title: Model of vasculogenesis from embryonic stem cells for vascular research and regenerative medicine.
abstract: Embryonic stem (ES) cells are highlighted as promising cell sources for regenerative medicine. Here, we focused on providing the platform that forced ES cells to reproduce the vascular organization process, leading to efficiency and safety evaluation as preclinical testing of biological agents. Murine ES cell-derived embryoid bodies on matrigel, but not collagen or gelatin, could be differentiated into sprouting blood vessels without the addition of growth factors. The expression of endothelial cell marker CD31 and smooth muscle marker alpha-smooth muscle actin was partially colocalized and started to increase 7 days after culture on matrigel, accompanied by the induction of a number of growth factors, such as vascular endothelial growth factor, fibroblast growth factor-2, hepatocyte growth factor, transforming growth factor-beta, and angiopoietin-1. Moreover, notch-related genes, such as Del1 or Del4 (delta-like 1/4) and hey1 or hey2 (hairy/enhancer of split related TRPW motif 1/2), were upregulated in a similar time course. The treatment of neutralizing antibodies against these growth factors failed to inhibit the differentiation into the sprouting blood vessels, whereas arginine-glycine-aspartic peptide, a selective inhibitor for the alphavbeta3-integrins, did inhibit differentiation. An anticancer drug to inhibit angiogenesis, TNP-470, also blocked the vascular formation in this model. ES cells could reproduce the vascular organization process on the biosynthetic scaffolds, such as matrigel, without the addition of growth factors. In the future, a human ES-based tissue model would be an optional tool for the screening of pharmaceutical drugs for vascular disease.
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.forename: Namika
authors.initials: N
authors.lastname: Nakagawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takeya
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Kashiwagi
authors.forename: Chisato
authors.initials: C
authors.lastname: Ishida
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Hayashi
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D000906:Antibodies; D001808:Blood Vessels / Q000166:cytology / Q000254:growth & development*; D002454:Cell Differentiation; D002460:Cell Line; D003094:Collagen; D004338:Drug Combinations; D004622:Embryo, Mammalian / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology*; D015870:Gene Expression; D007797:Laminin; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D018919:Neovascularization, Physiologic; D011509:Proteoglycans; D012333:RNA, Messenger / Q000096:biosynthesis; D044968:Regenerative Medicine; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen