Spatial transcriptomics reveals regionally altered gene expression that drives retinal degeneration.

Photoreceptor cell death is a hallmark of age-related macular degeneration. Environmental, lifestyle and genetic risk factors are known contributors to disease progression, whilst at the molecular level, oxidative stress and inflammation are central pathogenetic drivers. However, the spatial and cellular origins of these molecular mechanisms remain unclear. We used spatial transcriptomics to investigate the spatio-temporal gene expression changes in the adult mouse retina in response to photo-oxidative stress. We identify regionally distinct transcriptomes, with higher expression of immunity related genes in the superior retina. Exposure to stress induced expression of genes involved in inflammatory processes, innate immune responses, and cytokine production in a highly localised manner. A distinct region ~800 µm superior from the optic nerve head seems a key driver of these molecular changes. Further, we show highly localised early molecular changes in the superior mouse retina during retinal stress and identify novel genes drivers. We provide evidence of angiogenic changes in response to photo-oxidative stress and suggest additional angiogenic signalling pathways within the retina including VEGF, pleiotrophin and midkine. These new insights into retinal angiogenesis pave the way to identify novel drivers of retinal neovascularisation with an opportunity for therapeutic development.