利用人体多能干细胞生成脑室去甲肾上腺素神经元，这一成果由美国威斯康星大学麦迪逊分校Su-Chun Zhang、Yunlong Tao团队经过不懈努力而取得。2023年11月16日，国际学术期刊《自然-生物技术》发表了这一成果。

为了更好的对中枢去甲肾上腺素（NE）神经元进行研究，研究人员开发了一种方法可以诱导人类多能干细胞生成40-60%的人神经节（LC）-NE神经元。该方法依赖于研究人员在背侧菱形体1（r1）祖细胞中发现的，调节LC-NE生产的转录因子ACTIVIN A。体外生成的人LC-NE神经元具有广泛的轴突分枝、NE的释放和吸收并表现出起搏器活动、钙振荡和对二氧化碳的化学感受器活动。

在多个时间点进行的单核RNA测序（snRNA-seq）分析证实了NE细胞的特性，并揭示了从后脑祖细胞到NE神经元的分化轨迹，其经历了表达ASCL1的前体阶段。用NE传感器诱导的LC-NE神经元能可靠地表征细胞外NE水平。功能性人LC-NE神经元的诱导有助于研究它们在精神和神经退行性疾病中的作用，并为治疗药物的研发提供了工具。

研究人员表示，NE神经元主要位于神经节，与多种精神和神经退行性疾病有关，是新兴药物的靶点之一。

附：英文原文

Title: Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells

Author: Tao, Yunlong, Li, Xueyan, Dong, Qiping, Kong, Linghai, Petersen, Andrew J., Yan, Yuanwei, Xu, Ke, Zima, Seth, Li, Yanru, Schmidt, Danielle K., Ayala, Melvin, Mathivanan, Sakthikumar, Sousa, Andre M. M., Chang, Qiang, Zhang, Su-Chun

Issue&Volume: 2023-11-16

Abstract: Central norepinephrine (NE) neurons, located mainly in the locus coeruleus (LC), are implicated in diverse psychiatric and neurodegenerative diseases and are an emerging target for drug discovery. To facilitate their study, we developed a method to generate 40–60% human LC-NE neurons from human pluripotent stem cells. The approach depends on our identification of ACTIVIN A in regulating LC-NE transcription factors in dorsal rhombomere 1 (r1) progenitors. In vitro generated human LC-NE neurons display extensive axonal arborization; release and uptake NE; and exhibit pacemaker activity, calcium oscillation and chemoreceptor activity in response to CO2. Single-nucleus RNA sequencing (snRNA-seq) analysis at multiple timepoints confirmed NE cell identity and revealed the differentiation trajectory from hindbrain progenitors to NE neurons via an ASCL1-expressing precursor stage. LC-NE neurons engineered with an NE sensor reliably reported extracellular levels of NE. The availability of functional human LC-NE neurons enables investigation of their roles in psychiatric and neurodegenerative diseases and provides a tool for therapeutics development.

DOI: 10.1038/s41587-023-01977-4

Source: https://www.nature.com/articles/s41587-023-01977-4