Trophoblast-Guided Uterine Transformation in the Establishment of Pregnancy

PROJECT SUMMARY/ABSTRACT Trophoblast cell derivatives of the embryo contribute to restructuring the uterine environment, an event required for the establishment of a successful pregnancy. The rat and human each possess a uterine- placental interface that is characterized by deep intrauterine infiltration of trophoblast cells, which contribute to dynamic changes in uterine immune cell, endothelial cell, smooth muscle cell, and stromal cell constituents. This important developmental process is directed by specialized trophoblast cells possessing invasive properties with the potential of targeting maternal cells within the uterine compartment. In the human, these invasive trophoblast cells are referred to as extravillous trophoblast (EVT). Disruptions in differentiation of the invasive trophoblast/EVT cell lineage, intrauterine trophoblast cell invasion, and/or trophoblast cell-directed uterine cell modulation contribute to early pregnancy loss, placental dysfunction, pregnancy-related diseases, and a range of postnatal health issues. The project focuses on placenta specific 1 (PLAC1), an intrinsic regulator of placentation. Our long-term goal is to elucidate regulatory processes controlling development of the invasive trophoblast/EVT cell lineage and its role in establishing the uterine-placental interface. In this project, our efforts are focused on two aims. In Aim 1, we dissect the actions of PLAC1 in the establishment of the invasive trophoblast cell lineage. In Aim 2 we investigate trophoblast cell-uterine cell crosstalk and plasticity at the uterine-placental interface. Experimentation utilizes genetically manipulated loss-of-function rat models, trophoblast stem cells, and genome-wide analyses of transcriptomes and chromatin landscapes. Execution of this research project will facilitate elucidation of molecular pathways controlling trophoblast-guided transformation of the uterine environment and will create a platform for understanding the pathogenesis of early pregnancy loss and placental anomalies leading to pregnancy disorders.