Abstract
Hyperthrophic scarring of the skin is caused by excessive activity of skin myofibroblasts after wound healing and often leads to functional and/or aesthetic disturbance with significant impairment of patient quality of life. MicroRNA (miRNA) gene therapies have recently been proposed for complex processes such as fibrosis and scarring. In this study, we focused on the role of miR-145 in skin scarring and its influence in myofibroblast function. Our data showed not only a threefold increase of miR-145 levels in skin hypertrophic scar tissue but also in transforming growth factor β1 (TGF-β1)-induced skin myofibroblasts compared with healthy skin or nontreated fibroblasts (p < 0.001). Consistent with the upregulation of miR-145 induced by TGF-β1 stimulation of fibroblasts, the expression of Kruppel-like factor 4 (KLF4) was decreased by 50% and α-smooth muscle actin (α-SMA) protein expression showed a threefold increase. Both could be reversed by miR-145 inhibition (p < 0.05). Restoration of KLF4 levels equally abrogated TGF-β1-induced α-SMA expression. These data demonstrate that TGF-β1 induces miR-145 expression in fibroblasts, which in turn inhibits KLF4, a known inhibitor of α-SMA, hence upregulating α-SMA expression. Furthermore, treatment of myofibroblasts with a miR-145 inhibitor strongly decreased their α-1 type I collagen expression, TGF-β1 secretion, contractile force generation and migration. These data demonstrate that upregulation of miR-145 plays an important role in the differentiation and function of skin myofibroblasts. Additionally, inhibition of miR-145 significantly reduces skin myofibroblast activity. Taken together, these results suggest that miR-145 is a promising therapeutic target to prevent or reduce hypertrophic scarring of the skin.
Highlights
Pathological skin scarring has a high clinical impact in both developing and industrialized countries
Our preliminary data show that for most candidate miRNAs, there was no apparent difference in expression levels between healthy skin and skin scar (Table 1). miR-133b, which was reported to be downregulated in mouse corneal scar tissue [15], was slightly upregulated in skin scar tissue compared with healthy skin. miR-29b, which was previously reported to be downregulated in skin scar [10], did not show a significant change between healthy and scarred skin
Our results show that Kruppel-like factor 4 (KLF4) expression is significantly decreased and α-smooth muscle actin (α-SMA) expression is increased in skin scar tissue versus healthy skin and in transforming growth factor β1 (TGF-β1)–induced myofibroblasts compared with nontreated fibroblasts
Summary
Pathological skin scarring has a high clinical impact in both developing and industrialized countries. Surgery or trauma of the skin, burn injuries, can trigger excessive fibrotic responses that frequently result in hypertrophic scarring [1]. Pathological scars often cause a significant impairment of the patient’s quality of life because of functional limitations or aesthetic disfigurement [2]. The treatment of pathological scars is difficult because of a lack of effective therapeutic options and frequently involves scar revision surgery, a procedure that itself induces renewed scar formation [1]. It is of high importance to unravel the molecular mechanisms underlying pathological scarring and identify novel preventive and therapeutic strategies to adequately remedy the problem. Progenitor cells such as fibroblasts are acti-
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