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.
摘要：
个体间的遗传变异影响许多疾病的易感性和进展。然而,研究人类个体大脑在正常发育和疾病表型方面的差异的努力受到缺乏忠实细胞人体模型的限制，以及将当前系统扩展为代表多个人的困难。在这里，我们展示了人类大脑中的嵌合物，一个高度可重复的，多供体人类大脑皮质类器官模型是由一组个体供体在单个类器官中共同开发的。通过在神经干细胞或神经祖细胞阶段重新聚集来自多个单供体器官的细胞，我们产生嵌合蛋白，其中每个供体产生大脑皮层的所有细胞谱系，即使使用具有显著生长偏差的多能干细胞系。我们使用Chimentoids来研究对表现出高临床表型变异性的神经毒性触发因素的易感性的个体差异：乙醇和抗癫痫药物丙戊酸。个体供体对靶细胞类型的影响的外显率各不相同，以及每种受影响细胞类型内的分子表型。我们的结果表明，人类遗传背景可能是神经毒素易感性的重要介质，并引入嵌合体作为可扩展的系统，用于高通量研究大脑发育和疾病过程中的个体差异。
