A bovine 3D endometrium-on-a-chip reveals the role of conceptus-derived proteins, CAPG and PDI, in conceptus–endometrial communication

Abstract

Early embryo loss affects all mammalian species, including humans, and agriculturally important food-producing mammals such as cattle. The developing conceptus (embryo and extraembryonic membranes) secretes proteins that can modify the endometrium and can be critical for early pregnancy processes, such as maternal recognition of pregnancy (MRP) or enhancing uterine receptivity to implantation. For example, a competent bovine conceptus secretes interferon tau (IFNT) to initiate MRP. The bovine conceptus also secretes other proteins at the time of MRP, including CAPG and PDI, which are highly conserved among placental mammals. We have previously shown that these proteins act upon the endometrium to modulate receptivity, embryo development, and implantation in species with different implantation strategies (humans and cattle). We hypothesize that developing a novel 3D bovine endometrium-on-a-chip system will enhance our understanding of the role of conceptus-derived factors in altering the endometrium and/or uterine luminal fluid (ULF) secretion. Here, we have developed a 3D bovine endometrium-on-a-chip system, comprising both stromal and epithelial cell culture combined with culture medium flow. This system better mimics the in vivo endometrium, and endometrial exposure to conceptus-derived factors, than conventional 2D endometrial cell culture. We have demonstrated that the conceptus-derived proteins, CAPG and PDI, modulate the endometrial transcriptome and secretory response to promote pathways associated with early pregnancy and alter ULF composition. This work highlights the critical need for more robust and in vivo-like culture systems to study endometrial–conceptus interactions in vitro to further investigate the role of conceptus-derived factors for pregnancy success.