Abstract
Scar formation following skin injury can be a major psychosocial and physiological problem. However, the mechanisms of scar formation are still not completely understood. Previous studies have shown that wound healing in oral mucosa is faster, associates with a reduced inflammatory response and results to significantly reduced scar formation compared with skin wounds. In the present study, we hypothesized that oral mucosal fibroblasts from human gingiva are inherently distinct from fibroblasts from breast and abdominal skin, two areas prone to excessive scar formation, which may contribute to the preferential wound healing outcome in gingiva. To this end, we compared the phenotype of human gingival and skin fibroblasts cultured in in vivo-like three-dimensional (3D) cultures that mimic the cells' natural extracellular matrix (ECM) niche. To establish 3D cultures, five parallel fibroblast lines from human gingiva (GFBLs) and breast skin (SFBLs) were seeded in high density, and cultured for up to 21 days in serum and ascorbic acid containing medium to induce expression of wound-healing transcriptome and ECM deposition. Cell proliferation, morphology, phenotype and expression of wound healing and scar related genes were analyzed by real-time RT-PCR, Western blotting and immunocytochemical methods. The expression of a set of genes was also studied in three parallel lines of human abdominal SFBLs. Findings showed that GFBLs displayed morphologically distinct organization of the 3D cultures and proliferated faster than SFBLs. GFBLs expressed elevated levels of molecules involved in regulation of inflammation and ECM remodeling (MMPs) while SFBLs showed significantly higher expression of TGF-β signaling, ECM and myofibroblast and cell contractility-related genes. Thus, GFBLs display an inherent phenotype conducive for fast resolution of inflammation and ECM remodeling, characteristic for scar-free wound healing, while SFBLs have a profibrotic, scar-prone phenotype.
Highlights
Scar formation is a common yet unwanted wound healing outcome in skin
The findings showed that gingival fibroblasts proliferated faster and expressed significantly higher levels of molecules that are involved in modulation of inflammation and extracellular matrix (ECM) remodeling (MMPs), while skin cells showed significantly elevated expression of TGF-b signaling, ECM, myofibroblast and cell contractilityrelated genes
The key finding was that gingival fibroblast lines (GFBLs) and SFBLs are markedly distinct, the former proliferating faster and expressing higher levels of molecules involved in modulation of inflammation and ECM remodeling (MMPs), while SFBLs displayed significantly higher expression of fibrillar and non-fibrillar (SLRPs and matricellular proteins) ECM proteins, and molecules involved in TGF-b signaling, regulation of myofibroblast phenotype and cell contractility
Summary
Scar formation is a common yet unwanted wound healing outcome in skin. The hallmark of scar formation is excessive accumulation of abnormally organized type I collagen-rich extracellular matrix (ECM) during the remodeling stage of wound healing. TGF-b1 and other factors may perturb functions of fibroblasts, cells responsible for ECM production and remodeling. They may promote recruitment, survival or accumulation of scar prone fibroblast subpopulations that deposit the excessive ECM [4]. The importance of fibroblast phenotype in scar formation is supported by findings showing that, for instance, scarless wound healing in the first and second trimester fetal skin associates with distinct phenotype of fibroblasts [3,5]. Scars may display persistence of active myofibroblasts subpopulations [7]
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