The embryo-derived protein PDI is highly conserved among placental mammals and alters the function of the endometrium in species with different implantation strategies

Abstract

ABSTRACTPregnancy establishment in mammals requires a complex sequence of events, including bi-lateral embryo-maternal communication, leading up to implantation. This is the time when most pregnancy loss occurs in mammals (including humans and food production species) and dysregulation in embryo-maternal communication contributes to pregnancy loss. Embryo-derived factors modify the function of the endometrium for pregnancy success. We hypothesise that these previously unexplored conceptus-derived proteins may be involved in altering the function of the endometrium to facilitate early pregnancy events in mammals with different early pregnancy phenotypes. Here, we show that protein disulphide-isomerase (PDI) is a highly conserved protein among mammals, and provide evidence for a species-specific roles for PDI in endometrial function in mammals with different implantation strategies. We show how PDI alters the endometrial transcriptome in human and bovinein vitroin a species-specific manner, and using a microfluidic approach we demonstrate that it alters the secretome capability of the endometrium. We also provide evidence fromin vitroassays using human-derived cells thatMNS1,a transcript commonly downregulated in response to PDI in human and bovine endometrial epithelial cells, may be involved in the attachment (but not invasion) phase of implantation. We propose that the trophoblast-derived protein PDI, is involved in supporting the modulation of the uterine luminal fluid secreted by the endometrium to support conceptus nourishment, and also in the process of embryo attachment to the uterine lumen for pregnancy success in mammals.SIGNIFICANCE STATEMENTWe provide evidence that a highly conserved protein (PDI) alters the endometrial transcriptome in a species- and cell-specific manner. Exposure of endometrial epithelia to PDI altered genes belonging to immune modulatory, pro-inflammatory, and adhesion-pathways. One transcript, MNS1, was commonly downregulated in endometrial epithelia from species with superficial (bovine) and invasive (human) implantation morphologies. Knockdown of MNS1 expression in humans epithelia altered the ability of human trophoblast BeWo spheroids to attach suggesting a mechanism by which PDI affects implantation in human and bovine. In addition, using a microfluidics approach we have shown that PDI alters the secretome in a species-specific manner demonstrating PDI alters a key function of the endometrium in mammals.