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

Yang, L.; Lin, S.; Tao, Y.; Pan, Q.; Cai, T.; Ye, Y.; Liu, J.; Zhou, Y.; Yi, Q.; Lu, Z. H.; Chen, L.; McKay, G.; Rankin, R.; Shao, Y.; Meng, W.

doi:10.1101/2025.02.07.637193

bioRxiv · 10.1101/2025.02.07.637193

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

Yang, L.·Lin, S.·Tao, Y.·Pan, Q.·Cai, T.·Ye, Y.·Liu, J.·Zhou, Y.·Yi, Q.·Lu, Z. H.·Chen, L.·McKay, G.·Rankin, R.·Shao, Y.·Meng, W.

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Abstract

Diabetic retinopathy (DR) is a major cause of vision loss worldwide. Here, we conduct single-cell RNA sequencing of twenty human retina samples (from living and post-mortem donors) across non-diabetic, diabetic, and DR states to create a comprehensive transcriptomic atlas. We identify two stable microglial populations--homeostatic and inflammatory--that exist along a functional continuum, plus a neutrophil cluster within C1QA+ myeloid cells with dynamic transitions occurring throughout disease progression. Module-level analysis reveals divergent transcriptional trajectories: homeostatic microglia maintain energetic programs while selectively upregulating stress elements, whereas inflammatory microglia layer additional pro-inflammatory programs onto preserved biosynthetic foundations. Eleven co-expression modules organize into two major axes: an inflammatory-stress axis, and a regulatory/metabolic-motility axis, with a stable translation module persisting across disease stages. 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.

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Yang, L., Lin, S., Tao, Y., Pan, Q., Cai, T., Ye, Y., Liu, J., Zhou, Y., Yi, Q., Lu, Z. H., Chen, L., McKay, G., Rankin, R., Shao, Y., Meng, W.. 2025-02-08. Single-Cell Transcriptomics Reveals Dynamic Microglial States and Neural-Immune Networks in Human Diabetic Retinopathy. https://doi.org/10.1101/2025.02.07.637193

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