|
骨髓间充质干细胞（bone marrow-derived mesenchymal stem cells，BMSCs）在器官和组织损伤修复中发挥多种重要作用，主要通过旁分泌作用实现，包括分泌细胞外囊泡如外泌体作为促进细胞间通讯的介质，并将其内容物传递给靶细胞来调节受体细胞。 近日，来自重庆医科大学附属第一医院的研究人员发现，BMSCs通过分泌包含有靶向结合免疫球蛋白蛋白质（binding immunoglobulin protein，BIP）的miR-199a-5p的外泌体来保护肾脏缺血再灌注损伤，并在再灌注的早期阶段抑制内质网应激。肾缺血/再灌注（ischemia-reperfusion，I/R）损伤是急性肾损伤（acuterenal injury，AKI）和肾衰竭的主要原因，在全世界范围内造成高死亡率。该研究探索了源自BMSCs的外泌体（bone marrow exosomes，BMexos）对肾缺血再灌注损伤影响的时间依赖性以及与再灌注时间相关的潜在机制。研究首次在体外和体内发现，BMexos在早期再灌注阶段，特别是体外再灌注后4-8小时和体内再灌注8-16小时可以保护肾脏免受I/R损伤。有趣的是，研究人员同时发现内质网应激在体外和体内给予BMexos后具有相似的时间依赖性。此外，富含于BMSCs的miR-199a-5p以时间依赖性方式转移到肾小管上皮细胞（NRK-52E）中，并通过靶向BIP显著抑制I/R诱导的ER应激。与miR-199a-5p过表达的BMSCs共培养后，会抑制ER应激并进一步保护其免受I/R损伤。与miR-199a-5p敲低的BMSCs共培养显著增加ER应激并逆转BMexos诱导的保护作用，并且NRK-52E中的siRNA-1098沉默BIP抑制了这些作用。 这项研究表明，在早期再灌注阶段给予BMexos可显著预防肾脏I/R损伤，而ER应激与这种保护效应密切相关，为肾脏I/R损伤的早期再灌注阶段的新治疗策略开发提供了理论支持。 推荐阅读原文：
BMSCs protect against renal ischemia-reperfusion injury by secreting exosomes loaded with miR-199a-5p that target BIP to inhibit endoplasmic reticulum stress at the very early reperfusion stages.
Bone marrow-derived mesenchymal stem cells (BMSCs) have been recently reported to play a variety of vital roles in organ and tissue damage repair, mainly via potent paracrine activity, including secreting extracellular vesicles, such as exosomes, that serve as mediators facilitating intercellular communication and reprogramming recipient cells by delivering their contents to target cells. However, the underlying mechanisms are diverse and complex, and the influencing characteristics have rarely been studied. Accordingly, we designed this study to explore the time dependence of the effects of exosomes derived from BMSCs (BMexos) on renal ischemia-reperfusion (I/R) injury and the underlying mechanisms associated with the reperfusion time. Impressively, our study is the first to find that BMexos protected against renal I/R injury in vitro and in vivo at the very early reperfusion stages, especially 4-8 h after reperfusion in vitro and 8-16 h after reperfusion in vivo. Interestingly, we simultaneously found that endoplasmic reticulum (ER) stress was significantly suppressed following the administration of BMexos in vitro and in vivo with a similar time dependence. Additionally, we discovered that miR-199a-5p, which was abundant in the BMSCs, was transferred into renal tubular epithelial cells (NRK-52E) in a time-dependent manner and significantly inhibited I/R-induced ER stress by targeting binding immunoglobulin protein (BIP). Cocultivation with miR-199a-5p-overexpressing BMSCs amplified the suppression of ER stress and further protected against I/R injury. However, coculture with miR-199a-5p-knockdown BMSCs obviously increased ER stress and reversed the BMexos-induced protection, and silencing BIP by small interfering RNA-1098 in NRK-52E inhibited these effects. This study provides evidence that administering BMexos at the very early reperfusion stages significantly protects against renal I/R injury, and ER stress is closely linked to this protection. These results suggest a novel therapeutic strategy during the very early reperfusion stages of renal I/R injury.
|
