Peroxisome proliferator-activated receptor-γ modulates differentiation of human trophoblast in a ligand-specific manner

The ligand-dependent nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) regulates the differentiation of several tissues and cell types. PPAR gamma was recently determined to be essential for murine placental development and differentiation. We therefore assessed the influence of PPAR gamma on differentiation of human placental trophoblasts. We initially used immunohistochemistry to examine term human placentas for PPAR gamma expression and found that PPAR gamma is present in syncytiotrophoblasts and cytotrophoblasts in placental villi. We correlated the expression of PPAR gamma with differentiation of primary human trophoblasts and found that 8-bromo-cAMP, a known enhancer of trophoblast differentiation, stimulates PPAR gamma activity, but has no effect on PPAR gamma expression. We demonstrated that the PPAR gamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) (15 Delta PGJ(2)) and the thiazolidinedione troglitazone stimulate PPAR gamma activity in the trophoblast cell line BeWo. Importantly, whereas exposure of cultured primary trophoblasts to troglitazone enhances biochemical and morphological trophoblast differentiation, 15 Delta PGJ(2) diminishes trophoblast differentiation. Furthermore, 15 Delta PGJ(2), but not troglitazone, up-regulates p53 expression and promotes trophoblast apoptosis. These data indicate that PPAR gamma is expressed in human placental trophoblasts, and that ligand-specific activation of PPAR gamma results in opposing effects on trophoblast differentiation. Our results suggest that PPARy plays an important role in placental differentiation during human pregnancy.