Brain Chimeroids reveal individual susceptibility to neurotoxic triggers

• 成果类型: Article
• 署名作者: Anton-Bolanos, 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
• 署名单位: Harvard University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Roche Holding; Roche Holding USA; Genentech
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5043
• DOI: 10.1038/s41586-024-07578-8
• 发表日期: 2024-07-04
• 关键词: differential expression analysis; fetal alcohol syndrome; autism; genetics; platform

摘要

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. An analysis in 3D multidonor Chimeroids-a scalable multidonor human brain organoid model-shows that human genetic background may be an important mediator of neurotoxin susceptibility.