ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells

Rimpei Morita, Mayu Suzuki, Hidenori Kasahara, Nana Shimizu, Takashi Shichita, Takashi Sekiya, Akihiro Kimura, Ken Ichiro Sasaki, Hideo Yasukawa, Akihiko Yoshimura

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)160-165
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number1
DOIs
Publication statusPublished - 2015 Jan 6

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Proto-Oncogene Proteins c-ets
Endothelial Cells
Fibroblasts
Transcription Factors
Pluripotent Stem Cells
Inbred NOD Mouse
SCID Mice
von Willebrand Factor
Blood Vessels
Extremities
Cell Count
Transplantation
Skin
Liver

Keywords

  • Angiogenesis
  • Direct conversion
  • Endothelial cells
  • ETV2

ASJC Scopus subject areas

  • General

Cite this

ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells. / Morita, Rimpei; Suzuki, Mayu; Kasahara, Hidenori; Shimizu, Nana; Shichita, Takashi; Sekiya, Takashi; Kimura, Akihiro; Sasaki, Ken Ichiro; Yasukawa, Hideo; Yoshimura, Akihiko.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 1, 06.01.2015, p. 160-165.

Research output: Contribution to journalArticle

Morita, Rimpei ; Suzuki, Mayu ; Kasahara, Hidenori ; Shimizu, Nana ; Shichita, Takashi ; Sekiya, Takashi ; Kimura, Akihiro ; Sasaki, Ken Ichiro ; Yasukawa, Hideo ; Yoshimura, Akihiko. / ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 1. pp. 160-165.
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