近日，美国斯隆凯特琳癌症研究所Lorenz Studer及其团队发现，小分子联合治疗可加速人类多能干细胞衍生神经元的成熟。这一研究成果于2024年1月2日在线发表在国际学术期刊《自然—生物技术》上。

研究人员设计了一种基于人类多能干细胞（hPSC）衍生皮层神经元形态学和功能读数的高内涵成像检测，并确定了多种驱动神经元成熟的化合物，包括赖氨酸特异性去甲基化酶1抑制剂、端粒酶样1破坏剂和钙依赖性转录激活剂。由四种因子（GSK2879552、EPZ-5676、N-甲基-D-天冬氨酸和Bay K 8644，统称为GENtoniK）组成的鸡尾酒触发了所有测试参数的成熟，包括突触密度、电生理学和转录组学。

成熟效应在皮层类器官、脊髓运动神经元和非神经系（包括黑色素细胞和胰腺β细胞）中得到了进一步验证。在广泛的hPSC衍生细胞类型中观察到的对成熟的影响表明，控制人类成熟时间的某些机制可能是各谱系共有的。

据了解，hPSC衍生神经元的成熟模拟了人类大脑发育的漫长时间，从数月到数年才能达到类似成体的功能。体外成熟时间过长对基于干细胞的神经疾病建模和治疗应用提出了重大挑战。

附：英文原文

Title: Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons

Author: Hergenreder, Emiliano, Minotti, Andrew P., Zorina, Yana, Oberst, Polina, Zhao, Zeping, Munguba, Hermany, Calder, Elizabeth L., Baggiolini, Arianna, Walsh, Ryan M., Liston, Conor, Levitz, Joshua, Garippa, Ralph, Chen, Shuibing, Ciceri, Gabriele, Studer, Lorenz

Issue&Volume: 2024-01-02

Abstract: The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months to years for reaching adult-like function. Prolonged in vitro maturation presents a major challenge to stem cell-based applications in modeling and treating neurological disease. Therefore, we designed a high-content imaging assay based on morphological and functional readouts in hPSC-derived cortical neurons which identified multiple compounds that drive neuronal maturation including inhibitors of lysine-specific demethylase 1 and disruptor of telomerase-like 1 and activators of calcium-dependent transcription. A cocktail of four factors, GSK2879552, EPZ-5676, N-methyl-D-aspartate and Bay K 8644, collectively termed GENtoniK, triggered maturation across all parameters tested, including synaptic density, electrophysiology and transcriptomics. Maturation effects were further validated in cortical organoids, spinal motoneurons and non-neural lineages including melanocytes and pancreatic β-cells. The effects on maturation observed across a broad range of hPSC-derived cell types indicate that some of the mechanisms controlling the timing of human maturation might be shared across lineages.

DOI: 10.1038/s41587-023-02031-z

Source: https://www.nature.com/articles/s41587-023-02031-z