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

The ligand-dependent nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) regulates the differentiation of several tissues and cell types. PPARγ was recently determined to be essential for murine placental development and differentiation. We therefore assessed the influence of PPARγ on differentiation of human placental trophoblasts. We initially used immunohistochemistry to examine term human placentas for PPARγ expression and found that PPARγ is present in syncytiotrophoblasts and cytotrophoblasts in placental villi. We correlated the expression of PPARγ with differentiation of primary human trophoblasts and found that 8-bromo-cAMP, a known enhancer of trophoblast differentiation, stimulates PPARγ activity, but has no effect on PPARγ expression. We demonstrated that the PPARγ ligand 15-deoxy-Δ^12,14-prostaglandin J₂ (15ΔPGJ₂) and the thiazolidinedione troglitazone stimulate PPARγ activity in the trophoblast cell line BeWo. Importantly, whereas exposure of cultured primary trophoblasts to troglitazone enhances biochemical and morphological trophoblast differentiation, 15ΔPGJ₂ diminishes trophoblast differentiation. Furthermore, 15ΔPGJ₂, but not troglitazone, up-regulates p53 expression and promotes trophoblast apoptosis. These data indicate that PPARγ is expressed in human placental trophoblasts, and that ligand-specific activation of PPARγ results in opposing effects on trophoblast differentiation. Our results suggest that PPARγ plays an important role in placental differentiation during human pregnancy.