模型中有效移植凋亡后多巴胺神经元，并实现广泛的神经支配和功能恢复。因此，瞬时TNF-α抑制剂是一种与临床相关的策略，可提高凋亡后hPSC衍生的多巴胺神经元的存活率并实现其在PD中的移植。

据悉，正在进行的早期临床试验表明，基于人多能干细胞（hPSC）的细胞疗法在PD方面具有转化潜力。然而，移植后大量细胞死亡是一个尚未解决的难题。

附：英文原文

Title: TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons

Author: Tae Wan Kim, So Yeon Koo, Markus Riessland, Fayzan Chaudhry, Benjamin Kolisnyk, Hyein S. Cho, Marco Vincenzo Russo, Nathalie Saurat, Sanjoy Mehta, Ralph Garippa, Doron Betel, Lorenz Studer

Issue&Volume: 2024-06-11

Abstract: Ongoing, early-stage clinical trials illustrate the translational potential of humanpluripotent stem cell (hPSC)-based cell therapies in Parkinson’s disease (PD). However,an unresolved challenge is the extensive cell death following transplantation. Here,we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survivalin vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamineneuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclearfactor κB (NF-κB) signaling in limiting cell survival. As a translationally relevantstrategy to purify postmitotic dopamine neurons, we identified cell surface markersthat enable purification without the need for genetic reporters. Combining cell sortingand treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficientengraftment of postmitotic dopamine neurons with extensive reinnervation and functionalrecovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presentsa clinically relevant strategy to enhance survival and enable engraftment of postmitotichPSC-derived dopamine neurons in PD.

DOI: 10.1016/j.cell.2024.05.030

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00575-0