CTHRC1+ fibroblasts are stimulated by macrophage‐secreted SPP1 to induce excessive collagen deposition in keloids

Abstract

Editor, Fibrosis is characterized by fibroblast dysfunction and excessive deposition of cell-matrix that affect the normal functioning of the original tissue or organ. 1 The pathogenesis of keloids is complex and remains elusive. Multiple studies have suggested that skin color and tension, 2 immunity, 3 hormones, inflammatory stimulation, 4 genes 5 and other factors play critical roles in the onset and development of keloids. In addition to fibroblasts, immune cells that include macrophages, 6 mast cells 7 and lymphocytes 8 are also important to keloid pathogenesis via cytokine secretion and the triggering of abnormal signaling pathways. 9,10 Therefore, performing single-cell RNA-sEquation (scRNA-seq) that can identify heterogenous cell populations and cellular developmental pathways is thus valuable, as it will provide insight into the key pathogenic cell-types and the molecular patterns.In this study, we performed scRNA-seq on six pairs of keloid samples to elucidate the pathogenesis of skin fibrosis. Detailed methods and single-cell sequencing analysis are described in the Supplemental materials.We obtained lesion and non-lesion skin biopsies from six keloid patients (Figure 1A, Figure S1A,B, Table S1) and performed hematoxylin and eosin (H&E) and Masson staining (Figure 1B). Then we applied single-cell sequencing (scRNA-seq) to 12 skin samples that included both lesion and non-lesion areas (Figure 1C). After stringent quality-control procedures, 60,732 high-quality cells were obtained for further analysis. We first visualized all subgroups by uniform manifold approximation and projection (UMAP) and then determined the different cell types that included fibroblasts, keratinocytes, endothelial cells, T cells, pericytes, myeloid cells, mast cells, B cells, adipocytes, melanocytes and salivary gland cells (Figure 1C,D). All cell types were identified in each sample, and we observed minimal batch effects in our study (Figure S1C--F). Top-marked signatures for each cell typeThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…Our NMF analysis revealed factors in the IPF and the d7 and d21 BLM datasets that shared key marker genes indicative of macrophages ( SPP1 , CD68 , APOE ). SPP1+ profibrotic macrophages, displaying an M2 polarization phenotype, have previously been implicated in ECM remodeling and fibrosis development 6,54 . The activity of the selected macrophage factors was largely localized near fibrosis-associated bronchial regions.…”

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