title: miR-145 Contributes to Hypertrophic Scarring of the Skin by Inducing Myofibroblast Activity.
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.
authors: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors: Christiane
authors: C
authors: Gras
authors: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors: Dominica
authors: D
authors: Ratuszny
authors: Department of Plastic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany.
authors: Catarina
authors: C
authors: Hadamitzky
authors: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors: Haijiao
authors: H
authors: Zhang
authors: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors: Rainer
authors: R
authors: Blasczyk
authors: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors: Constança
authors: C
authors: Figueiredo
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics; D017439:Cicatrix, Hypertrophic / Q000235:genetics*; D024042:Collagen Type I / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1