Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology

Microglia play critical roles in brain development, homeostasis, and disease. Microglia in animal models cannot accurately model human microglia due to notable transcriptomic and functional differences between human and other animal microglia. Incorporating human pluripotent stem cell (hPSC)-derived microglia into brain organoids provides unprecedented opportunities to study human microglia. However, an optimized method that integrates appropriate amounts of microglia into brain organoids at a proper time point, resembling in vivo brain development, is still lacking. Here, we report a new brain region-specific, microglia-containing organoid model by coculturing hPSC-derived primitive neural progenitor cells and primitive macrophage progenitors. In the organoids, the number of human microglia can be controlled, and microglia exhibit phagocytic activity and synaptic pruning function. Furthermore, human microglia respond to Zika virus infection of the organoids. Our findings establish a new microglia-containing brain organoid model that will serve to study human microglial function in a variety of neurological disorders.

Automated summary

By coculturing human pluripotent stem cell (hPSC)-derived microglia and primitive macrophage progenitors, a new brain region-specific organoid model containing microglia has been established. This model allows control of the number of human microglia, which exhibit phagocytic activity and synaptic pruning function. Additionally, human microglia in the organoids respond to Zika virus infection, providing a novel platform to study human microglial function in various neurological disorders.