Single-Cell Transcriptomics Reveals Dynamic Microglial States and Neural-Immune Networks in Human Diabetic Retinopathy

Diabetic retinopathy (DR) is a major cause of vision loss worldwide. Here, we perform single-cell RNA sequencing of thirteen human retina samples (from living and post-mortem donors) across non-diabetic, diabetic, and DR states to create a comprehensive transcriptomic atlas. We uncover three distinct microglial states—homeostatic, stress-response, and inflammatory—along a functional continuum, rather than discrete activation states, with dynamic transitions occurring throughout disease progression. Trajectory analysis indicates bifurcating paths starting from the homeostatic state branching toward stress-response and inflammatory states. Three major functional modules: ribosomal/translation, coordinated immune cell function, and inflammatory/transcriptional regulation, showing disease-specific activation patterns were identified. Cell communication analysis further highlights sophisticated neural-immune interactions, particularly between photoreceptors and microglia. Our findings provide insights into the complex cellular dynamics of DR progression and suggest potential therapeutic targets for early intervention.