Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, China; Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, China.
Surgical ICU, The Third Affiliated Hospital of Sun Yat-sen University, China.
Biomaterials. 2022 May;284:121486. doi: 10.1016/j.biomaterials.2022.121486. Epub 2022 Apr 2.
As nanotherapeutics, mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are considered a potent alternative for whole-cell therapy and are gradually entering the clinical field of liver diseases. In this study, neutrophil extracellular traps (NETs) formation in liver tissue was verified as a critical factor for liver ischaemia-reperfusion injury (IRI) in both clinical samples and animal models. Human umbilical cord-derived MSC-EVs (hUC-MSC-EVs) might function to reduce the NETs formation and subsequently improve liver IRI. Mechanistically, we showed that hUC-MSC-EVs contain functional mitochondria that are transferred to intrahepatic neutrophils. This effect triggers mitochondrial fusion and subsequently restores the mitochondrial status and functions in neutrophils to reduce NETs formation. Collectively, our findings suggest that MSC-EVs exert a nanotherapeutic effect on inhibiting local NETs formation by transferring functional mitochondria to intrahepatic neutrophils and repairing their mitochondrial function, which highlights the therapeutic value of hUC-MSC-EVs for liver IRI.
作为纳米疗法，间充质基质细胞衍生的细胞外囊泡 (MSC-EVs) 被认为是全细胞治疗的有效替代品，正逐渐进入肝脏疾病的临床领域。在本研究中，在临床样本和动物模型中均证实肝组织中性粒细胞胞外诱捕网（NETs）的形成是肝缺血再灌注损伤（IRI）的关键因素。人脐带间充质基质细胞衍生的细胞外囊泡（hUC-MSC-EVs）可能通过减少 NETs 的形成，从而改善肝 IRI。从机制上讲，我们表明 hUC-MSC-EVs 含有可转移至肝内中性粒细胞的功能性线粒体。这种作用触发线粒体融合，随后恢复中性粒细胞中的线粒体状态和功能，减少 NETs 的形成。总的来说，我们的研究结果表明，MSC-EVs 通过向肝内中性粒细胞转移功能性线粒体并修复其线粒体功能，对抑制局部 NETs 的形成发挥纳米治疗作用，这突出了 hUC-MSC-EVs 在治疗肝 IRI 方面的治疗价值。
