Human microglia maturation is underpinned by specific gene regulatory networks

Immunity. 2023 Sep 12;56(9):2152-2171.e13. doi: 10.1016/j.immuni.2023.07.016. Epub 2023 Aug 14.

Abstract

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.

Keywords: epigenomics; humanized; microglia; neurodevelopment; neurological disorders; stem cells; transcription factors; transcriptomics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Humans
  • Induced Pluripotent Stem Cells*
  • Mice
  • Microglia*