Apoptotic Vesicles Modulate Endothelial Metabolism and Ameliorate Ischemic Retinopathy via PD1/PDL1 Axis.

Pathological angiogenesis with subsequent disturbed microvascular remodeling is a major cause of irreversible blindness in a number of ischemic retinal diseases. The current anti-VEGF therapy can effectively inhibit angiogenesis, but it also brings significant side effects. The emergence of stem cell derived extracellular vesicles provides a new underlining strategy for ischemic retinopathy. We extracted apoptotic vesicles (apoVs) from stem cells from human exfoliated deciduous teeth (SHED). SHED-apoVs were delivered into the eyeballs of oxygen induced retinopathy (OIR, a most common model of angiogenic retinal dieseases) mice through intravitreal injection. The retinal neovascularization and non-perfusion area, vascular structure, and density changes were observed during the neovascularization phase (P17) and vascular remodeling phase (P21), and visual function was measured. The expression of ECAR and lactic acid testing were used to detect endothelial cells (ECs) glycolytic activity. Furthermore, we used lentivirus and neutralizing antibody to block PD1-PDL1 axis, investigating the effects of SHED-apoVs on glycolysis and angiogenic activities. Our work showed that SHED-apoVs were taken up by ECs and modulated the ECs glycolysis, leading to the decrease of abnormal neovessels and vascular remodeling. Furthermore, we found that, at the molecular level, apoVs-carried PD1 interacted with PDL1 on hypoxic ECs to regulate the angiogenic activation. SHED-apoVs inhibited pathological angiogenesis and promoted vascular remodeling in ischemic retinopathy partially by modulating ECs glycolysis through PD1/PDL1 axis. Our study provides a new potential strategy for the clinical treatment of pathological retinal neovascularization . This article is protected by copyright. All rights reserved.