体内观察源自内皮细胞的细胞外囊泡表明通过聚集诱导发射发光剂改善了缺血性中风后的星形胶质细胞功能,ACS Nano

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体内观察源自内皮细胞的细胞外囊泡表明通过聚集诱导发射发光剂改善了缺血性中风后的星形胶质细胞功能
ACS Nano ( IF 15.8 ) Pub Date : 2023-08-03 , DOI: 10.1021/acsnano.3c05309
Xiangyu Gao ₁ , Heqi Gao _{2,

3} , Kangyi Yue ₁ , Xiuli Cao ₄ , Erwan Yang ₁ , Zhuoyuan Zhang _{1,

5} , Yutao Huang ₁ , Xin Li ₆ , Dan Ding ₂ , Peng Luo ₁ , Xiaofan Jiang ₁

Affiliation

从内皮细胞（EC）获得的细胞外囊泡（EV）在缺血性中风（IS）个体的临床管理中具有显着的治疗潜力，因为它们可以有效治疗动物模型中的缺血性中风。然而，由于缺乏同时具有高标记效率和示踪剂稳定性的分子探针，监测 EC-EV 在大脑中的作用仍然很困难。EC-EV 作用于大脑中产生保护作用的特定细胞内靶标仍然未知，这极大地阻碍了它们在临床环境中的使用。在这项研究中，我们创建了一种具有聚集诱导发射（AIE）特性（即 TTCP）的探针，能够有效标记 EC-EV，同时保留其生理特性。在体外，TTCP比商业EV标签PKH-67和DiI同时具有更高的EC-EV标记效率和更好的示踪剂稳定性。在体内，TTCP 在小鼠 IS 模型中精确跟踪 EC-EV 的行为，而不影响其保护作用。此外，通过利用TTCP，确定星形胶质细胞是受EC-EVs影响的特定细胞，并且EC-EVs在脑缺血再灌注（I/R）损伤后对星形胶质细胞表现出保护作用。这些保护作用包括减少炎症反应和细胞凋亡以及增强细胞增殖。进一步分析表明，EC-EV 携带的 miRNA-155-5p 通过调节 c-Fos/AP-1 通路发挥这些保护作用；这些信息为 IS 治疗提供了策略。总之，TTCP 在 IS 治疗期间具有较高的 EC-EV 标记效率和良好的体内示踪剂稳定性。此外，EC-EVs在脑I/R损伤期间被星形胶质细胞吸收，并通过c-Fos/AP-1信号通路的调节促进神经功能的恢复。

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Observing Extracellular Vesicles Originating from Endothelial Cells in Vivo Demonstrates Improved Astrocyte Function Following Ischemic Stroke via Aggregation-Induced Emission Luminogens

Extracellular vesicles (EVs) obtained from endothelial cells (ECs) have significant therapeutic potential in the clinical management of individuals with ischemic stroke (IS) because they effectively treat ischemic stroke in animal models. However, because molecular probes with both high labeling efficiency and tracer stability are lacking, monitoring the actions of EC-EVs in the brain remains difficult. The specific intracellular targets in the brain that EC-EVs act on to produce their protective effects are still unknown, greatly impeding their use in clinical settings. For this research, we created a probe that possessed aggregation-induced emission (AIE) traits (namely, TTCP), enabling the effective labeling of EC-EVs while preserving their physiological properties. In vitro, TTCP simultaneously had a higher EC-EV labeling efficiency and better tracer stability than the commercial EV tags PKH-67 and DiI. In vivo, TTCP precisely tracked the actions of EC-EVs in a mouse IS model without influencing their protective effects. Furthermore, through the utilization of TTCP, it was determined that astrocytes were the specific cells affected by EC-EVs and that EC-EVs exhibited a safeguarding impact on astrocytes following cerebral ischemia-reperfusion (I/R) injury. These protective effects encompassed the reduction of the inflammatory reaction and apoptosis as well as the enhancement of cell proliferation. Further analysis showed that miRNA-155-5p carried by EC-EVs is responsible for these protective effects via regulation of the c-Fos/AP-1 pathway; this information provided a strategy for IS therapy. In conclusion, TTCP has a high EC-EV labeling efficiency and favorable in vivo tracer stability during IS therapy. Moreover, EC-EVs are absorbed by astrocytes during cerebral I/R injury and promote the restoration of neurological function through the regulation of the c-Fos/AP-1 signaling pathway.

更新日期：2023-08-03

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