Single cell profiling of Hofbauer cells and fetal brain microglia reveals shared programs and functions

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many of which are mediated by in utero microglial programming. Microglia remain inaccessible at birth and throughout development, thus identification of noninvasive biomarkers that can reflect fetal brain microglial programming may permit screening and intervention during critical developmental windows. Here we used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells). Single-cell RNA sequencing of murine fetal brain and placental macrophages demonstrated shared transcriptional programs. Comparison with human datasets demonstrated that placental resident macrophage signatures are highly conserved between mice and humans. Single-cell RNA-seq identified sex differences in fetal microglial and Hofbauer cell programs, and robust differences between placenta-associated maternal macrophage/monocyte (PAMM) populations in the context of a male versus a female fetus. We propose that Hofbauer cells, which are easily accessible at birth, provide novel insights into fetal brain microglial programs, potentially facilitating the early identification of offspring most vulnerable to neurodevelopmental disorders.