低氧促进间充质干细胞外囊泡生成并增强缺血再灌注肾损伤修复能力的机制研究

Ischemia reperfusion injury (IRI) is one of the main causes of acute renal injury, and extracellular vesicles (EV) secreted by mesenchymal stem cells (MSC) can alleviate renal IRI.Our previous experiments found that hypoxia can promote the generation of MSC-EV and enhance its therapeutic effect on renal ischemia reperfusion injury (IRI), but the mechanism was unclear. Hif-1α / miR-21 is activated in hypoxic cells, and the delivery of micro-RNA molecules is considered as an important pathway for tissue damage repair.Based on this discovery and relevant theoretical basis, we proposed the scientific hypothesis that Hif-1α activation in MSC under hypoxic conditions can regulate and promote the generation of MSC-EV, and meanwhile increase the content of miR-21 in EV, which enhancing its therapeutic effect on renal IRI.This project intends to verify this hypothesis on the basis of preliminary experiments, and clarify the internal mechanism of hypoxia in promoting the generation of MSC-EV and the repair of renal IRI. The results of this project will provide a new research idea for the efficient acquisition and utilization of MSC-EV in renal IRI treatment, and provide theoretical basis for clinical application.

缺血再灌注损伤（IRI）是导致急性肾损伤的主要原因之一，间充质干细胞（MSC）分泌的细胞外囊泡（EV）可减轻肾脏IRI。前期实验发现，低氧可以促进MSC-EV的生成，并增强其对肾脏IRI的治疗作用，但具体机制不清。低氧下细胞内HIF-1α/miR-21激活，而MSC-EV内micro-RNA分子的传递，被认为是其发挥作用的重要途径。基于此发现及理论基础，我们提出科学假设：低氧下MSC内HIF-1α活化，可促进MSC-EV的生成，同时上调EV内miR-21含量，增强对肾脏IRI的治疗作用。本项目拟在前期实验基础上证实该假设，阐明低氧促进MSC-EV生成，增强肾脏IRI修复的内在机制，为高效获取及利用MSC-EV治疗肾脏IRI提供新的研究思路，并为临床应用提供理论依据。

缺血再灌注损伤（IRI）是导致急性肾损伤的主要原因之一，临床常见，但缺乏有效的干预治疗措施。间充质干细胞（MSC）分泌的细胞外囊泡（EV）可减轻肾脏IRI，然而目前获取治疗量的EV往往需要消耗大量细胞，同时对EV的获取及生成仍然处于探索阶段。因此，了解EV的生成机制，探寻促进EV生成及提高EV利用效率的新方法，值得深入探究。本课题从低氧预刺激MSC方向出发，靶定细胞内HIF-1α信号通路，阐明低氧促进MSC-EV生成，并增强肾脏IRI修复的内在机制。实验结果提示低氧预处理促进MSC的增殖，提高EV的生成产量，激活细胞内HIF-1α相关增殖以及EV生成相关信号通路。在急性IRI动物实验的研究中发现，低氧来源MSC-EV可以通过尾静脉注射的方法到达受损肾脏，通过调控损伤肾脏中增殖以及凋亡相关信号通路，增强对急性肾损伤的修复能力。本课题的研究结果，为高效获取及利用MSC-EV治疗肾脏IRI提供新的研究思路，并为将来相关临床应用提供理论依据。