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Specialized Retinal Endothelial Cells Modulates Blood-Retina- Barrier in Diabetic Retinopathy

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posted on 2023-11-17, 17:49 authored by Xuyang Yao, Ziyan Zhao, Wenhui Zhang, Ruixin Liu, Tianwen Ni, Bohao Cui, Yi Lei, Jie Du, Ding Ai, Hongfeng Jiang, Huizhen Lv, Xiaorong Li

Abstract

Endothelial cells (EC) play essential roles in retinal vascular homeostasis. This study aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing. Systematic analysis of cellular compositions and cell-cell interaction networks identified a unique EC cluster with high inflammatory gene expression in diabetic retina; sphingolipid metabolism is a prominent aspect correlated with changes in retinal function. Among sphingolipid-related genes, alkaline ceramidase 2 (ACER2) showed the most significant increase. Plasma samples of patients with non-proliferative diabetic retinopathy (NPDR) with or without diabetic macular edema (DME) and active PDR were collected for mass spectrometry analysis. Metabolomic profiling revealed that the ceramide levels were significantly elevated in NPDR-NDME/DME and further increased in active PDR compared with control patients. In vitro analyses showed that ACER2 overexpression retarded endothelial barrier breakdown induced by ceramide, while silencing of ACER2 further disrupted the injury. Moreover, intravitreal injection of the recombinant ACER2 adeno-associated virus rescued diabetes-induced vessel leakiness, inflammatory response, and neurovascular disease in diabetic mouse models. Together, this study revealed a new diabetes-specific retinal EC population and a negative feedback regulation pathway that reduces ceramide content and endothelial dysfunction by upregulating ACER2 expression. These findings provide insights into cell-type targeted interventions for diabetic retinopathy.

Keywords: diabetes, retina, endothelial cells, blood-retina-barrier, ACER2

Article Highlights

v Endothelial cells (EC) play essential roles in retinal vascular homeostasis. We aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing

v We investigated whether the sphingolipid metabolism involved in diabetes-induced retinal endothelial dysfunction and vascular permeability

v We found a new diabetes-specific retinal EC population and a negative feedback regulation pathway that reduces ceramide content and endothelial dysfunction by upregulating ACER2 expression

v Our study provide insights into cell-type targeted interventions for diabetic retinopathy

Funding

Ministry of Science and Technology of the People's Republic of China > National Natural Science Foundation of China 82171085

Open Project of Tianjin Key Laboratory of Retinal Functions and Diseases x 2021tjswmq001

the Science&Technology Development Fund of Tianjin Education Commission for Higher Education x 2021KJ234

Tianjin Key Medical Discipline (Specialty) Construction Project x TJYXZDXK-037A

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