Abstract
We previously reported that Smad anchor for receptor activation (SARA) plays a critical role in maintaining epithelial cell phenotype. Here, we show that SARA suppressed myofibroblast precursor transdifferentiation in a mouse model of scleroderma. Mice overexpressing SARA specifically in PDGFR-β+ pericytes and pan-leukocytes (SARATg) developed significantly less skin fibrosis in response to bleomycin injection compared with wild-type littermates (SARAWT). Single-cell RNA-Seq analysis of skin PDGFR-β+ 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 mice, but not in SARATg mice, after bleomycin treatment. Th2-specific Il-31 expression was increased in skin of the bleomycin-treated SARAWT mice and patients with scleroderma (or systemic sclerosis, SSc). Receptor-ligand analyses indicated that lymphocytes mediated pericyte transdifferentiation in SARAWT mice, while with SARA overexpression the myofibroblast activity of pericytes was suppressed. Together, these data suggest a potentially novel crosstalk between myofibroblast precursors and immune cells in the pathogenesis of SSc, in which SARA plays a critical role.
| Original language | English (US) |
|---|---|
| Article number | e160977 |
| Journal | JCI Insight |
| Volume | 7 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 8 2022 |
Funding
Generation of SARATg mouse, imaging work, mouse histology sample preparation, flow cytometry, and scRNA-Seq were performed at Transgenic and Targeted Mutagenesis Laboratory, Center for Advanced Microscopy, Mouse Histology and Phenotyping Laboratory, Flow Cytometry and Sequencing Core Facilities of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, respectively. The Core Facilities were supported by NIH National Cancer Institute CCSG P30 CA060553 awarded to the Cancer Center. SSc skin biopsy samples and healthy controls were acquired from the service provided by the Northwestern University Skin Biology and Disease Resource-based Center, supported by a grant from NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases, 1P30AR075049. The present work is supported partially by the following grants to TH: NIH National Institute of Diabetes and Digestive and Kidney Diseases R01DK0775663 and R01DK105055-01; NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases Pilot and Feasibility Award via the Skin Biology and Disease Resource-based Center 1 P30AR075049; and Scleroderma Foundation of Illinois Established researcher award from Scleroderma Foundation of Chicago.
ASJC Scopus subject areas
- General Medicine