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首页> 外文期刊>Journal of Cellular Physiology >Activation of Smad-mediated TGF-β signaling triggers epithelial-mesenchymal transitions in murine cloned corneal progenitor cells
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Activation of Smad-mediated TGF-β signaling triggers epithelial-mesenchymal transitions in murine cloned corneal progenitor cells

机译：激活Smad-mediated TGF -β信号触发epithelial-mesenchymal转换中克隆小鼠角膜祖细胞

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Epithelial-mesenchymal transition (EMT), via activation of Wnt signaling, is prevailing in embryogenesis, but postnatally it only occurs in pathological processes, such as in tissue fibrosis and tumor metastasis. Our prior studies led us to speculate that EMT might be involved in the loss of limbal epithelial stem cells in explant cultures. To examine this hypothesis, we successfully grew murine corneal/limbal epithelial progenitors by prolonging the culture time and by seeding at a low density in a serum-free medium. Single cell-derived clonal growth was accompanied by a gradient of Wnt signaling activity, from the center to the periphery, marked by a centrifugal loss of E-cadherin and β-catenin from intercellular junctions, coupled with nuclear translocation of β-catenin and LEF-1. Large-colony-forming efficiency at central location of colony was higher than peripheral location. Importantly, there was also progressive centrifugal differentiation, with positive K14 keratin expression and the loss of p63 and PCNA nuclear staining, and irreversible EMT, evidenced by cytoplasmic expression of α-SMA and nuclear localization of S100A4; and by nuclear translocation of Smad4. Furthermore, cytoplasmic expression of α-SMA was promoted by high-density cultures and their conditioned media, which contained cell density-dependent levels of TGF-β1, TGF-β2, GM-CSF, and IL-1α. Exogenous TGF-β1 induced α-SMA positive cells in a low-density culture, while TGF-β1 neutralizing antibody partially inhibited α-SMA expression in a high-density culture. Collectively, these results indicate that irreversible EMT emerges in the periphery of clonal expansion where differentiation and senescence of murine corneal/limbal epithelial progenitors occurs as a result of Smad-mediated TGF-β-signaling.
机译：Epithelial-mesenchymal过渡(EMT),通过Wnt信号激活,是流行的产后胚胎发生,但它只发生在病理过程,如在组织肝纤维化、肿瘤转移。让我们推测EMT可能参与缘的上皮干细胞的损失外植体的文化。成功了小鼠角膜缘的上皮细胞祖细胞以延长文化时间和播种密度低无血清培养基。增长是伴随着Wnt的梯度信号活动,从中心到边缘,以离心损失钙粘蛋白和β连环蛋白从细胞间连接,加上核易位β连环蛋白和LEF-1。效率在殖民地的中心位置高于边缘位置。也有进步的离心分化,用积极K14角蛋白表达和p63和PCNA核的损失染色和不可逆转的EMT,证明了这一点胞质表达αsma和核S100A4的本地化;Smad4的易位。α的表达sma被高密度提升文化和他们的条件媒体含有细胞的密度制约的水平TGF -β1、TGF -β2、gm - csf和il - 1α。转化生长因子-β1诱导αsma阳性细胞低密度的文化,而TGF -β1中和抗体部分抑制αsma表达一种高密度的文化。结果表明,不可逆转的EMT出现克隆的外围扩张分化和小鼠的衰老角膜缘的上皮/祖细胞发生的由于Smad-mediated TGF -β信号。

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