Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 1, Pages 160-165Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1413234112
Keywords
endothelial cells; angiogenesis; ETV2; direct conversion
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Society for the Promotion of Science [A 22249009]
- Core Research for Evolutional Science and Technology Program (Reprograming of immune system by modulation of intracellular signal transduction) of the Japan Science and Technology Agency
- Takeda Science Foundation
- Uehara Memorial Foundation
- Mochida Memorial Foundation
- SENSHIN Medical Research Foundation
- Keio Gijuku Academic Development Funds
- Grants-in-Aid for Scientific Research [25670234, 26713019, 26670470] Funding Source: KAKEN
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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.
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