Search for a new prevention strategy of proliferative vitreoretinopathy by targeting Smad-dependent epithelial-mesenchymal transition

目的：已知视网膜色素上皮细胞经历上皮-间质转化（EMT），其主要由转化生长因子B（TGF B）/Smad 2（3）4信号传导介导。Smad 7通过阻止这种Smad复合物进入细胞核来抑制这种信号传导。因此，我们确定了Smad 7基因转移在预防视网膜色素上皮纤维化反应的影响，视网膜脱离后增殖性玻璃体视网膜病变（PVR）的主要原因之一，在mice.Methods：视网膜脱离诱导PVR的小鼠模型。一只眼睛接受Smad 7或Cre重组酶基因的腺病毒基因转移。对眼睛进行组织学分析。结果：Smad 7基因转染可抑制ARPE-19细胞TGF β 2/Smad信号通路，抑制I型胶原和TGF β 1的表达，但对基础水平无影响。结论：Smad 7基因转染可抑制视网膜色素上皮细胞对TGF β 2的致纤维化反应，临床意义：Smad 7基因转染可能成为防治PVR的新策略。

Objective: Retinal pigment epithelium is known to undergo epithelial-mesenchymal transition (EMT), which is mediated mainly by transforming growth factor b (TGFb)/Smad2(3)4 signaling. Smad7 suppresses such signaling by blocking this Smad complex from entering the nucleus. Accordingly, we determined the effects of Smad7 gene transfer in prevention of fibrogenic responses by retinal pigment epithelium, one of the major causes of post-retinal detachment proliferative vitreoretinopathy (PVR) in mice.Methods: Retinal detachment induced PVR in a mouse model. An eye received either an adenoviral gene transfer of Smad7 or Cre recombinase gene only. The eyes were histologically analyzed. A retinal pigment epithelial cell line, ARPE-19, was used to determine if Smad7 gene transfection suppresses the fibrogenic response to TGFb2exposure.Results: Smad7 gene transfer inhibited TGFb2/Smad signaling in ARPE 19 cells and expression of collagen type I and TGFb1, but had no effect on their basal levels. In vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and of the fibrogenic response to EMT by retinal pigment epithelium.Conclusion: Smad7 gene transfer suppresses fibrogenic responses to TGFb2 by retinal pigment epithelial cells in vitro and in vivo.Clinical relevance: Smad7 gene transfer might be a new strategy to prevent and treat PVR.