miR-218 regulates focal adhesion kinase-dependent TGFβ signaling in fibroblasts.
miR-218 regulates focal adhesion kinase-dependent TGFβ signaling in fibroblasts.
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DOI：
10.1091/mbc.e13-08-0451
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发表时间：
2014-04
影响因子：
3.3
通讯作者：
Leask A
中科院分区：
文献类型：
--
作者：
Guo F;Carter DE;Leask A
与身体的其他组织不同，口腔不会留下疤痕。肌成纤维细胞是瘢痕组织形成过程中必不可少的细胞类型；在TGFβ的作用下，牙龈成纤维细胞相对不能分化为肌成纤维细胞。这种差异反应归因于牙龈成纤维细胞中miR-218的相对缺乏。瘢痕形成基本上发生在所有成人组织中，其特征是结缔组织中表达α-平滑肌肌动蛋白（SMA）的肌成纤维细胞过度产生和重塑细胞外基质。过多的疤痕会导致器官衰竭和死亡。口腔牙龈不结疤。与真皮成纤维细胞相比，牙龈成纤维细胞对转化生长因子β (TGFβ)的反应较弱，这是由于这种细胞类型的局灶黏着激酶（FAK）的表达和活性降低。我们发现，与真皮成纤维细胞相比，牙龈成纤维细胞miR-218的表达降低。将pre-miR-218引入牙龈成纤维细胞可提高FAK的表达，并通过FAK/src依赖机制，导致TGFβ诱导α-SMA的能力。去泛素酶cezanne是miR-218的直接靶点，与真皮成纤维细胞相比，其在牙龈成纤维细胞中的表达增加。在牙龈成纤维细胞中，cezanne基因敲低可增加FAK的表达，使TGFβ诱导α-平滑肌肌动蛋白（α-SMA）的表达。这些结果表明，miR-218通过cezanne/FAK调节TGFβ诱导成纤维细胞分化的能力。
Unlike other tissues in the body, the oral cavity does not scar. Myofibroblasts are the essential cell type in scar tissue formation; gingival fibroblasts are relatively unable to differentiate into myofibroblasts in response to TGFβ. This differential response is attributed to the relative lack of miR-218 in gingival fibroblasts. Scarring, which occurs in essentially all adult tissue, is characterized by the excessive production and remodeling of extracellular matrix by α-smooth muscle actin (SMA)–expressing myofibroblasts located within connective tissue. Excessive scarring can cause organ failure and death. Oral gingivae do not scar. Compared to dermal fibroblasts, gingival fibroblasts are less responsive to transforming growth factor β (TGFβ) due to the reduced expression, due to the reduced expression and activity of focal adhesion kinase (FAK) by this cell type. Here we show that, compared with dermal fibroblasts, gingival fibroblasts show reduced expression of miR-218. Introduction of pre–miR-218 into gingival fibroblasts elevates FAK expression and, via a FAK/src-dependent mechanism, results in the ability of TGFβ to induce α-SMA. The deubiquitinase cezanne is a direct target of miR-218 and has increased expression in gingival fibroblasts compared with dermal fibroblasts. Knockdown of cezanne in gingival fibroblasts increases FAK expression and causes TGFβ to induce α-smooth muscle actin (α-SMA). These results suggest that miR-218 regulates the ability of TGFβ to induce myofibroblast differentiation in fibroblasts via cezanne/FAK.