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

Abstract

The expansion and differentiation of trophoblast stem (TS) cells are critical for defining fundamental properties of the placenta. Specialized trophoblast cells called extravillous trophoblast (EVT) cells in human and invasive trophoblast cells in rat, exit the placenta, enter and transform the uterus. This includes the restructuring of uterine spiral arteries, essential for the transfer of nutrients to the fetus. Mechanisms governing invasive trophoblast cell differentiation remain poorly understood. Here, we investigate peroxisome proliferator-activated receptor gamma (PPARG) as a potential regulator of EVT/invasive trophoblast cell development. In first trimester human placentas, PPARG is expressed in the EVT cell column and increases in amount as human TS cells differentiate into EVT cells. PPARG disruption impairs EVT cell differentiation and alters the expression of genes controlling EVT cell lineage development. Rat invasive trophoblast cells similarly express PPARG. Conditional inactivation of PPARG within rat invasive trophoblast cells establishes PPARG as an essential cell-autonomous regulator of invasive trophoblast cells in vivo. In conclusion, PPARG is a conserved regulator of placentation and is essential for directing trophoblast cell-guided uterine transformation. PPARG is a conserved and essential regulator of human EVT cell and rat invasive trophoblast cell differentiation. Complementary human in vitro and rat in vivo models link PPARG to a critical facet of hemochorial placental development and its dysregulation to pregnancy complications associated with defective placentation. PPARG expression is enriched in EVT cell columns of first-trimester human placentas and increases during in vitro trophoblast stem cell differentiation into EVT cells. Loss of PPARG impairs trophoblast cell differentiation, disrupting EVT cell lineage development, their migratory capacity, and the expression of genes required for EVT cell identity. In vivo conditional deletion of PPARG in rat invasive trophoblast cells establishes an essential cell-autonomous role of PPARG in promoting intrauterine trophoblast cell invasion and trophoblast cell-guided uterine transformation. PPARG expression is enriched in EVT cell columns of first-trimester human placentas and increases during in vitro trophoblast stem cell differentiation into EVT cells. Loss of PPARG impairs trophoblast cell differentiation, disrupting EVT cell lineage development, their migratory capacity, and the expression of genes required for EVT cell identity. In vivo conditional deletion of PPARG in rat invasive trophoblast cells establishes an essential cell-autonomous role of PPARG in promoting intrauterine trophoblast cell invasion and trophoblast cell-guided uterine transformation. PPARG is a conserved and essential regulator of human EVT cell and rat invasive trophoblast cell differentiation. Complementary human in vitro and rat in vivo models link PPARG to a critical facet of hemochorial placental development and its dysregulation to pregnancy complications associated with defective placentation.