Systemic sclerosis (SSc) is a multisystem chronic disease manifesting autoimmunity, vasculopathy, and extensive organ fibrosis. Although its pathogenesis still remains unknown, adipokines have recently caught much attention as a family of cytokines regulating the three cardinal pathological features of this disease. On the other hand, our studies have demonstrated that the deficiency of transcription factor Fli1 induces SSc-like phenotypes in various　cells, such as dermal fibroblasts, endothelial cells, macrophages, and epithelial cells. Therefore, we generated adipocyte-specific Fli1 knockout (Fli1 AdipoKO) mice (Fli1flox/flox;Adipo-Cre) and investigated whether these mice recapitulate the three cardinal features of SSc. Of note, Fli1 AdipoKO mice spontaneously developed dermal fibrosis at the age of 3 months. In double immunofluorescence for a-smooth muscle actin and perilipin, double positive fusiform cells were evident throughout the deep dermis in Fli1 AdipoKO mice, suggesting the promotion of adipocyte-to-myofibroblast transdifferentiation. In addition, vascular structural and functional abnormalities, such as arteriolar stenosis and increased permeability, were remarkable in Fli1 AdipoKO mice. Importantly, bone marrow-derived mesenchymal stem cells, a precursor of pro-angiogenic hematopoietic cells, exhibited de-differentiated phenotype characterized by a-smooth muscle actin downregulation and Rgs5 up-regulation, suggesting the contribution of defective vasculogenesis to the development of vascular abnormalities. Taken together, these results indicate that Fli1-deficient adipocytes may be involved in the development of dermal fibrosis and vasculopathy recapitulating SSc, suggesting a potential contribution of phenotypically altered adipocytes to the development of SSc.

Fli1-deficient adipocytes promote the spontaneous development of dermal fibrosis and vasculopathy mimicking systemic sclerosis through adipocytes-to-myofibroblast transdifferentiation and defective vasculogenesis