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Proliferative diabetic retinopathy subtypes defined by immune defense and endothelial mitochondrial dysfunction
Maximilian A McCann1, Basma Baccouche1, Yueru Li1
1Department of Ophthalmology & Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Signal Transduction and Targeted Therapy
|October 21, 2025
Summary
Proliferative diabetic retinopathy (PDR) presents distinct subtypes, one driven by immune cells and another by endothelial mitochondrial dysfunction. Anti-VEGF therapy impacts both cell types, influencing treatment strategies.
Area of Science:
- Ophthalmology
- Diabetology
- Cell Biology
Background:
- Proliferative diabetic retinopathy (PDR) involves pathological retinal angiogenesis, a significant diabetes complication.
- Current treatments like vitrectomy offer limited insight into PDR's underlying mechanisms.
- Clinical specimens from PDR patients are crucial for identifying disease drivers.
Purpose of the Study:
- To profile endothelial and immune cells in PDR specimens to uncover disease mechanisms.
- To investigate the impact of anti-vascular endothelial growth factor (VEGF) therapy on cellular transcriptional programs.
- To compare PDR endothelial cell signatures with healthy retinas and animal models.
Main Methods:
- Single-cell profiling of endothelial and immune cells from human PDR surgical samples.
- Transcriptional analysis to identify gene expression patterns.
- Comparison of human PDR data with nondiabetic donor retinas and the murine oxygen-induced retinopathy (OIR) model.
Main Results:
- PDR patient samples showed heterogeneity, with some enriched in endothelial cells and others in immune cells.
- Immune cells displayed anti-endothelial gene expression, suggesting an endogenous defense mechanism.
- Anti-VEGF therapy modulated transcriptional programs in both endothelial and immune cells.
- PDR endothelial cells exhibited a distinct molecular signature, including mitochondrial dysfunction, absent in the OIR model.
- The OIR model partially replicated PDR angiogenesis but lacked key molecular features like mitochondrial dysfunction.
Conclusions:
- PDR is heterogeneous, with distinct subtypes possibly involving immune-mediated vessel clearance or endothelial mitochondrial dysfunction.
- Anti-VEGF therapy affects both endothelial and immune cells, necessitating broader treatment considerations.
- The OIR model has limitations for studying PDR, particularly regarding mitochondrial dysfunction, impacting preclinical therapeutic target validation.
