Smad Anchor for Receptor Activation (SARA) prevents skin fibrosis via inhibiting pericyte transdifferentiation to myofibroblasts

Myofibroblast activation is a major feature of skin fibrosis, but the origins of myofibroblasts are yet uncertain. While pericytes have been suggested as myofibroblast progenitors in various organs, their contribution to skin fibrosis is not clear. Our previous data suggest that SARA is an anti-fibrotic molecule that acts by modulating cell phenotype. Here, we studied a role for SARA in pericyte activation in a mouse model of skin fibrosis. To test role of SARA, we generated a mouse that constitutively expresses human full-length SARA cDNA specifically in pericytes under the control of PDGFRβ promoter-driven Cre recombinase activity (SARATg; PDGFRβ-Cre), and further crossed them with the Z/EG strain to mark the PDGFRβ+ pericytes with GFP. Thickening of the dermal layer and PDGFRβ+GFP+ cell expansion in dermis were significant in SARATg- mice treated with bleomycin compared to healthy controls, whereas the changes were less overt in SARATg+; Z/EG; PDGFRβ-Cre mice (mean dermal thickness; 166 and 156 μm in SARATg- or Tg+ mouse without bleomycin, 222 and 147 um in SARATg- or Tg+ mouse with bleomycin). The majority of control PDGFRβ+GFP+ cells were αSMA-, while 56% of them were αSMA+ in skin subjected to bleomycin, suggesting that PDGFRβ+ cells transdifferentiated into myofibroblasts. Approximately 34% of PDGFRβ+GFP+ cells were SARA+ in healthy mouse skin, which was decreased to 12% in mice subjected to bleomycin. In contrast, SARA levels were preserved in SARATg+ mice even after bleomycin injection. The reduction was also confirmed by SARA mRNA levels (1.09 vs. 0.59 relative expression, P=0.018). These data suggest that PDGFRβ+ pericytes contribute to skin fibrosis in mice, and SARA overexpression in pericytes prevents their transdifferention, hence preventing fibrosis. Therefore, SARA could be a novel therapeutic target in treating skin fibrosis.