In Vivo Tracking of Mesenchymal Stem Cell-Derived Extracellular Vesicles Improving Mitochondria! Function in Renal Ischemia- Reperfusion Injury
In Vivo Tracking of Mesenchymal Stem Cell-Derived Extracellular Vesicles Improving Mitochondria! Function in Renal Ischemia- Reperfusion Injury
复制标题
体内追踪间充质干细胞衍生的细胞外囊泡改善线粒体！肾缺血再灌注损伤中的功能
DOI：
10.1021/acsnano.9b08207
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发表时间：
2020-04-28
期刊：
影响因子：
17.1
通讯作者：
Wang, Yuebing
中科院分区：
文献类型：
--
作者：
Cao, Hongmei;Cheng, Yuanqiu;Wang, Yuebing
间充质干细胞 (MSC) 释放的细胞外囊泡 (EV) 在缺血再灌注 (I/R) 急性肾损伤 (AKI) 动物模型中表现出再生能力，被认为是直接 MSC 治疗的潜在替代方案。然而，MSC-EV 在肾缺血再灌注损伤中的实时体内成像尚未建立。负责其再生作用的 MSC-EV 的肾细胞内靶点也仍然难以捉摸。在这里，我们报告说，我们实时观察到 MSC-EV 在受损肾脏中特异性积累，并通过 DPA-SCP 被肾近端肾小管上皮细胞 (TEC) 吸收，具有聚集诱导发射 (ME) 特性。 DPA-SCP 在肾 I/R 损伤小鼠模型中精确跟踪 MSC-EV 的命运 72 小时，并表现出优于流行的市售 EV 跟踪器 PKH26 的时空分辨率和跟踪能力。进一步分析显示，积累的 MSC-EV 通过激活 Keap1-Nrf2 信号通路刺激线粒体抗氧化防御和 ATP 产生，从而通过减少线粒体碎片、使线粒体膜电位正常化和增加线粒体 DNA 拷贝数来保护 TEC 免受氧化损伤。 MSC-EV 诱导的肾脏 TEC 中 microRNA-200a-3p 表达增加被确定为一种调节机制，有助于保护线粒体并刺激肾脏信号转导途径。总之，MSC-EVs在肾I/R损伤期间在肾小管中积累，并通过激活Keap1-Nrf2信号通路和增强TECs的线粒体功能促进肾功能的恢复。具有 AIE 特性的 DPA-SCP 可以实现肾脏修复中 MSC-EV 的无创且精确的体内可视化。
Extracellular vesicles (EVs) released by mesenchymal stem cells (MSCs) have exhibited regenerative capability in animal models of ischemia-reperfusion (I/R) acute kidney injury (AKI) and are considered as potential alternatives to direct MSC therapy. However, real-time in vivo imaging of MSC-EVs in renal I/R injury has yet to be established. Renal intracellular targets of MSC-EVs responsible for their regenerative effects also remain elusive. Here, we report that we real-time observed MSC-EVs specifically accumulated in the injured kidney and were taken up by renal proximal tubular epithelia cells (TECs) via DPA-SCP with aggregation-induced emission (ME) characteristics. DPA-SCP precisely tracked the fate of MSC-EVs in a renal I/R injury mouse model for 72 h and exhibited superior spatiotemporal resolution and tracking ability to popular commercially available EV tracker PKH26. Further analysis revealed that the accumulated MSC-EVs stimulated mitochondrial antioxidant defense and ATP production via activating the Keap1-Nrf2 signaling pathway, which protected TECs against oxidative insult by reducing mitochondrial fragmentation, normalizing mitochondrial membrane potential, and increasing mitochondrial DNA copy number. Increased microRNA-200a-3p expression in renal TECs induced by MSC-EVs was identified as a regulatory mechanism contributing to the protective actions on mitochondria as well as stimulating the renal signal transduction pathways. In conclusion, MSC-EVs accumulated in the renal tubules during renal I/R injury and promoted the recovery of kidney function via activating the Keap1-Nrf2 signaling pathway and enhancing mitochondrial function of TECs. DPA-SCP with AIE characteristics allows noninvasive and precise in vivo visualization of MSC-EVs in kidney repair.