Type I interferon exposure of an implantation-on-a-chip device alters invasive extravillous trophoblast function.

Abstract

Inappropriate type I interferon (IFN) signaling during embryo implantation and placentation is linked to poor pregnancy outcomes. Here, we evaluate the consequence of elevated type I IFN exposure on implantation using a human implantation in an organ-on-a-chip device. We reveal that type I IFN reduces extravillous trophoblast (EVT) invasion capacity. Analyzing single-cell transcriptomes, we uncover that IFN truncates invasive EVT emergence in the implantation-on-a-chip device by stunting EVT epithelial-to-mesenchymal transition. Disruptions to the epithelial-to-mesenchymal transition are associated with the pathogenesis of preeclampsia, a life-threatening disorder of pregnancy. Strikingly, IFN stimulation induces genes associated with increased preeclampsia risk in EVTs. These dysregulated EVT phenotypes ultimately reduce EVT-mediated endothelial cell vascular remodeling in the implantation-on-a-chip device. Overall, our work implicates unwarranted type I IFN as a maternal disturbance that can result in abnormal EVT function that could trigger preeclampsia.