title: ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells.
abstract: Transplantation of endothelial cells (ECs) is a promising therapeutic approach for ischemic disorders. In addition, the generation of ECs has become increasingly important for providing vascular plexus to regenerated organs, such as the liver. Although many attempts have been made to generate ECs from pluripotent stem cells and nonvascular cells, the minimum number of transcription factors that specialize in directly inducing vascular ECs remains undefined. Here, by screening 18 transcription factors that are important for both endothelial and hematopoietic development, we demonstrate that ets variant 2 (ETV2) alone directly converts primary human adult skin fibroblasts into functional vascular endothelial cells (ETVECs). In coordination with endogenous FOXC2 in fibroblasts, transduced ETV2 elicits expression of multiple key endothelial development factors, including FLI1, ERG, and TAL1, and induces expression of endothelial functional molecules, including EGFL7 and von Willebrand factor. Consequently, ETVECs exhibits EC characteristics in vitro and forms mature functional vasculature in Matrigel plugs transplanted in NOD SCID mice. Furthermore, ETVECs significantly improve blood flow recovery in a hind limb ischemic model using BALB/c-nu mice. Our study indicates that the creation of ETVECs provides further understanding of human EC development induced by ETV2.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Tokyo 102-0076, Japan; rimpeim@a7.keio.jp yoshimura@a6.keio.jp.
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Mayu
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kasahara
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Nana
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Tokyo 102-0076, Japan; PRESTO (Precursory Research for Embryonic Science and Technology), Chiyoda-ku, Tokyo 102-0075, Japan; and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shichita
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekiya
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Tokyo 102-0076, Japan;
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Tokyo 102-0076, Japan; rimpeim@a7.keio.jp yoshimura@a6.keio.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000328:Adult; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010477:Perfusion; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C000597090:ETV2 protein, human; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein
keywords: ETV2; angiogenesis; direct conversion; endothelial cells