Brain Chimeroids reveal individual susceptibility to neurotoxic triggers

• Published in: Nature (London) Vol. 631; no. 8019; pp. 142 - 149
• Main Authors: Antón-Bolaños, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-07-2024; Nature Publishing Group
• Subjects: 13/100; 13/106; 13/51; 38/39; 38/91; 631/136/1425; 631/532/2182; Antiepileptic agents; Brain; Cell Lineage - drug effects; Cell lines; Cerebral cortex; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Chimera - genetics; Ethanol; Ethanol - adverse effects; Ethanol - toxicity; Female; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic variability; Genetic Variation; Humanities and Social Sciences; Humans; Investigations; Male; multidisciplinary; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neurotoxicity; Neurotoxins; Neurotoxins - toxicity; Organoids; Organoids - cytology; Organoids - drug effects; Organoids - metabolism; Phenotype; Phenotypes; Phenotypic variations; Pluripotency; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - drug effects; Pluripotent Stem Cells - metabolism; Progenitor cells; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Susceptibility; Tissue Donors; Toxins; Valproic acid; Valproic Acid - adverse effects; Valproic Acid - toxicity
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07578-8

Interindividual genetic variation affects the susceptibility to and progression of many diseases
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. 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.