title: p63 inhibits extravillous trophoblast migration and maintains cells in a cytotrophoblast stem cell-like state.
abstract: Proper differentiation of placental epithelial cells, called trophoblast, is required for implantation. Early during placentation, trophoblast cell columns help anchor the developing embryo in the uterine wall. Although proximally continuous with villous cytotrophoblast (CTB) distally, these cells differentiate into invasive extravillous trophoblast. We previously reported that p63, a p53 family member, is highly expressed in proliferative villous CTB and required for induction of the trophoblast lineage in human pluripotent stem cells. We now further explore its function in human trophoblast by using both primary CTB from the early placenta and established trophoblast cell lines. We show that p63 is expressed in epidermal growth factor receptor-positive CTB and that its expression decreases with differentiation into HLA-G(+) extravillous trophoblast. In trophoblast cell lines, p63 is expressed in JEG3 cells but absent from HTR8 cells. Overexpression of p63 in both cell lines enhances cell proliferation and significantly reduces cell migration; conversely, down-regulation of p63 in JEG3 cells reduces cell proliferation and restores cell migration. Analysis of epithelial-to-mesenchymal transition, cell adhesion, and matrix degradation pathways shows that p63 blocks epithelial-to-mesenchymal transition, promotes a CTB-specific cell adhesion profile, and inhibits expression of matrix metalloproteinases. Taken together, these data show that p63 maintains the proliferative CTB state, at least partially through regulation of epithelial-to-mesenchymal transition, cell adhesion, and matrix degradation pathways.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California; Department of Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California; Department of Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California.
authors.forename: Matteo
authors.initials: M
authors.lastname: Moretto-Zita
authors.affiliation: Department of Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California; Department of Reproductive Medicine, University of California San Diego, La Jolla, California.
authors.forename: Sandra
authors.initials: S
authors.lastname: Leon-Garcia
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California; Department of Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California. Electronic address: mparast@ucsd.edu.
authors.forename: Mana M
authors.initials: MM
authors.lastname: Parast
mesh_terms: D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D006063:Chorionic Gonadotropin / Q000737:chemistry; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D010641:Phenotype; D010920:Placenta / Q000378:metabolism; D010929:Placentation; D039904:Pluripotent Stem Cells / Q000166:cytology; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D006063:Chorionic Gonadotropin; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor