Abstract
Fibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix. Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. In this study, we explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases, by using single-cell RNA-seq. Our results indicate that keloid fibroblasts can be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory. Interestingly, the percentage of mesenchymal fibroblast subpopulation is significantly increased in keloid compared to normal scar. Functional studies indicate that mesenchymal fibroblasts are crucial for collagen overexpression in keloid. Increased mesenchymal fibroblast subpopulation is also found in another fibrotic skin disease, scleroderma, suggesting this is a broad mechanism for skin fibrosis. These findings will help us better understand skin fibrotic pathogenesis, and provide potential targets for fibrotic disease therapies.
Highlights
Fibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix
The development of single-cell RNA-sequencing gives us an opportunity to explore fibroblast heterogeneity of the skin under homeostasis and pathology. scRNA-seq suggested that fibroblasts can be divided into multiple subgroups in normal human dermis13–16. scRNA-seq has been used to study the heterogeneity of fibroblasts in some fibrotic diseases, such as lung fibrosis, systemic sclerosis, and Dupuytren’s disease[17,18,19]
The immunofluorescence experiments showed similar results that only part of ADAM12 positive mesenchymal fibroblasts were α-SMA positive in keloid (Supplementary Fig. 4b). These results suggested that part of mesenchymal fibroblasts were myofibroblasts, and most of the myofibroblasts were in the mesenchymal fibroblast subpopulation in keloid
Summary
Fibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix. We explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases, by using single-cell RNA-seq. Increased mesenchymal fibroblast subpopulation is found in another fibrotic skin disease, scleroderma, suggesting this is a broad mechanism for skin fibrosis These findings will help us better understand skin fibrotic pathogenesis, and provide potential targets for fibrotic disease therapies. Compared to normal scar tissue, the percentage of a subpopulation of fibroblasts expressing mesenchymal cell markers was significantly increased in keloid. These findings will help us more thoroughly understand fibrotic skin diseases and provide potential targets for fibrosis therapies
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