细胞自噬在来源于诱导性多能干细胞的外泌体对血管内膜增生性疾病防治中的作用

Vascular diseases are the main causes of human death. It is urgent to find new therapeutic approach for them. The development of vascular diseases is a chronic process, from being attacked by harmful factors, maintaining vascular homeostasis, cell senescence to neointimal proliferation. Induced pluripotent stem cells (iPS) are highly active cells. We found iPS-produced exosomes selectively contain a large amount of proteins required for vigorous cells. They promoted cell viability, inhibited cell autophagy and prevented cell senescence of vascular endothelial cells. iPS-produced exosomes received via tail vein selectively trafficked to injured endothelial cells, leading to inhibited neointial proliferation and stenosis of the “cuff injured” carotid artery. This project aims to: 1）further demonstrating the effect and universality of iPS-produced exosomes on maintaining vascular homeostasis and preventing or ameliorating pathological vascular remodeling; 2) further demonstrating molecular mechanism that mediates the trafficking of iPS-produced exosomes to injured vessels; 3) exploring the interaction between the uptaken iPS-produced exosomes and residential autophagosome in endothelial cells and the effect caused by the interaction on vascular homeostasis and neointimal vascular diseases, under normal and pathologically increased autophagic burdens as well as in the presence of autophagy inducer or inhibitor. The implementation of this project may provide new strategy for preventing cell senescence or even rejuvenate cells that have already deteriorated but yet senescence, in order to maintain vascular vigorosity and inhibit pathological remodeling.

心脑血管疾病是人类主要杀手之一，迫切需要新的治疗方法。血管从接触危险因素、维稳应变、衰老到血管内膜增生是一个慢性的渐变过程。诱导性多能干细胞（iPS）是高度活力的细胞，我们发现iPS的外泌体选择性含有大量保持细胞活力所需的蛋白质，可增强接受其过继的血管内皮细胞活力、抑制细胞自噬和衰老。尾静脉注射的iPS外泌体选择性地融合于扩张被血管外人工套环限制的颈动脉的内皮细胞，并抑制血管内膜增生和血管狭窄。本项目拟进一步明确iPS外泌体对维持血管稳态，以及避免或改善病理性重构中的作用及普适性；阐明iPS外泌体定向着床于损伤血管的分子机制；探讨在自噬水平正常、病理性增高、人为诱导或阻断自噬条件下，iPS外泌体-内皮细胞自噬相互作用在iPS外泌体抗血管衰老和防治血管内膜疾病中的作用。为避免血管细胞衰老进而使衰老的血管细胞再青春化，保持血管健康活力和避免病理性重构提供新策略。

心脑血管疾病是人类主要杀手之一，迫切需要新的治疗方法。血管从接触危险因素、维稳应变、衰老到血管内膜增生是一个慢性的渐变过程。诱导性多能干细胞（iPS）是高活力的细胞，我们发现iPS通过外泌体选择性地将细胞内大量多余的、具有维持细胞活力功能的蛋白质和RNA排除细胞外，增强接受其过继的血管内皮细胞活力、抑制细胞自噬和衰老；尾静脉注射的iPS外泌体可选择性地被损伤的动脉内皮细胞摄取，抑制血管内膜增生和血管狭窄；在血管内皮细胞内，被摄取的iPS外泌体选择性地与细胞内固有的自噬小体发生相互作用，降低自噬流，从而调节损伤内皮细胞自噬水平，促进内皮细胞增殖、微血管样结构形成并抑制细胞衰老。然而，自噬诱导剂和抑制剂均可降低iPS外泌体的抗损伤作用。结果表明iPS外泌体-内皮细胞自噬相互作用在iPS外泌体抗血管衰老和防治血管内膜疾病中起重要的作用。为避免血管细胞衰老进而使衰老的血管细胞再青春化，保持血管健康活力和避免病理性重构提供新策略。