Divergent Redox Responses of Macular and Peripheral Müller Glia: Implications for Retinal Vulnerability

The predilection of many conditions, such as macular telangiectasia type 2, for the human macula suggests it may be more susceptible to stress than the peripheral retina. In this study, we have comprehensively investigated the genetic profiling of the macula and peripheral retina in response to stress. We conducted single-cell RNA sequencing analysis on the macula and peripheral retina of four donors cultured ex vivo with or without exposure to light stress. We found that the peripheral retina generally exhibited more transcriptional changes than the macula in response to stress. Interestingly, the most pronounced changes were observed in a subgroup of Müller cells that are dominant in the peripheral retina. Genes more abundantly expressed in peripheral retinal Müller cells were mainly associated with stress responses and were more influenced by light stress. In contrast, genes that were highly expressed in Müller cells that predominate in the macula played roles in cellular function and were less influenced by light stress. We identified that Metallothionein 1 (MT1), A Kinase Anchor Protein 12 (AKAP12) and MAF BZIP Transcription Factor F (MafF) were more abundantly expressed in peripheral Müller cells than in macular Müller cells. We found that these genes were also activated in the mouse retina in the early stages of development of subretinal neovascularization. Knockdown of the MT1, AKAP12 and MafF genes in human primary Müller cells reduced cell viability in response to light stress and disrupted several stress response pathways. Taken together, our findings indicate that macular Müller cells are more directed toward maintaining retinal cell function rather than mounting a stress response when they are exposed to stress, which may contribute to the macula’s vulnerability to degenerative disease.