Peroxisome Proliferator-Activated Receptor Gamma Regulates Invasive Trophoblast Cell Differentiation and Hemochorial Placentation [ChIP-seq]

Establishing a successful pregnancy relies on the proper function of trophoblast cells. The expansion and differentiation of trophoblast stem (TS) cells are critical for defining the fundamental properties of the placenta. These include specialized trophoblast cells, which exit the placenta and enter and transform the uterus, including restructuring uterine spiral arteries. In the human these cells are referred to as extravillous trophoblast (EVT) cells, whereas in the rat they are termed invasive trophoblast cells. Mechanisms governing trophoblast cell differentiation into these specialized invasive trophoblast cell lineages remain poorly understood. We investigated the role of peroxisome proliferator-activated receptor gamma (PPARG), a ligand-activated transcription factor, as a potential regulator of EVT/invasive trophoblast cell development and establishment of the uterine-placental interface. In first trimester human placentas, PPARG transcripts and protein were detected in the EVT cell column and increased in amount as human TS cells differentiated into EVT cells. Disruption of PPARG impaired differentiation of human TS cells into EVT cells, including failure to activate their downstream gene regulatory network and migratory capacity. Invasive trophoblast cells of the rat placentation site similarly expressed PPARG. Invasive trophoblast cell-specific conditional inactivation of PPARG was used to assess the in vivo role of PPARG in placentation. PPARG was established as a cell-autonomous regulator of the invasive trophoblast cell lineage with profound effects on placentation, including effects on placental compartmentalization and the integrity and cellular composition of the uterine-placental interface. In conclusion, PPARG is a conserved regulator of placentation and is essential for directing trophoblast cell-guided uterine transformation