Endothelial Cells Communicate with Microglia and Retinal Ganglion Cells Through Igfbp3-Tmem219 and Cxcl12-Ackr3 Pathways in Diabetic Retinopathy

Introduction/Objective The purpose of this research is to retrospectively analyze diabetic mouse retina datasets to obtain new insights into Diabetic Retinopathy (DR). Methods In this study, we performed single-cell RNA-sequencing (scRNA-seq) on combined diabetic mice retina datasets obtained from previous studies and validated the findings using real-time PCR. Results Our findings revealed that the final glucose level, compared to disease progression duration, determines diabetic severity. Pseudobulk RNA-seq analysis of key cell types, such as Endothelial Cells (ECs), microglia, and Retinal Ganglion Cells (RGCs), showed notable communication pathways between them that outweigh even the immune-related responses during hyperglycemia. Lastly, cell-cell communication analysis mapped out notable communication pathways among the three cell types. In essence, ECs secrete more Igfbp3 and less Cxcl12 to Tmem219 receptors on microglia and Ackr3 receptors on RGCs, respectively. Discussion Current clinical therapy can only slow disease progression in the retina but not reverse it. Accordingly, the elucidation of early biomarkers for detection is preferred. These results provide potential targets that can be regulated for detection or therapeutic purposes. Conclusion Our results indicate that the severity of diabetes is primarily determined by the final blood glucose level, rather than the length of time the disease has progressed. Secondly, our analysis demonstrated significant crosstalk between ECs, microglia, and RGCs that outweighs the significance of immune-related responses when the retina was exposed to extreme levels of blood glucose. Lastly, we validated these communication pathways, specifically Cxcl12-Ackr3 and Igfbp3-Tmem219, to be uniquely initiated by the ECs to RGCs and microglia, respectively.