Human microglia maturation is underpinned by specific gene regulatory networks

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage-and disease-specific phenotypes.

Automated summary

This study characterized the transcriptomes and epigenetic landscapes of fetal and postnatal human microglia, as well as in induced pluripotent stem cell-derived microglia and cerebral organoids, and after engraftment into humanized mice. Computational approaches were developed to predict gene regulatory networks associated with the maturation of microglia. The results suggest that many features of the fetal-to-postnatal transition can be replicated in a time-dependent manner following engraftment.