Brain Chimeroids reveal individual susceptibility to neurotoxic triggers

Noelia Antón-Bolaños, Irene Faravelli, Tyler Faits, Sophia Andreadis, Rahel Kastli, Sebastiano Trattaro, Xian Adiconis, Anqi Wei, Abhishek Sampath Kumar, Daniela J. Di Bella, Matthew Tegtmeyer, Ralda Nehme, Joshua Z. Levin, Aviv Regev and Paola Arlotta ()
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Noelia Antón-Bolaños: Harvard University
Irene Faravelli: Harvard University
Tyler Faits: Harvard University
Sophia Andreadis: Harvard University
Rahel Kastli: Harvard University
Sebastiano Trattaro: Harvard University
Xian Adiconis: Broad Institute of MIT and Harvard
Anqi Wei: Harvard University
Abhishek Sampath Kumar: Harvard University
Daniela J. Di Bella: Harvard University
Matthew Tegtmeyer: Harvard University
Ralda Nehme: Harvard University
Joshua Z. Levin: Broad Institute of MIT and Harvard
Aviv Regev: Broad Institute of MIT and Harvard
Paola Arlotta: Harvard University

Nature, 2024, vol. 631, issue 8019, 142-149

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07578-8

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