UC San Diego

The human placenta is a transient organ that mediates essential feto-maternal interactions that are critical for a successful pregnancy. Trophoblast cells are specialized placental epithelial cells that arise from the trophectoderm, the first lineage to segregate during embryonic development [139]. Impaired trophoblast development and function is associated with fetal and neonatal, as well as maternal, morbidity and mortality, and has been correlated with diseases later in life [19]. Due to fundamental differences between humans and model organisms, and the ethical and safety concerns of experimental access to early human embryos, human pluripotent stem cells(hPSCs) and trophoblast stem cells (hTSCs) are valuable tools for investigating early development [168].This dissertation extends early human placental development research to further characterize the genomic and transcriptomic landscape of hPSCs, hTSCs, and primary trophoblast with the goal of using stem cells to model early human placental development. In the following chapters, I systematically characterize trophoblast precursor cells, hPSCs and hTSCs, and primary trophoblast to increase our understanding of early human placental development and provide a framework for future efforts to model this development. First, I use bioinformatic and experimental methods to characterize two quasi-stable pluripotent substates, termed the “naı̈ve” and “primed” pluripotent states. I highlight the genomic, epigenomic, and transcriptomic differences between the two substates. In the next chapter, I show that hTSCs can be derived from not only naı̈ve pluripotent stem cells but also from the primed substate. Finally, I present the results from comprehensive profiling of first trimester and term extravillous trophoblast (EVT), the invasive trophoblast cells that anchor the placenta to the uterine wall. Overall, this dissertation describes a model of early human placental development and provides a better understanding of normal EVT formation and function, therefore providing future studies an in vitro hPSC to EVT framework to build upon.