Myofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin

Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin expressing cells. The number of myofibroblasts in SSc skin correlates with the modified Rodnan skin score, the most widely used clinical measure of skin disease severity. Murine fibrosis models indicate that myofibroblasts can arise from a variety of different cell types, but their origin in SSc skin has remained uncertain. Utilizing single cell RNA-sequencing, we define different dermal fibroblast populations and transcriptome changes, comparing SSc to healthy dermal fibroblasts. Here, we show that SSc dermal myofibroblasts arise in two steps from an SFRP2(hi)/DPP4-expressing progenitor fibroblast population. In the first step, SSc fibroblasts show globally upregulated expression of transcriptome markers, such as PRSS23 and THBS1. A subset of these cells shows markers indicating that they are proliferating. Only a fraction of SFRP2(hi) SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, SFRP4 and FNDC1. Bioinformatics analysis of the SSc fibroblast transcriptomes implicated upstream transcription factors, including FOSL2, RUNX1, STAT1, FOXP1, IRF7 and CREB3L1, as well as SMAD3, driving SSc myofibroblast differentiation. Myofibroblasts drive fibrosis in systemic sclerosis (SSc), but the cellular progenitors are unknown. Utilizing single cell RNA-sequencing, the authors show that SSc dermal myofibroblasts arise in a two-step process from SFRP2/DPP4-expressing progenitors and implicate upstream transcription factors.

Automated summary

Research indicates that dermal myofibroblasts in systemic sclerosis arise in a two-step process from progenitor fibroblasts expressing SFRP2/DPP4. These cells exhibit distinct transcriptome expression patterns, with some showing signs of proliferation. Only a fraction of progenitor cells differentiate into myofibroblasts under the control of various upstream transcription factors.