Seeing the whole transcriptomics picture: Spatial gene expression analysis reveals photoreceptor stress as modulator of retinal vascular changes

Photoreceptor cell death is a hallmark feature of many retinal degenerative diseases including age-related macular degeneration. At the molecular level, oxidative stress and inflammation are known central pathogenetic drivers, but the spatial and cellular origins of the underlying molecular mechanisms remain unclear. We used spatial transcriptomics to investigate the spatio-temporal gene expression changes in the mouse retina in response to photo-oxidative damage. In both the healthy and degenerating retina, we uncover regionally distinct transcriptomes, with higher expression of immunity related genes in the superior retina. Exposure to photo-oxidative damage increased the expression of genes involved in inflammatory processes, innate immune responses, and cytokine production in a highly localised manner. This focal region seems a key driver of molecular changes, including upregulation of angiogenic pathways. Consequently, we show substantial alterations in vacular endothelial growth factor, pleiotrophin and midkine signalling between retinal layers, some of which are novel angiogenic signalling pathways within the retina. Parasaggital cross-sections of C57Bl6/J mouse eyes were subjected to Visium spatial gene expression. Tissue from dim-reared (DR) controls was compared to tissue from a 1-day (1PD), 3-day (3PD) and 5-day (5PD) photo-oxidative damage time course, respectively. The experiments were performed in biological duplicates.