title: Three-dimensional spheroidal culture of cytotrophoblast cells mimics the phenotype and differentiation of cytotrophoblasts from normal and preeclamptic pregnancies.
abstract: Normal placental development is dependent on the orchestrated differentiation of cytotrophoblast (CTB) cells. This study was aimed at studying cytotrophoblast cells from normal and preeclamptic pregnancies in a three-dimensional spheroid-based cell culture model. First trimester cytotrophoblast cells cultured as spheroids maintain their high proliferative and invasive phenotype and respond to different cytokines upon stimulation in a three-dimensional invasion assay. In contrast, third trimester cytotrophoblast spheroids maintain their quiescent nonproliferating phenotype and invasion can only be induced by EGF. Contrasting the regular spheroidal arrangement of cytotrophoblast cells from normal third trimester pregnancies, spheroidal organization of preeclamptic cytotrophoblast cells is disturbed and the cells downregulate CD105 in vivo and in vitro. Furthermore, the invasion of both normal and preeclamptic third trimester, but not first trimester cytotrophoblast cells, is inhibited by pro-inflammatory cytokines. Plasma samples from pregnant women with preeclampsia significantly stimulate the invasion of first trimester cytotrophoblast cells and the sprouting of human umbilical vein endothelial cells (HUVECs) compared to plasma samples from healthy pregnant women. Taken together, the data establish the spheroidal cytotrophoblast model as a powerful system to mimic the in vivo phenotype of first and third trimester and preeclamptic cytotrophoblast cells and demonstrate that plasma-derived factors modulate the differentiation of cytotrophoblast cells.
authors.affiliation: Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center, D-79106 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Korff
authors.forename: Thomas
authors.initials: T
authors.lastname: Krauss
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
mesh_terms: D042702:Angiopoietin-2 / Q000494:pharmacology; D015703:Antigens, CD / Q000097:blood / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D010641:Phenotype; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood / Q000503:physiopathology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000494:pharmacology; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third; D018874:Spheroids, Cellular; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D042702:Angiopoietin-2; D015703:Antigens, CD; D016207:Cytokines; C000608036:PGF protein, human; D011257:Pregnancy Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000072483:Placenta Growth Factor; D004815:Epidermal Growth Factor