Saika Shizuya, Kono-Saika Satoko, Tanaka Takeshi, Yamanaka Osamu, Ohnishi Yoshitaka, Sato Misako, Muragaki Yasuteru, Ooshima Akira, Yoo Jiyun, Flanders Kathleen C, Roberts Anita B
Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama, Japan.
Lab Invest. 2004 Oct;84(10):1245-58. doi: 10.1038/labinvest.3700156.
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.
视网膜色素上皮（RPE）细胞在视网膜脱离后会去分化并经历上皮-间质转化（EMT），在脱离视网膜上纤维组织的形成和玻璃体后脱离（增殖性玻璃体视网膜病变（PVR））中起核心作用。我们已经建立了一种对PVR有启示意义的视网膜下纤维化小鼠模型，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）一直被认为与RPE细胞的EMT以及PVR的发展有关。利用Smad3基因敲除小鼠（Smad3是TGF-β和激活素受体下游的关键信号中间体），我们发现Smad3对于视网膜脱离诱导的RPE细胞EMT至关重要。在野生型小鼠而非Smad3基因敲除小鼠的实验性视网膜脱离后，可见源自多层RPE细胞的纤维组织重新积累。在Smad3基因敲除小鼠的眼中也未观察到α-平滑肌肌动蛋白（这种细胞类型中EMT的标志）以及细胞外基质成分（核心蛋白聚糖和胶原蛋白VI）的表达。我们的数据表明，Smad3依赖的TGF-β信号诱导血小板衍生生长因子-BB（PDGF-BB）可能是疾病过程中一个重要的继发性增殖成分。结果表明，阻断Smad3途径可能对PVR的预防/治疗有益。
