We previously reported that Smad Anchor for Receptor Activation (SARA) plays a critical role in maintaining epithelial cell phenotype. Here, we show that SARA suppresses myofibroblast precursor transdifferentiation in a mouse model of scleroderma. Mice overexpressing SARA specifically in PDGFRβ+ pericytes and pan-leukocytes (SARATg) developed significantly less skin fibrosis in response to bleomycin injection compared to wild-type littermates (SARAWT).Single cell RNASeq analysis of skin PDGFRβ+ cells implicated pericyte subsets assuming myofibroblast characteristics under fibrotic stimuli, and SARA overexpression blocked the transition. In addition, a cluster that expresses molecules associated with Th2 cells and macrophage activation was enriched in SARAWT, but not in SARATg mouse, after bleomycin treatment. Th2- specific Il-31 expression was increased in skin of the bleomycin-treated SARAWT mice, and scleroderma patients. Receptor-ligand analyses indicated that lymphocytes mediate pericyte transdifferentiation in SARAWT mice, while with SARA overexpression the myofibroblast activity of pericytes was suppressed. Together, these data suggest a novel crosstalk between myofibroblast precursors and immune cells in the pathogenesis of SSc, for which SARA plays a critical role.
Katia Corano-Scheri, Xiaoyan Liang, Vidhi Dalal, I. Caroline Le Poole, John Varga, Tomoko Hayashida
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