Gras Christiane, Ratuszny Dominica, Hadamitzky Catarina, Zhang Haijiao, Blasczyk Rainer, Figueiredo Constança
Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
Department of Plastic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany.
Mol Med. 2015 Apr 9;21(1):296-304. doi: 10.2119/molmed.2014.00172.
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.
皮肤肥厚性瘢痕形成是由伤口愈合后皮肤肌成纤维细胞过度活跃引起的，常导致功能和/或美观方面的障碍，严重损害患者的生活质量。最近，微小RNA（miRNA）基因疗法已被用于治疗诸如纤维化和瘢痕形成等复杂过程。在本研究中，我们聚焦于miR-145在皮肤瘢痕形成中的作用及其对肌成纤维细胞功能的影响。我们的数据显示，与健康皮肤或未处理的成纤维细胞相比（p < 0.001），皮肤肥厚性瘢痕组织中miR-145水平增加了两倍，在转化生长因子β1（TGF-β1）诱导的皮肤肌成纤维细胞中亦是如此。与TGF-β1刺激成纤维细胞诱导miR-145上调一致，Kruppel样因子4（KLF4）的表达降低了50%，而α-平滑肌肌动蛋白（α-SMA）蛋白表达增加了两倍。两者均可通过抑制miR-145而逆转（p < 0.05）。恢复KLF4水平同样可消除TGF-β1诱导的α-SMA表达。这些数据表明，TGF-β1诱导成纤维细胞中miR-145表达，进而抑制KLF4（一种已知的α-SMA抑制剂），从而上调α-SMA表达。此外，用miR-145抑制剂处理肌成纤维细胞可显著降低其Ⅰ型α1胶原蛋白表达、TGF-β1分泌、收缩力产生和迁移能力。这些数据表明，miR-145上调在皮肤肌成纤维细胞的分化和功能中起重要作用。此外，抑制miR-145可显著降低皮肤肌成纤维细胞活性。综上所述，这些结果表明miR-145是预防或减少皮肤肥厚性瘢痕形成的一个有前景的治疗靶点。
