Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice
Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice
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DOI：
10.1038/labinvest.3700156
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发表时间：
2004-10-01
影响因子：
5
通讯作者：
Roberts, AB
中科院分区：
文献类型：
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作者：
Saika, S;Kono-Saika, S;Roberts, AB
视网膜色素上皮（RPE）细胞在视网膜脱离后去分化并经历上皮-间充质转化（EMT），在脱离的视网膜上的纤维组织形成和玻璃体退缩（增生性玻璃体视网膜病变（PVR））中起核心作用。我们已经开发了一种视网膜下纤维化的小鼠模型，其涉及PVR，其中诱导视网膜脱离而不直接损伤RPE细胞。长期以来，转化生长因子-β（TGF-β）与RPE的EMT和PVR的发展有关。使用小鼠空Smad 3，TGF-β和激活素受体下游的关键信号中间体，我们表明，Smad 3是必不可少的视网膜脱离诱导的RPE细胞的EMT。在野生型而非Smad 3缺失小鼠的眼睛中，在实验性视网膜脱离后观察到源自多层RPE细胞的纤维组织的从头积累。α-平滑肌肌动蛋白的表达，EMT在这种细胞类型中的标志，和细胞外基质成分，Lumican和胶原VI，也没有观察到Smad 3-null小鼠的眼睛。我们的数据表明，通过Smad 3依赖性TGF-β信号传导诱导PDGF-BB可能是疾病过程中重要的继发性增殖成分。结果表明，阻断Smad 3通路可能有利于预防/治疗PVR。
Retinal pigment epithelial (RPE) cells dedifferentiate and undergo epithelial-mesenchymal transition (EMT) following retinal detachment, playing a central role in formation of fibrous tissue on the detached retina and vitreous retraction (proliferative vitreoretinopathy (PVR)). We have developed a mouse model of subretinal fibrosis with implications for PVR in which retinal detachment is induced without direct damage to the RPE cells. Transforming growth factor-beta (TGF-beta) has long been implicated both in EMT of RPEs and the development of PVR. Using mice null for Smad3, a key signaling intermediate downstream of TGF-beta and activin receptors, we show that Smad3 is essential for EMT of RPE cells induced by retinal detachment. De novo accumulation of fibrous tissue derived from multilayered RPE cells was seen following experimental retinal detachment in eyes of wild type, but not Smad3-null mice. Expression of alpha-smooth muscle actin, a hallmark of EMT in this cell type, and extracellular matrix components, lumican and collagen VI, were also not observed in eyes of Smad3-null mice. Our data show that induction of PDGF-BB by Smad3-dependent TGF-beta signaling is likely an important secondary proliferative component of the disease process. The results suggest that blocking the Smad3 pathway might be beneficial in prevention/treatment of PVR.