Role of Decidual Extracellular Vesicles in Mediating Placental Insufficiency

PROJECT SUMMARY Placental insufficiency- caused by deficient extravillous trophoblast invasion and/or syncytiotrophoblast nutrient transport and inadequate blood flow to the placenta- is a central hallmark in numerous obstetrical diseases, including fetal growth restriction (FGR) and preeclampsia. These diseases each affect 3-8% of pregnancies worldwide and have lifelong complications for both the mother and baby. While placental insufficiency is a common pathological feature, whether this arises from intrinsic placental developmental defects or altered maternal signals, eg. during viral infection that increases FGR and preeclampsia risk, remain unknown. Findings from our lab and others have implicated maternal endometrial dysfunction in the early pathophysiology of FGR and preeclampsia. Endometrial stromal cells are the major cell type of the endometrium and they undergo decidualization spontaneously every month in preparation for pregnancy. Decidualized endometrial stromal cells (decidual cells) promote endometrial receptivity and regulate placentation and vascular remodeling at the maternal-fetal interface. These effects can be mediated by decidual secretion of extracellular vesicles (EVs) that contain specific miRNA cargos. We have shown that exposure to viral double-stranded RNA (dsRNA) impairs decidualization and alters the miRNA cargo of decidual EVs. These decidual cells and EVs negatively impacted trophoblast stem cell differentiation and angiogenesis in vitro and in vivo. Based on these findings, our central hypothesis is that uncontrolled uterine inflammation alters decidual EV miRNA cargo which impairs trophoblast stem cell differentiation to syncytiotrophoblast while increasing uterine vascular dysfunction, leading to placental insufficiency. We will take a targeted hypothesis-driven approach to examine the effects of decidual EVs, and EV-associated miR-30a-5p and miR-206, on trophoblast stem cell differentiation, syncytiotrophoblast function (Aim 1) and uterine vascular functions (Aim 2) using physiologically-relevant trophoblast models, 3D models of angiogenesis and ex vivo vascular studies. Finally, we will confirm these findings clinically by examining markers of decidual inflammation and altered EV cargo in biospecimens from patients with FGR and preeclampsia (Aim 3). Successful completion of this project will highlight the importance of maternal decidual health for pregnancy success and reveal decidual EVs as an early pathological player in the pathogenesis of FGR and preeclampsia. The long-term goal of this research program is to identify new opportunities for the development of early biomarkers and therapeutic strategies to lessen the immediate and lifelong impacts of placental insufficiency.