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

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.

Th17 cells carrying TCR recognizing epidermal autoantigen induce psoriasis-like skin inflammation.

Psoriasis is considered a Th17-type autoimmune skin inflammatory disease; however, involvement of an autoantigen-specific TCR has not been established. In this study, we show that psoriasis-like skin inflammation can be induced by autoreactive Th17 cells. We previously developed the desmoglein 3-specific TCR-transgenic (Dsg3H1) mouse, in which CD4⁺ T cells recognize physiological epidermal autoantigen. T cells from Dsg3H1 mice were polarized into Th17 cells in vitro and then adoptively transferred into Rag2⁻/⁻ mice. Dsg3H1-Th17 cells induced severe psoriasis-like skin inflammation within 2 wk after transfer in the tissues in which desmoglein 3 is expressed. Such pathology was not observed when wild-type Th17 cells or Th1-skewed Dsg3H1 T cells were transferred, and it was strongly suppressed by anti-IL-12/23 and anti-IL-17 Abs. Although IFN-γ⁺/IL-17⁺ T cells accumulated in the skin lesions of mice that received Dsg3H1-Th17 cells, IFN-γ-deficient Dsg3H1-Th17 cells were fully pathogenic. These results demonstrate that cutaneous psoriasis-like immunopathology can be developed by epidermis-specific recognition of Th17 cells, which is strictly dependent on IL-17 but not IFN-γ.