Single Cell RNA-sequencing Identifies Distinct Fibroblast Subsets in a Human 3D Skin Model of Systemic Sclerosis

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Abstract Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by skin and organ fibrosis, autoantibody formation, and vascular injury. Due to the systemic nature of this disease, 30–40% of patients die within the first 10 years after diagnosis. There are currently no FDA-approved disease-modifying therapies for SSc and available treatments fail to target the origins of skin and organ fibrosis 1. There is a need to identify targetable cell populations and molecular mediators responsible for disease. Here we report single cell RNA-sequencing (scRNA-seq) profiles of 11,140 human fibroblasts, macrophages, and keratinocytes from eight 3D SSc human skin equivalents 2. We isolated 956 macrophages, 606 keratinocytes, and 9578 fibroblasts from this model system. The keratinocyte cluster was identified by high expression of keratin genes such as KRT6A and KRT16, while the macrophage cluster was identified by upregulation of HLA-DR, CD163, and CD206. The fibroblast population was composed of six different subpopulations distinguished by differentially expressed features. Three of the fibroblast subpopulations were driven by genes encoding collagen proteins such as COL1A1 and COL3A1, while the other three subpopulations were driven by genes encoding mitochondrial and ribosomal components, metal and ion binding proteins, and lipoproteins. These distinct fibroblast subpopulations may represent targetable cell types for therapeutic intervention.