Single cell mapping of the metabolic landscape of skin fibrosis in systemic sclerosis

Tissue resident cells undergo metabolic reprogramming during fibrotic tissue remodeling to meet their changing metabolic demands required for extracellular matrix production and phenotypic transitions in fibrosis. However, the metabolic reprogramming in fibrotic tissues has not yet been explored at single cell level with spatial resolution. Moreover, the spatial organization of metabolic niches in fibrotic tissues remains understudied. To address these gaps, we used imaging mass cytometry (IMC) and characterized the metabolic regulome, indicative of the activity in several key metabolic pathways in systemic sclerosis (SSc) as a prototypic systemic fibrotic disease. We identified a distinct metabolically active profile with high activity of glycolysis, TCA/OXPHOS, hypoxia and ROS signaling in fibroblasts, endothelial cells and macrophages in SSc patients with progressive skin fibrosis. These metabolic profiles are associated with expression of markers of profibrotic activation. Metabolically active fibroblasts might shape their microenvironment to induce a similar metabolic phenotype in neighboring endothelial cells and macrophages, facilitating profibrotic interactions. Consistently, specific interactions between metabolically defined, activated cell subsets are associated with the extent or progression of skin fibrosis. Thus, interfering with these metabolic niches might provide therapeutic opportunities in fibrotic diseases.