Sexually Dimorphic Crosstalk at the Maternal-Fetal Interface

Context: Crosstalk through receptor ligand interactions at the maternal-fetal interface is impacted by fetal sex.This affects placentation in the first trimester and differences in outcomes. Sexually dimorphic signaling at early stages of placentation are not defined. Objective: Investigate the impact of fetal sex on maternal-fetal crosstalk. Design: Receptors/ligands at the maternal-fetal surface were identified from sexually dimorphic genes between fetal sexes in the first trimester placenta and defined in each cell type using single-cell RNA-Sequencing (scRNA-Seq). Setting: Academic institution. Samples: Late first trimester (similar to 10-13 weeks) placenta (fetal) and decidua (maternal) from uncomplicated ongoing pregnancies. Main outcome measures: Transcriptomic profiling at tissue and single-cell level; immunohistochemistry of select proteins. Results: We identified 91 sexually dimorphic receptor-ligand pairs across the maternalfetal interface. We examined fetal sex differences in 5 major cell types (trophoblasts, stromal cells, Hofbauer cells, antigen-presenting cells, and endothelial cells). Ligands from the CC family chemokine ligand (CCL) family were most highly representative in females, with their receptors present on the maternal surface. Sexually dimorphic trophoblast transcripts, Mucin-15 (MUC15) and notum, palmitoleoyl-protein carboxylesterase (NOTUM) were also most highly expressed in syncytiotrophoblasts and extra-villous trophoblasts respectively. Gene Ontology (GO) analysis using sexually dimorphic genes in individual cell types identified cytokine mediated signaling pathways to be most representative in female trophoblasts. Upstream analysis demonstrated TGFB1 and estradiol to affect all cell types, but dihydrotestosterone, produced by the male fetus, was an upstream regulator most significant for the trophoblast population. Conclusions: Maternal-fetal crosstalk exhibits sexual dimorphism during placentation early in gestation.