近日，美国哈佛大学Paola Arlotta及其课题组发现，脑Chimeroids揭示个体对神经毒性诱因的易感性。相关论文于2024年6月26日在线发表在《自然》杂志上。

研究人员展示了人脑Chimeroids，这是一种可重复性极高的多供体人脑皮层类器官模型，由来自单个供体的细胞共同发育而成。通过在神经干细胞或神经祖细胞阶段对来自多个单供体类器官的细胞进行重新组合，研究人员生成了Chimeroids，其中每个供体都能产生大脑皮层的所有细胞谱系，即使使用的多能干细胞系存在明显的生长偏差。

研究人员利用Chimeroids揭示了个体间对神经毒性诱因（乙醇和抗癫痫药物丙戊酸）易感性的差异，这些诱因表现出很高的临床表型变异性。捐献者个体在对目标细胞类型的影响穿透性和每种受影响细胞类型的分子表型方面都存在差异。研究结果表明，人类遗传背景可能是神经毒素易感性的重要介质，并将Chimeroids作为一种可扩展的系统，用于高通量研究大脑发育和疾病过程中的个体差异。

研究人员表示，个体间的遗传变异影响着许多疾病的易感性和发展。然而，由于缺乏忠实的细胞人体模型，以及难以扩展现有系统以代表多人，研究个体人脑在正常发育和疾病表型方面的差异的努力受到了限制。

附：英文原文

Title: Brain Chimeroids reveal individual susceptibility to neurotoxic triggers

Author: Antn-Bolaos, Noelia, Faravelli, Irene, Faits, Tyler, Andreadis, Sophia, Kastli, Rahel, Trattaro, Sebastiano, Adiconis, Xian, Wei, Anqi, Sampath Kumar, Abhishek, Di Bella, Daniela J., Tegtmeyer, Matthew, Nehme, Ralda, Levin, Joshua Z., Regev, Aviv, Arlotta, Paola

Issue&Volume: 2024-06-26

Abstract: Interindividual genetic variation affects the susceptibility to and progression of many diseases1,2. However, efforts to study how individual human brains differ in normal development and disease phenotypes are limited by the paucity of faithful cellular human models, and the difficulty of scaling current systems to represent multiple people. Here we present human brain Chimeroids, a highly reproducible, multidonor human brain cortical organoid model generated by the co-development of cells from a panel of individual donors in a single organoid. By reaggregating cells from multiple single-donor organoids at the neural stem cell or neural progenitor cell stage, we generate Chimeroids in which each donor produces all cell lineages of the cerebral cortex, even when using pluripotent stem cell lines with notable growth biases. We used Chimeroids to investigate interindividual variation in the susceptibility to neurotoxic triggers that exhibit high clinical phenotypic variability: ethanol and the antiepileptic drug valproic acid. Individual donors varied in both the penetrance of the effect on target cell types, and the molecular phenotype within each affected cell type. Our results suggest that human genetic background may be an important mediator of neurotoxin susceptibility and introduce Chimeroids as a scalable system for high-throughput investigation of interindividual variation in processes of brain development and disease.

DOI: 10.1038/s41586-024-07578-8

Source: https://www.nature.com/articles/s41586-024-07578-8