The maternal-fetal interface is a dynamic site where uterine and placental structures cooperate to promote development of the fetus. The rat, mouse, and human each possess a hemochorial placenta. Trophoblast cells are the parenchymal cells of the placenta and have the capacity to differentiate into specialized cell types, including cells that exhibit invasive properties with the potential to enter the vasculature and restructure uterine spiral arteries. In the human, these invasive trophoblast cells are referred to as extra villous trophoblast cells. Disruptions of trophoblast invasion and trophoblast-directed uterine spiral remodeling are centerpieces of the ?Great Obstetrical Syndromes?, including early pregnancy loss, preeclampsia, intrauterine growth restriction, and pre-term birth. The hemochorial placenta comes in different forms, which impact the suitability of animal models for investigating trophoblast cell invasion and uterine spiral artery remodeling. In contrast to the mouse, the rat exhibits hemochorial placentation with deep intrauterine trophoblast cell invasion, a feature also observed in human placentation. The rat can be effectively used to test the physiological relevance of putative regulators of invasive/extra villous trophoblast cell development. The long-term goal of our research is to identify conserved regulators of invasive/extra villous trophoblast cell development and invasive trophoblast/extra villous trophoblast-guided uterine spiral artery remodeling. We will use single-cell RNA-sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin-sequencing (ATAC-seq) of cell populations isolated from the uterine-placental interface through gestation of the rat. Sequencing data will be interrogated through robust computational analyses and integrated with existing datasets generated for cells within the human uterine-placental interface. This task is best accomplished through the coordinated efforts of experts on rat placentation and computational analysis of the trophoblast transcriptome. The experimentation will provide a robust list of candidate-conserved regulators of invasive trophoblast/extra villous trophoblast cell development and trophoblast-guided uterine spiral artery remodeling for future analysis. Furthermore, we will gain new insights into other essential constituents of the uterine- placental interface, including immune, endothelial, stromal, and smooth muscle cells, which importantly contribute to the health and success of pregnancy. The insights gained from the investigation will fuel future analyses using a pipeline of loss-of-function and gain-of-function approaches in human trophoblast stem cells and genetically manipulated rat models.
Central to the etiology of the ?Great Obstetric Syndromes? (early pregnancy loss, preeclampsia, intrauterine growth restriction, and pre-term birth) is the maldevelopment of the maternal-fetal interface. Construction of the maternal-fetal interface depends on its constituents, including the interplay between invasive trophoblast cells arising from extraembryonic lineages and uterine cells of maternal origin. Identification of candidate conserved regulators of the maternal-fetal interface will permit relevant in vivo modeling and the discovery of targets for therapeutic intervention.