Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro
Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro
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DOI：
10.1242/jcs.111302
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发表时间：
2013-05-15
影响因子：
4
通讯作者：
de Crombrugghe, Benoit
中科院分区：
文献类型：
--
作者：
Sonnylal, Sonali;Xu, Shiwen;de Crombrugghe, Benoit
结缔组织生长因子（CTGF）在慢性纤维化疾病的发病机制中发挥着重要作用。然而，CTGF 的旁分泌作用控制邻近上皮细胞的细胞命运的机制尚不清楚。在本研究中，我们研究了 Col1a2-CTGF 转基因小鼠成纤维细胞中过表达的 CTGF 对皮肤和肺上皮细胞的旁分泌作用。检查 Col1a2-CTGF 转基因小鼠的皮肤和肺部的上皮活化和分化以及信号转导途径刺激的表型标记。除了 Col1a2-CTGF 转基因小鼠的真皮区室扩张外，表皮还具有局灶性增生的特征，基底细胞的 α SMA、Snail、S100A4 和 Sox9 染色呈阳性，表明这些细胞的遗传程序发生了变化。在皮肤的颗粒层和角质层中观察到磷酸化 p38 和磷酸化 Erk1/2 的激活。肺纤维化与 Col1a2-CTGF 小鼠病变和未受影响的肺组织中共表达上皮和间质标记物的细胞显着增加有关。在用 TGF beta 处理的上皮细胞中，CTGF 特异性 siRNA 介导的敲低抑制了 Snail、Sox9、S100A4 蛋白水平并恢复了 E-钙粘蛋白水平。上皮细胞中 CTGF 的腺病毒表达和重组 CTGF 处理均诱导 EMT 样形态变化和 α-SMA 表达。我们的体内和体外数据支持这样的观点：皮肤和肺的间充质细胞中的 CTGF 表达可以导致邻近上皮细胞的分化程序发生变化。我们推测这些变化可能有助于纤维形成。
Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathways. In addition to an expansion of the dermal compartment in Col1a2-CTGF transgenic mice, the epidermis was characterized by focal hyperplasia, and basal cells stained positive for alpha SMA, Snail, S100A4 and Sox9, indicating that these cells had undergone a change in their genetic program. Activation of phosphorylated p38 and phosphorylated Erk1/2 was observed in the granular and cornified layers of the skin. Lung fibrosis was associated with a marked increase in cells co-expressing epithelial and mesenchymal markers in the lesional and unaffected lung tissue of Col1a2-CTGF mice. In epithelial cells treated with TGF beta, CTGF-specific siRNA- mediated knockdown suppressed Snail, Sox9, S100A4 protein levels and restored E-cadherin levels. Both adenoviral expression of CTGF in epithelial cells and treatment with recombinant CTGF induced EMT-like morphological changes and expression of alpha-SMA. Our in vivo and in vitro data supports the notion that CTGF expression in mesenchymal cells in the skin and lungs can cause changes in the differentiation program of adjacent epithelial cells. We speculate that these changes might contribute to fibrogenesis.