Abstract
Keloid and hypertrophic scars are skin fibrosis-associated disorders that exhibit an uncontrollable proliferation of fibroblasts and their subsequent contribution to the excessive accumulation of extracellular matrix (ECM) in the dermis. In this study, to elucidate the underlying mechanisms, we investigated the pivotal roles of epidermal growth factor (EGF) in modulating fibrotic phenotypes of keloid and hypertrophic dermal fibroblasts. Our initial findings revealed the molecular signatures of keloid dermal fibroblasts and showed the highest degree of skin fibrosis markers, ECM remodeling, anabolic collagen-cross-linking enzymes, such as lysyl oxidase (LOX) and four LOX-like family enzymes, migration ability, and cell–matrix traction force, at cell–matrix interfaces. Furthermore, we observed significant EGF-mediated downregulation of anabolic collagen-cross-linking enzymes, resulting in amelioration of fibrotic phenotypes and a decrease in cell motility measured according to the cell–matrix traction force. These findings offer insight into the important roles of EGF-mediated cell–matrix interactions at the cell–matrix interface, as well as ECM remodeling. Furthermore, the results suggest their contribution to the reduction of fibrotic phenotypes in keloid dermal fibroblasts, which could lead to the development of therapeutic modalities to prevent or reduce scar tissue formation.
Highlights
Keloid and hypertrophic scars are defined as abnormal healing of injured or irritated skin during wound healing caused by a pathologically uncontrollable proliferation of fibroblasts in the dermis layer, which eventually results in overabundant accumulation of extracellular matrix (ECM) components [1,2,3,4]
Histologic analyses to evaluate differences in dermal tissue revealed that both keloid and hypertrophic scars showed thickening of the epidermis, and more nuclei were observed in their dermis regions, which was confirmed by hematoxylin and eosin (H&E) staining (Figure 1b)
To further evaluate fibrotic tissue formation in the dermis, Masson’s trichrome and Picrosirius red staining revealed abundant and dense collagen deposition in both keloid and hypertrophic scar tissues (Figure 1c,d). These results clearly suggest that hypertrophic and keloid scar tissues exhibit excessive ECM deposition on skin tissues, which is a typical phenotype of skin fibrosis pathology
Summary
Keloid and hypertrophic scars are defined as abnormal healing of injured or irritated skin during wound healing caused by a pathologically uncontrollable proliferation of fibroblasts in the dermis layer, which eventually results in overabundant accumulation of extracellular matrix (ECM) components [1,2,3,4]. Emerging evidence reveals that the LOX and LOXL family are involved in various diseases related to pathogenic tissue fibrosis, including idiopathic pulmonary fibrosis (IPF), renal fibrosis, cardiac fibrosis, hepatic fibrosis and systemic sclerosis [14,15,16,17,18]. Their potential implications in keloid skin disorders are not fully understood. A previous study reported that EGF treatment of human dermal fibroblasts downregulates ECM production, including expression of type I procollagen protein, and upregulates MMP-1 expression [21]
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