Gao Furong, Wang Lei, Wu Binxin, Ou Qingjian, Tian Haibin, Xu Jingying, Jin Caixia, Zhang Jieping, Wang Juan, Lu Lixia, Xu Guo-Tong
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, 389 Xincun Road Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, 200092, China.
Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, 200092, China.
Exp Eye Res. 2022 Oct;223:109207. doi: 10.1016/j.exer.2022.109207. Epub 2022 Aug 2.
Age-related macular degeneration (AMD) is one of the most common leading causes of irreversible blindness, and there is no effective treatment for it. It has been reported that aging is the greatest risk factor for AMD, and epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells plays an important role in the pathogenesis of AMD. To clarify the relationship between senescence and EMT in RPE cells, we used the replicative senescence model, HO- and/or Nutlin3a-induced senescence model, and low-density and/or TGF-β-induced EMT model to detect the expression of senescence-, RPE- and EMT-related genes, and assessed the motility of cells by using a scratch wound migration assay. The results showed that replicative senescence of RPE cells was accompanied by increased expression of EMT markers. However, senescent RPE cells themselves did not undergo EMT, as the HOand Nutlin3a treated cells showed no increase in EMT characteristics, including unchanged or decreased expression of EMT markers and decreased motility. Furthermore, conditioned medium (CM) from senescent cells induced EMT in presenescent RPE cells, and EMT accelerated the process of senescence. Importantly, dasatinib plus quercetin, which selectively eliminates senescent cells, inhibited low-density-induced EMT in RPE cells. These findings provide a better understanding of the interconnection between senescence and EMT in RPE cells. Removal of senescent cells by certain methods such as senolytics, might be a promising potential approach to prevent or delay the progression of RPE-EMT-related retinal diseases such as AMD.
年龄相关性黄斑变性（AMD）是不可逆失明的最常见主要原因之一，且尚无有效的治疗方法。据报道，衰老是AMD的最大风险因素，视网膜色素上皮（RPE）细胞的上皮-间质转化（EMT）在AMD的发病机制中起重要作用。为了阐明RPE细胞衰老与EMT之间的关系，我们使用了复制性衰老模型、HO-和/或Nutlin3a诱导的衰老模型以及低密度和/或TGF-β诱导的EMT模型来检测衰老、RPE和EMT相关基因的表达，并通过划痕伤口迁移试验评估细胞的运动性。结果表明，RPE细胞的复制性衰老伴随着EMT标志物表达的增加。然而，衰老的RPE细胞本身并未发生EMT，因为用HO和Nutlin3a处理的细胞在EMT特征方面没有增加，包括EMT标志物的表达未改变或降低以及运动性降低。此外，衰老细胞的条件培养基（CM）诱导了早衰RPE细胞中的EMT，而EMT加速了衰老过程。重要的是，选择性清除衰老细胞的达沙替尼加槲皮素抑制了RPE细胞中低密度诱导的EMT。这些发现有助于更好地理解RPE细胞衰老与EMT之间的相互联系。通过某些方法（如衰老细胞溶解剂）清除衰老细胞，可能是预防或延缓RPE-EMT相关视网膜疾病（如AMD）进展的一种有前景的潜在方法。
