PPARγ and human trophoblast differentiation

The peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a member of the nuclear receptor superfamily that controls in a ligand-dependent manner the expression of a large array of genes involved in the control of energy homeostasis and in cell differentiation, proliferation, apoptosis, and the inflammatory process. Unexpectedly, genetic studies performed in mice established that PPAR gamma is essential for placental development. In the human placenta, PPAR gamma is specifically expressed in the trophoblast, both endocrine villous and invasive extravillous cytotrophoblasts (EVCT). Activation of PPAR gamma induces accumulation of lipids, villous trophoblast differentiation and inhibits trophoblast invasiveness. Oxidized LDLs that contain potential PPAR gamma ligands, but not native LDL, induce PPAR gamma transcriptional activity and inhibit trophoblast invasion in vitro. Recently, human cytomegalovirus (HCMV) was shown to activate trophoblastic PPAR gamma for its own replication and consequently inhibits invasiveness of infected cytotrophoblasts. Analysis of PPAR gamma target genes revealed trophoblastic factors described to control trophoblast invasiveness and surprisingly chorionic gonadotropin hormone (hCG), known to be mainly produced by the endocrine villous trophoblast. Analysis of hCG gene expression revealed opposite regulation by PPAR gamma in the two trophoblast subtypes. Finally, a hyperglycosylated form of hCG (hCG-H) only produced by invasive EVCT was shown to promote trophoblast invasion. Together, these data underscore the major role of PPAR gamma and its target genes, such as hCG, in the control of human trophoblast differentiation and invasion, and suggest that over-activation of this nuclear receptor following HCMV infection or by excess of ligands at the maternal-fetal interface could impair implantation and placentation and therefore embryonic development. (C) 2011 Elsevier Ireland Ltd. All rights reserved.