Single-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases

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.

Single-Cell and Bulk Transcriptome Data Integration Reveals Dysfunctional Cell Types and Aberrantly Expressed Genes in Hypertrophic Scar

“…The integrative analysis of the scRNA-seq and bulk RNA-seq data identified CREB3L1 and TWIST2 as the critical TFs involved in the myofibroblast of HS. Consistently, CRBE3L1 has been identified as one of the critical TFs involved in fibrotic skin diseases by a scRNA-seq study (Deng et al, 2021). The other TF, TWIST2, was relevant to Setleis syndrome (SS), a focal facial dermal dysplasia presenting with bilateral temporal skin lesions (Crespo et al, 2021).…”

“…Also, activation of PI3K/AKT pathway could lead to hypertrophic scar formation and ECM deposition via upregulated expression of Collagen I, Collagen III, α-SMA, and Cleaved caspase-3 in hypertrophic scar fibroblasts ( Xiao, 2020 ; Zhi et al, 2021 ). In addition, some transcription factors (TFs) such as CRBE3L1 and TWIST2 have been identified as critical regulators in skin diseases ( Crespo et al, 2021 ; Deng et al, 2021 ). Importantly, the two TFs were also involved in kidney fibrosis ( Grunz-Borgmann et al, 2017 ; Yamamoto et al, 2021 ).…”

Single-Cell Sequencing Analysis and Weighted Co-Expression Network Analysis Based on Public Databases Identified That TNC Is a Novel Biomarker for Keloid

“…In cluster3, 7, 8, and 9, which we annotated as chondrocytes, we found high expression levels of genes related to skeletal development, ossification, and osteoblasts, such as “COL11A1’,”COMP”, and “POSTN”. By reading the original text of this dataset, they probably should have been more accurately annotated as mesenchymal fibroblasts with high expression of osteogenic genes ( 8 ). Finally, we marked the keloid and normal samples as red and blue respectively.…”

“…Single-cell sequencing analysis is a revolutionary research method ( 7 ), allowing for the clustering of the cells to study the differences in gene expression among the groups and the differences in cell development ( 8 ). Keloids are composed of a variety of cells which include fibroblasts, myofibroblasts, and mesenchymal stem cells ( 3 ).…”

Beneficial Effects of Green Tea EGCG on Skin Wound Healing: A Comprehensive Review

“…Fibroblasts are mesenchymal cells that play important roles in the fibrosis process. Fibroblasts are related to ECM accumulation and inflammation, contributing to fibrosis pathogenesis [ 108 ]. A keloid is a common fibroproliferative disorder related with an abnormal wound healing process [ 70 ].…”