Abstract：
The retinal pigment epithelium (RPE) is fundamental to sustaining retinal homeostasis. RPE abnormality leads to visual defects and blindness, including age-related macular degeneration (AMD). Although breakthroughs have been made in the treatment of neovascular AMD, effective intervention for atrophic AMD is largely absent. The inadequate knowledge of RPE pathology is hindered by a lack of patient RPE datasets, especially at the single-cell resolution. In this study, we delved into a large-scale single-cell resource of AMD donors in which RPE cells were occupied in a substantial proportion. Bulk RNA-seq datasets of atrophic AMD were integrated to extract molecular characteristics of RPE in the pathogenesis of atrophic AMD. Both in vivo and in vitro models revealed that carboxypeptidase X, M14 family member 2 (CPXM2) was specifically expressed in the RPE cells of atrophic AMD, which might be induced by oxidative stress and involved in the epithelial-mesenchymal transition of RPE cells. Additionally, silencing of CPXM2 inhibited the mesenchymal phenotype of RPE cells in an oxidative stress cell model. Thus, our results demonstrate that CPXM2 plays a crucial role in regulating atrophic AMD and may serve as a potential therapeutic target for atrophic AMD.
摘要：
视网膜色素上皮（RPE）是维持视网膜稳态的基础。RPE异常导致视觉缺陷和失明，包括年龄相关性黄斑变性（AMD）。虽然新生血管性AMD的治疗取得了突破性进展,对萎缩性AMD的有效干预大多缺乏。缺乏患者RPE数据集阻碍了RPE病理学知识的不足，特别是在单细胞分辨率下。在这项研究中,我们深入研究了AMD供体的大规模单细胞资源,其中RPE细胞占据了相当大的比例.整合萎缩性AMD的大量RNA-seq数据集以提取RPE在萎缩性AMD发病机制中的分子特征。体内和体外模型均显示羧肽酶X，M14家族成员2（CPXM2）在萎缩性AMD的RPE细胞中特异性表达，这可能是由氧化应激诱导的，并参与了RPE细胞的上皮-间质转化。此外,在氧化应激细胞模型中，CPXM2的沉默抑制了RPE细胞的间充质表型。因此，我们的研究结果表明,CPXM2在调节萎缩性AMD中起着至关重要的作用,并可能成为萎缩性AMD的潜在治疗靶点.
