188 scRNA-seq and RNA-seq for Stiff Skin Syndrome identify pericytes as a key pathogenic cell population and avenue for therapeutic targeting

Abstract

Stiff skin syndrome (SSS) is a rare (<100 reported cases), slowly progressive skin condition, caused by genetic mutation in the FBN1gene. It is characterized by thickened skin associated with muscle weakness and limited joint mobility. Currently there is no known treatment. While SSS is considered as scleroderma (Sc)-like disorder, there has not been any molecular study conducted to investigate the potential differences or similarities between the two diseases. Here, we report molecular profiling for the skin biopsies of 3 stiff skin syndrome and 3 scleroderma patients using bulk RNA-seq and single cell RNA-seq (scRNA-seq) techniques. We revealed >4,000 genes being differentially expressed in SSS skin that are highly correlated with genes dysregulated in scleroderma (Sc) skin. In stark contrast to scleroderma, which showed enrichment of myofibroblasts, there was marked enrichment of pericytes (distinguished by the expression of RGS5) in the dermal layer of SSS (10% in Sc versus >30% in SSS), confirmed by IHC. We also demonstrate expression of the therapeutically targetable adrenergic receptors (i.e. ADRA1D,ADRA2B) in pericytes, and ABCA1in fibroblasts in SSS. Previous work has suggested ADRA signaling as a promoter of fibroblast differentiation in smooth muscle. When restricting to SSS-dysregulated genes that are not differentially expressed in Sc, we identified fibroblast-expressing FGFR4(fibroblast growth factor receptor 4) as the most significantly up-regulated gene (FC=6.2; p=1.2x10-15). Our transcriptomic study illustrates the largely similar but subtle molecular differences between SSS and Sc and demonstrates that identification of dysregulated disease specific pathways can potentially facilitate the identification of therapeutic targets.