title: PPARγ and human trophoblast differentiation.
abstract: The peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ is essential for placental development. In the human placenta, PPARγ is specifically expressed in the trophoblast, both endocrine villous and invasive extravillous cytotrophoblasts (EVCT). Activation of PPARγ induces accumulation of lipids, villous trophoblast differentiation and inhibits trophoblast invasiveness. Oxidized LDLs that contain potential PPARγ ligands, but not native LDL, induce PPARγ transcriptional activity and inhibit trophoblast invasion in vitro. Recently, human cytomegalovirus (HCMV) was shown to activate trophoblastic PPARγ for its own replication and consequently inhibits invasiveness of infected cytotrophoblasts. Analysis of PPARγ 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 PPARγ 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 PPARγ 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.
authors.affiliation: INSERM, U767, 4 Avenue de l'Observatoire, Paris F-75006, France. Thierry.Fournier@parisdescartes.fr
authors.forename: Thierry
authors.initials: T
authors.lastname: Fournier
authors.forename: Jean
authors.initials: J
authors.lastname: Guibourdenche
authors.forename: Karen
authors.initials: K
authors.lastname: Handschuh
authors.forename: Vassilis
authors.initials: V
authors.lastname: Tsatsaris
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rauwel
authors.forename: Christian
authors.initials: C
authors.lastname: Davrinche
authors.forename: Danièle
authors.initials: D
authors.lastname: Evain-Brion
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000096:biosynthesis; D003587:Cytomegalovirus / Q000378:metabolism; D010064:Embryo Implantation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010929:Placentation / Q000502:physiology; D011247:Pregnancy; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism*
chemical_list: D006063:Chorionic Gonadotropin; D008055:Lipids; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors