Invasive trophoblast cell differentiation

PROJECT SUMMARY In the early stages of human pregnancy, cells from the developing placenta, termed extravillous trophoblast (EVT) cells, must interact with the uterus. In other species including the rat, this special class of trophoblasts are generically termed invasive trophoblast cells. The interaction between invasive trophoblast/EVT cells and the uterus results in the necessary remodeling of spiral arteries to meet the increased demand of blood flow and oxygen during pregnancy. Once remodeled, these arteries will integrate into the uterus to function in transporting nutrients and waste to and from the fetus through the maternal bloodstream. Importantly, differentiation into these specialized trophoblast cell types requires suppression of pathways essential for maintaining the trophoblast cell stem state and activation of the invasive/EVT cell differentiation program. In this project, we investigate roles for the leukemia inhibitory factor (LIF) and signal transducer and activator of transcription 3 (STAT3) pathway in the regulation of invasive/EVT cell development. Roles for LIF/STAT3 regulatory networks in human trophoblast stem cell models are the focus of Specific Aim 1. In Specific Aim 2, we will leverage a Stat3 conditional rat model to investigate STAT3 effects on the development and functionality of the invasive trophoblast cells at the uterine- placental interface. Experimentation includes genome-wide analyses of the transcriptome and the chromatin landscape. Completion of this research project will facilitate the discovery of molecular controllers responsible for regulating invasive/EVT cell lineage as well as create a platform for understanding the pathogenesis of early pregnancy loss. In addition, this proposal will provide the postdoctoral trainee with the mentorship, training, and skills required to become a successful independent investigator dedicated to human fertility research.