PPARG directs trophoblast cell fate and establishment of the uterine-placental interface

The expansion and differentiation of trophoblast stem (TS) cells are critical for defining fundamental properties of the placenta. Specialized trophoblast cells 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 invasive trophoblast cell differentiation remain poorly understood. We investigated peroxisome proliferator-activated receptor gamma (PPARG) as a potential regulator of EVT/invasive trophoblast cell development. 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. Invasive trophoblast cells of the rat placentation site similarly expressed PPARG. Conditional inactivation of PPARG within invasive trophoblast cells of the rat placenta was used to assess the in vivo role of PPARG on the uterine-placental interface. PPARG was established as an essential cell-autonomous regulator of the invasive trophoblast cell lineage with profound effects on placentation. In conclusion, PPARG is a conserved regulator of placentation and is essential for directing trophoblast cell-guided uterine transformation.