PPARγ Regulates Trophoblast Proliferation and Promotes Labyrinthine Trilineage Differentiation

Background: Abnormal trophoblast differentiation and function is the basis of many placenta-based pregnancy disorders, including pre-eclampsia and fetal growth restriction. PPAR gamma, a ligand-activated nuclear receptor, plays essential roles in placental development; null murine embryos die at midgestation due to abnormalities in all placental layers, in particular, small labyrinth and expanded giant cell layer. Previous studies have focused mostly on the role of PPAR gamma in trophoblast invasion. Based on the previously reported role of PPAR gamma in preadipocyte differentiation, we hypothesized that PPAR gamma also plays a pivotal role in trophoblast differentiation. To test this hypothesis, we report derivation of wild-type and PPAR gamma-null trophoblast stem (TS) cells. Methodology/Principal Findings: PPAR gamma-null TS cells showed defects in both proliferation and differentiation, specifically into labyrinthine trophoblast. Detailed marker analysis and functional studies revealed reduced differentiation of all three labyrinthine lineages, and enhanced giant cell differentiation, particularly the invasive subtypes. In addition, rosiglitazone, a specific PPAR gamma agonist, reduced giant cell differentiation, while inducing Gcm1, a key regulator in labyrinth. Finally, reintroducing PPAR gamma into null TS cells, using an adenovirus, normalized invasion and partially reversed defective labyrinthine differentiation, as assessed both by morphology and marker analysis. Conclusions/Significance: In addition to regulating trophoblast invasion, PPAR gamma plays a predominant role in differentiation of labyrinthine trophoblast lineages, which, along with fetal endothelium, form the vascular exchange interface with maternal blood. Elucidating cellular and molecular mechanisms mediating PPAR gamma action will help determine if modulating PPAR gamma activity, for which clinical pharmacologic agonists already exist, might modify the course of pregnancy disorders associated with placental dysfunction.