PROJECT II Very little is known about the formative early stages of human trophoblast (TB) differentiation, in particular, the steps between trophectoderm (TE) specification and formation of the TB populations of the chorionic villi. Recently, we identified the early-gestation human chorion as a niche for cells that coexpressed markers of pluripotency and TB fate determinants. This finding suggested that the chorion is a source of human TB progenitor cells (TBPCs). To test this theory, we established lines of continuously self renewing TBPCs from this membrane and showed that they differentiated into the mature human TB populations?multi-nucleated syncytiotrophoblasts and invasive cytotrophoblasts. Here we propose using this new cell culture model to analyze TBPC allocation, self-renewal and differentiation. The specific hypotheses to be tested are based on global transcriptional profiling, which showed that TBPCs expressed a combination of DNA binding proteins that have been implicated in human TB development or that regulate the fate of TBs or other stem cells in the mouse. Thus, we will test the hypothesis that these molecules control TB developmental transitions that are key components of human placentation (Aim 1). The results will give us new insights into early steps in TB differentiation that have yet to be studied in humans. Then we will use this information to study the analogous processes in preeclampsia (PE), a human pregnancy complication {e.g., maternal hypertension, proteinuria and edema ? intrauterine growth restriction) that is associated with faulty TB differentiation. We will test the hypothesis that the observed deficits can be explained, in part, by perturbations in the molecular circuitry that governs TBPC fate (Aim 2). Thus, these experiments address the molecular underpinnings of faulty placentation, which contributes to a spectrum of disorders ranging from infertility to PE. This project significantly benefits from all the other components of the U-54. With Project III and Core B we will expand our characterization of TBPCs to include microRNA profiling and functional analyses. With Project IV we will explore the dialogue between the placenta and the decidua in terms of decidualized stromal secreted factors (? endometriosis). We will contribute to Project I by assisting in the analysis of the oocyte secretome and to Core C by providing expertise in educational outreach that we gained by developing similar programs. Thus, these synergistic interactions expand on the experiments proposed in this project and allow us to study other important aspects of reproductive biology that contribute to infertility.

Public Health Relevance

In humans, the steps between specification of the trophectoderm at the blastocyst stage and formation of the trophoblast (TB) populations of the chorionic villi are very poorly understood. Our recent findings suggest that self-renewing TB progenitors of the chorion are the missing link. Having established lines of these cells, we propose using this new in vitro model to understand seminal early events in the continuum of human TB differentiation and the underiying defects in this process that underlie faulty placentation.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-L)
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University of California San Francisco
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