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.

Effect of Mucosal Cytokine Administration on Selective Expansion of Vaginal Dendritic Cells to Support Nanoparticle Transport.

PROBLEM: The capacity of antigen-carrying vaccine nanoparticles (NPs) administered vaginally to stimulate local immune responses may be limited by the relatively low numbers of antigen-presenting cells (APCs) in the genital mucosa. Because inflammation is associated with increased susceptibility to sexually transmitted infections, we sought to increase APC numbers without causing inflammation. METHOD OF STUDY: In this study, we evaluated intravaginal delivery of chemokines, growth factors, or synthetic adjuvants to expand APCs in reproductive tissues. RESULTS: We found that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated expansion of CD11b+ dendritic cells (DCs) within 24 hr of intravaginal administration, with no effect on Langerhans cells or macrophages. Expansion of the CD11b+ DC population was not associated with increased inflammatory cytokine production, and these cells retained phagocytic function. CONCLUSION: Our data suggest that non-inflammatory expansion of mucosal APCs by intravaginal GM-CSF could be used as an adjuvanting strategy to potentiate the genital immune response to nanoparticulate mucosal vaccines.