Ageing is a major risk factor for vision loss, and inflammation is an important contributor to retinal disease in the elderly. Regenerative medicine based on cell replacement strategies has emerged in recent years as a promising approach to restore vision. However, how the ageing process affects retinal homeostasis and inflammation in the retina and how this may impose a limitation to the success of such interventions remains unknown. Here we report that, in mice and humans, retinal ageing is associated with a reduction in MANF protein levels, specifically in the choroid, where increased densities of activated macrophages can be detected. We further show that the retina of old wild type mice, in the absence of any other genetic alteration, has limited homeostatic capacity after damage imposed by light exposure and reduced engraftment efficiency of exogenously supplied photoreceptors. Finally, we show that supplementation of MANF recombinant protein can improve retinal homeostasis and repair capacity in both settings, correlating with reduced numbers of activated macrophages in the old retina. Our work identifies age-related alterations in retinal homeostasis, independent of genetic alterations, leading to age-related retinal inflammation and damage susceptibility. We suggest that MANF therapy is a potential intervention to maintain retinal homeostasis in the elderly and improve the success of retinal regenerative therapies applied to aged individuals.

中文翻译：

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MANF 递送可改善衰老小鼠的视网膜稳态和细胞替代疗法。

衰老是视力丧失的主要危险因素，炎症是老年人视网膜疾病的重要诱因。近年来，基于细胞替代策略的再生医学已成为一种很有前景的恢复视力的方法。然而，衰老过程如何影响视网膜内稳态和炎症，以及这如何限制此类干预的成功仍然未知。在这里我们报告说，在小鼠和人类中，视网膜老化与 MANF 蛋白水平的降低有关，特别是在脉络膜中，可以检测到活化巨噬细胞的密度增加。我们进一步表明，在没有任何其他基因改变的情况下，老野生型小鼠的视网膜，在曝光造成损伤和外源提供的光感受器的植入效率降低后，其稳态能力有限。最后，我们表明补充 MANF 重组蛋白可以改善两种情况下的视网膜稳态和修复能力，这与旧视网膜中活化巨噬细胞数量的减少有关。我们的工作确定了与年龄相关的视网膜稳态改变，独立于遗传改变，导致与年龄相关的视网膜炎症和损伤易感性。我们建议 MANF 疗法是一种潜在的干预措施，可维持老年人视网膜稳态，并提高适用于老年人的视网膜再生疗法的成功率。我们表明，补充 MANF 重组蛋白可以改善两种情况下的视网膜稳态和修复能力，这与旧视网膜中活化巨噬细胞数量的减少有关。我们的工作确定了与年龄相关的视网膜稳态改变，独立于遗传改变，导致与年龄相关的视网膜炎症和损伤易感性。我们建议 MANF 疗法是一种潜在的干预措施，可维持老年人视网膜稳态，并提高适用于老年人的视网膜再生疗法的成功率。我们表明，补充 MANF 重组蛋白可以改善两种情况下的视网膜稳态和修复能力，这与旧视网膜中活化巨噬细胞数量的减少有关。我们的工作确定了与年龄相关的视网膜稳态改变，独立于遗传改变，导致与年龄相关的视网膜炎症和损伤易感性。我们建议 MANF 疗法是一种潜在的干预措施，可维持老年人视网膜稳态，并提高适用于老年人的视网膜再生疗法的成功率。