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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-01, Vol.112 (1), p.160-165
• Main Authors: Morita, Rimpei, Suzuki, Mayu, Kasahara, Hidenori, Shimizu, Nana, Shichita, Takashi, Sekiya, Takashi, Kimura, Akihiro, Sasaki, Ken-ichiro, Yasukawa, Hideo, Yoshimura, Akihiko
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biological Sciences; Biosynthesis; Blood Vessels - metabolism; Cell Proliferation; Cellular biology; Circulatory system; Endothelial Cells - cytology; Endothelial Cells - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Forkhead Transcription Factors - metabolism; Gene expression; Humans; Ischemia; Mice, Inbred NOD; Mice, SCID; Perfusion; Rodents; Transcription Factors - metabolism; Transplants & implants
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1413234112

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. Significance Endothelial cells (ECs) form vasculature to provide vital elements, such as nutrients and oxygen, to tissues and organs in the body. Thus, creating ECs from nonvascular cells by transducing some transcription factors not only leads to the development of new strategies for patient-specific therapeutic angiogenesis, but also facilitates the maintenance of the solid organs that are regenerated from pluripotent stem cells. In this paper, we show that the single transcription factor ETV2, which is lentivirally transduced, induces expression of the multiple EC-specific molecules in coordination with endogenous FOXC2 in the fibroblasts, resulting in the conversion of primary human adult skin fibroblasts into functional ECs that form mature perfused vessels in vivo.