THE IMMUNE RESPONSE MODULATES ZEBRAFISH RETINAL PIGMENT EPITHELIUM REGENERATION [RPE]

Loss of the retinal pigment epithelium (RPE) due to dysfunction or disease can lead to blindness in humans. Harnessing the intrinsic ability of the RPE to self-repair is an attractive therapeutic strategy; however, mammalian RPE is limited in its regenerative capacity. Zebrafish possess tremendous intrinsic regenerative potential in ocular tissues, including the RPE, but little is known about the mechanisms that drive RPE regeneration. Here, utilizing zebrafish, we identified elements of the immune response as critical mediators of intrinsic RPE regeneration. Macrophages/microglia are responsive to RPE damage and are required for the timely progression of the regenerative response and our data highlight that inflammation post-RPE injury is also critical for normal RPE regeneration. These data are the first to identify the molecular and cellular underpinnings of RPE regeneration in any system and hold significant potential for translational approaches aimed towards promoting a pro-regenerative environment in mammals.

因功能异常或疾病导致的视网膜色素上皮（retinal pigment epithelium, RPE）缺失可引发人类失明。利用RPE的内在自我修复能力是极具吸引力的治疗策略，但哺乳动物的RPE再生能力极为有限。斑马鱼（zebrafish）在包括RPE在内的眼部组织中具备极强的内在再生潜力，但目前对驱动RPE再生的具体机制仍所知甚少。本研究以斑马鱼为实验模型，鉴定出免疫应答的相关组分是RPE内在再生的关键介导因子。巨噬细胞/小胶质细胞（macrophages/microglia）可响应RPE损伤，且是再生应答按时序推进的必要条件；本研究数据同时显示，RPE损伤后的炎症反应对于正常RPE再生同样至关重要。本研究首次在任一研究体系中阐明了RPE再生的分子与细胞基础，其成果对于开发旨在促进哺乳动物形成促再生微环境的转化疗法具有重要应用潜力。