title: First trimester trophoblasts forming endothelial-like tubes in vitro emulate a 'blood vessel development' gene expression profile.
abstract: Extravillous cytotrophoblasts isolated from first trimester placenta, and immortalised cell lines derived from them, have the intrinsic ability to form endothelial-like tubes when cultured on Matrigel™ extracellular matrix. This in vitro tube formation may model placental angiogenesis and/or endovascular differentiation by trophoblasts. To interpret the relevance of this phenomenon to placental development, we used a gene expression microarray approach to identify which genes and pathways are associated with the tube-forming phenotype of HTR8/SVneo first trimester trophoblasts (HTR8-M), compared with HTR8/SVneo not forming tubes on plastic culture surface (HTR8-P). Furthermore, we used weighted gene co-expression network analysis (WGCNA) of microarray data to identify modules of co-expressed genes underlying the biological processes. There were 481 genes differentially expressed between HTR8-M and HTR8-P and these were significantly enriched for blood vessel development and related gene ontologies. WGCNA clustered the genes into 9 co-expression modules. One module was significantly associated with HTR8-M (p = 1.15E-05) and contained genes involved in actin cytoskeleton organization, cell migration and blood vessel development, consistent with tube formation on Matrigel. Another module was significantly associated with HTR8-P (p = 1.94E-05) and was enriched for genes involved in mitosis, consistent with proliferation by cells on plastic which do not differentiate. Up-regulation of angiogenesis and vascular development pathways in endovascular trophoblasts in vivo could underpin spiral artery remodelling processes, which are defective in preeclamptic pregnancies.
authors.affiliation: School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia. Electronic address: Amanda.highet@adelaide.edu.au.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Highet
authors.affiliation: School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Sam
authors.initials: S
authors.lastname: Buckberry
authors.affiliation: School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Mayne
authors.affiliation: School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Sultana M
authors.initials: SM
authors.lastname: Khoda
authors.affiliation: School of Agriculture, Food and Wine and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Tina
authors.initials: T
authors.lastname: Bianco-Miotto
authors.affiliation: School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Claire T
authors.initials: CT
authors.lastname: Roberts
mesh_terms: D001808:Blood Vessels / Q000254:growth & development / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004727:Endothelium / Q000254:growth & development / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D014176:Protein Biosynthesis / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*; D014327:Trophoblasts / Q000378:metabolism*
keywords: Angiogenesis; Microarray; Trophoblast; Tube formation; Weighted correlation network analysis