Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury
Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury
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DOI：
10.1016/s0002-9440(10)63153-7
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发表时间：
2004-02-01
影响因子：
6
通讯作者：
Roberts, AB
中科院分区：
文献类型：
--
作者：
Saika, S;Kono-Saika, S;Roberts, AB
透镜上皮细胞在损伤后经历上皮-间充质转化（EMT），如在白内障摘除术中，导致透镜囊的纤维化。前囊的纤维化可以通过透镜中的囊损伤在小鼠中建模，这导致透镜上皮的EMT和随后的细胞外基质沉积，而没有来自透镜外部的其他细胞类型的污染。我们先前已经表明，通过Smad 3（转化生长因子（TGF）-β和激活素受体下游的关键信号转导元件）的信号传导在透镜上皮细胞中在损伤后12小时被激活，并且这种Smad 3激活通过在小鼠中施用TGF-β 2中和抗体而被阻断。我们现在发现体外原代透镜上皮细胞的EMT依赖于TGF-β的表达，而体内损伤诱导的EMT更具体地依赖于通过Smad 3的信号传导。小鼠中Smad 3的缺失阻断了透镜上皮细胞向间充质表型的形态学变化以及响应于体内损伤或暴露于器官培养物中的外源性TGF-β的EMT标志物snail、α-平滑肌肌动蛋白、Lumican和I型胶原的表达。结果表明，阻断Smad 3通路可能有利于抑制损伤和/或手术后的囊纤维化。
Lens epithelial cells undergo epithelial-mesenchymal transition (EMT) after injury as in cataract extraction, leading to fibrosis of the lens capsule. Fibrosis of the anterior capsule can be modeled in the mouse by capsular injury in the lens, which results in EMT of the lens epithelium and subsequent deposition of extracellular matrix without contamination of other cell types from outside the lens. We have previously shown that signaling via Smad3, a key signal-transducing element downstream of transforming growth factor (TGF)-beta and activin receptors, is activated in lens epithelial cells by 12 hours after injury and that this Smad3 activation is blocked by administration of a TGF-beta2-neutralizing antibody in mice. We now show that EMT of primary lens epithelial cells in vitro depends on TGF-beta expression and that injury-induced EMT in vivo depends, more specifically, on signaling via Smad3. Loss of Smad3 in mice blocks both morphological changes of lens epithelium to a mesenchymal phenotype and expression of the EMT markers snail, a-smooth muscle actin, lumican, and type I collagen in response to injury in vivo or to exposure to exogenous TGF-beta in organ culture. The results suggest that blocking the Smad3 pathway might be beneficial in inhibiting capsular fibrosis after injury and/or surgery.