The peroxisome proliferator-activated receptor-gamma (PPARg) is a member of the nuclear receptor superfamily that controls the expression of a large array of genes in a ligand-dependent manner. Unexpectedly, genetic studies performed in mice established that PPARg is essential for placental development. Our objective was to decipher the role of PPARg in human trophoblast differentiation along the villous endocrine and extravillous invasive trophoblast pathways.
To study mechanisms that control trophoblast differentiation during early placental development and provide new insight in the understanding of pregnancy diseases from placental origin, we have developed first trimester in vitro models of human invasive extravillous trophoblasts (EVT) and formation of syncytiotrophoblast (ST) from primary villous cytotrophoblasts (VCT).
In the human placenta, PPARg is specifically expressed in nuclei of VCT, ST and EVT. Activation of PPARg by natural (15∆-PGJ2) or synthetic ligands (rosiglitazone) induced accumulation of lipids, ST formation and hCG secretion. In EVT, PPARg agonists decreased cell invasion in a concentration-dependent manner. Oxidized-LDLs that contain PPARg ligands (HODE, HETE), but not native LDLs, inhibited EVT invasiveness in vitro and induced PPARg transcriptional activity. We demonstrated recently that, for its replication, human cytomegalovirus (hCMV) activated cellular PPARg, and consequently inhibited invasiveness of infected trophoblasts. Among the EVT PPARg-target genes, hCG, which is predominantly produced by the ST, was also found to be expressed and secreted by invasive EVT. Notably, hCG gene expression was observed to be increased in ST and decreased in EVT following PPARg activation. Finally, we also showed that hCG of EVT origin was hyperglycosylated hCG (hCG-H) and promoted trophoblast invasion in an autocrine manner.
Together, these data underscore a major role for PPARg and its target genes such as hCG, in the control of human trophoblast differentiation and suggests that over activation PPARg may contribute to impaired implantation and placentation.
Funding source: Inserm, Paris Descartes, ANR MIE