GSE211810
scRNAseq dataset of PDGFRß+ cells in fibrosing skin and kidney with or without ZFYVE9/SARA overexpression
Activated myofibroblasts play an essential role in tissue fibrogenesis by producing extracellular matrixes (ECM).  ECMs replace normal functioning tissue, reducing tissue plasticity and impairing functions of the organ.  Recent studies suggested that pericytes are a major source of myofibroblast precursors.  We previously showed that Smad Anchor for Receptor Activation (SARA) prevents cellular phenotypic transdifferentiation toward mesenchymal cells, and depletion of SARA induces transdifferentiation of epithelial cells to fibroblast-like phenotype.  Here, we generated a transgenic mice that overexpress SARA specifically pericytes by using PDGFRß-Cre (SARATg, PDGFRß-Cre). When subjected to either subcutaneous injection of bleomycin or intraperitoneal administration of aristolochic acid, which induces skin and kidney fibrosis, respectively, SARATg, PDGFRß-Cre mice developed significantly less fibrosis compared to SARAWT, PDGFRß-Cre mice.  To decipher molecular signature and pericyte trajectory under fibrotic conditions and effects of SARA overexpression, we isolated PDGFR+ cells from skin or kidney of SARATg or WT, PDGFRß-Cre, Z/EG mice with or without fibrotic stimuli and performed scRNAseq analyses.  In both skin and kidney sample sets, we found pericytes and immune cell populations are the major cell components among the PDGFR+ GFP+ cells.  We found that pericyte populations are divided into canonical and non-canonical sub-populations and the latter has assumed myofibroblast characteristics.  Trajectory mapping revealed a single path from canonical to non-canonical pericyte sub-populations and SARA overexpression truncated the trajectory.  These results suggest that SARA prevents pericyte transdifferentiation into myofibroblasts under fibrotic condition, and therefore anti-fibrotic. Overall design: 8-week-old SARATg or WT mice crossed with PDGFRß-Cre and Z/EG reporter mice were subjected to either repeated subcutaneous bleomycin (20mg/kg BW 3x week for 2 weeks) or intraperitoneal injection of aristolochic acid (5mg/kg BW 3x week for 3 weeks) to induce skin or kidney fibrosis respectively, and skin an kiney were harvested.