Multidonor human cortical chimeroids reveal individual susceptibility to neurotoxic triggers

Inter-individual genetic variation affects the susceptibility to many diseases. Efforts to study the molecular mechanisms mediating the impact of human genetic variation are limited. Here, we present human brain “Chimeroids”, a highly reproducible, multi-donor human brain cortical organoid model. It is created by re-aggregating neural stem cells from multiple single-cell donor organoids in a manner that allows each donor to produce all cell lineages of the cerebral cortex, even when using pluripotent stem cell lines with notable growth biases. We leveraged Chimeroids to investigate inter-individual variation in susceptibility to neurotoxic stressors that exhibit high clinical phenotypic variability, and found that individual donors varied in the penetrance of the effect on target cell types. Our results show that human genetic background may be an important mediator of neurotoxin susceptibility and introduce Chimeroids as a scalable system for high-throughput investigation of the contribution of human genetic variation to brain development and disease.