Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids

Highlights

• Microglia culture models differentially attenuate and preserve gene signatures

• Brain organoid microenvironment preserves microglial homeostatic state

• Genes in the interferon response pathway are attenuated in the presence of microglia

• Microglia decrease double-stranded DNA breaks and cell stress in radial glia

Summary

Microglia are resident macrophages in the brain that emerge in early development and respond to the local environment by altering their molecular and phenotypic states. Fundamental questions about microglia diversity and function during development remain unanswered because we lack experimental strategies to interrogate their interactions with other cell types and responses to perturbations ex vivo. We compared human microglia states across culture models, including cultured primary and pluripotent stem cell-derived microglia. We developed a “report card” of gene expression signatures across these distinct models to facilitate characterization of their responses across experimental models, perturbations, and disease conditions. Xenotransplantation of human microglia into cerebral organoids allowed us to characterize key transcriptional programs of developing microglia in vitro and reveal that microglia induce transcriptional changes in neural stem cells and decrease interferon signaling response genes. Microglia additionally accelerate the emergence of synchronized oscillatory network activity in brain organoids by modulating synaptic density.