Schumann Ulrike, Liu Lixinyu, Aggio-Bruce Riemke, Cioanca Adrian V, Shariev Artur, Madigan Michele C, Valter Krisztina, Wen Jiayu, Natoli Riccardo
The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
The Shine-Dalgarno Centre for RNA Innovation, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
Commun Biol. 2025 Apr 18;8(1):629. doi: 10.1038/s42003-025-07887-2.
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.
光感受器细胞死亡是年龄相关性黄斑变性的一个标志。环境、生活方式和遗传风险因素是已知的疾病进展促成因素，而在分子水平上，氧化应激和炎症是主要的致病驱动因素。然而，这些分子机制的空间和细胞起源仍不清楚。我们使用空间转录组学来研究成年小鼠视网膜在光氧化应激反应中的时空基因表达变化。我们确定了区域特异性转录组，在视网膜上部免疫相关基因的表达更高。暴露于应激会以高度局部化的方式诱导参与炎症过程、固有免疫反应和细胞因子产生的基因表达。距视神经乳头约800微米上方的一个独特区域似乎是这些分子变化的关键驱动因素。此外，我们展示了小鼠视网膜上部在视网膜应激期间高度局部化的早期分子变化，并确定了新的基因驱动因素。我们提供了光氧化应激反应中血管生成变化的证据，并提出了视网膜内包括血管内皮生长因子、多效蛋白和中期因子在内的其他血管生成信号通路。这些对视网膜血管生成的新见解为识别视网膜新生血管形成的新驱动因素以及治疗开发机会铺平了道路。
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