Aging, chronic oxidative stress, and inflammation are major pathogenic factors in the development and progression of age-related macular degeneration (AMD) with the loss of retinal pigment epithelium (RPE). The human RPE contains a subpopulation of progenitors (i.e., RPE stem cells—RPESCs) whose role in the RPE homeostasis is under investigation. We evaluated the paracrine effects of mature RPE cells exposed to oxidative stress (H₂O₂) on RPESCs behavior through co-cultural, morphofunctional, and bioinformatic approaches. RPESCs showed a decline in proliferation, an increase of the senescence-associated β-galactosidase activity, the acquisition of a senescent-like secretory phenotype (SASP), and the reduction of their stemness and differentiation competencies. IL-6 and Superoxide Dismutase 2 (SOD2) seem to be key molecules in RPESCs response to oxidative stress. Our results get insight into stress-induced senescent-associated molecular mechanisms implicated in AMD pathogenesis. The presence of chronic oxidative stress in the microenvironment reduces the RPESCs abilities, inducing and/or maintaining a pro-inflammatory retinal milieu that in turn could affect AMD onset and progression.

衰老、慢性氧化应激和炎症是伴随视网膜色素上皮细胞 (RPE) 丧失的年龄相关性黄斑变性 (AMD) 发展和进展的主要致病因素。人类 RPE 包含一个祖细胞亚群（即RPE 干细胞-RPESCs），其在 RPE 稳态中的作用正在研究中。我们评估了暴露于氧化应激（H ₂ O _{2 ）的成熟 RPE 细胞的旁分泌作用。}) 通过共文化、形态功能和生物信息学方法研究 RPESCs 的行为。RPESCs 表现出增殖下降、衰老相关 β-半乳糖苷酶活性增加、获得衰老样分泌表型 (SASP) 以及其干性和分化能力的降低。IL-6 和超氧化物歧化酶 2 (SOD2) 似乎是 RPESC 对氧化应激反应的关键分子。我们的研究结果深入了解了与 AMD 发病机制有关的压力诱导的衰老相关分子机制。微环境中慢性氧化应激的存在降低了 RPESCs 的能力，诱导和/或维持促炎性视网膜环境，进而影响 AMD 的发病和进展。