Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response
Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response
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DOI：
10.1096/fj.201800131rr
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发表时间：
2018-09
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影响因子：
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通讯作者：
Jia Yao;Jun Zheng;Jianye Cai;K. Zeng;Chaorong Zhou;Jiebin Zhang;Shihui Li;Hui Li;Liang Chen-Liang-Che
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文献类型：
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作者：
Jia Yao;Jun Zheng;Jianye Cai;K. Zeng;Chaorong Zhou;Jiebin Zhang;Shihui Li;Hui Li;Liang Chen-Liang-Che
骨髓间充质干细胞（MSCs）在免疫调节、组织修复和再生等方面发挥着重要的治疗作用。越来越多的证据表明，来源于MSCs的细胞外囊泡（EV）可能有助于这些效应，并被认为是基于干细胞治疗的潜在替代品。然而，基于EV的治疗在肝脏缺血再灌注损伤（IRI）中的疗效和潜在机制仍不清楚。在此，我们证明了人脐带MSC‐EVs（huc‐MSC‐EVs）可通过减少中性粒细胞浸润和减轻体内肝组织的氧化应激来防止IRI诱导的肝细胞凋亡。同时，huc‐MSC‐EVs在体外减少了中性粒细胞的呼吸爆发，并防止了肝细胞氧化应激诱导的细胞死亡。有趣的是，我们发现位于线粒体的抗氧化酶锰超氧化物歧化酶（MnSOD）被包裹在huc‐MSC‐ EV中，并降低了肝脏IRI模型中的氧化应激。敲除huc-MSC中的MnSOD降低了huc-MSC-EVs中MnSOD的水平，减弱了huc-MSC-EVs的抗凋亡和抗氧化能力，MnSOD模拟物锰（III）5，10，15，20-四（4-苯甲酸）卟啉（MnTBAP）可部分挽救huc-MSC-EVs的抗凋亡和抗氧化能力。总之，这些发现为揭示huc‐MSC‐ EV对肝脏IRI的治疗作用和评价其临床前应用提供了新的线索。姚，J.，郑杰，蔡杰，曾，K.，Zhou，C.，中国地质大学，张杰，Li，S.，Li，H.，Chen，L.，中国地质大学，他，L.，陈洪，傅，H.，张，Q，陈，G.，杨，Y.， Zhang， Y.来源于人脐带间充质干细胞的细胞外囊泡通过抑制氧化应激和中性粒细胞炎症反应减轻大鼠肝脏缺血-再灌注损伤。《法国食品安全与环境委员会公报》第33卷，1695-1710页（2019年）。www.fasebj.org
Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on immunoregulation, tissue repair, and regeneration from the bench to the bedside. Increasing evidence demonstrates that extracellular vesicles (EVs) derived from MSCs could contribute to these effects and are considered as a potential replacement for stem cell‐based therapies. However, the efficacy and underlying mechanisms of EV‐based treatment in hepatic ischemia‐reperfusion injury (IRI) remain unclear. Here, we demonstrated that human umbilical cord MSC‐EVs (huc‐MSC‐EVs) could protect against IRI‐induced hepatic apoptosis by reducing the infiltration of neutrophils and alleviating oxidative stress in hepatic tissue in vivo. Meanwhile, huc‐MSC‐EVs reduced the respiratory burst of neutrophils and prevented hepatocytes from oxidative stress‐induced cell death in vitro. Interestingly, we found that the mitochondria‐located antioxidant enzyme, manganese superoxide dismutase (MnSOD), was encapsulated in huc‐MSC‐EVs and reduced oxidative stress in the hepatic IRI model. Knockdown of MnSOD in huc‐MSCs decreased the level of MnSOD in huc‐MSC‐EVs and attenuated the antiapoptotic and antioxidant capacities of huc‐MSC‐EVs, which could be partially rescued by MnSOD mimetic manganese (III) 5,10,15,20‐tetrakis (4‐benzoic acid) porphyrin (MnTBAP). In summary, these findings provide new clues to reveal the therapeutic effects of huc‐MSC‐EVs on hepatic IRI and evaluate their preclinical application.—Yao, J., Zheng, J., Cai, J., Zeng, K., Zhou, C., Zhang, J., Li, S., Li, H., Chen, L., He, L., Chen, H., Fu, H., Zhang, Q., Chen, G., Yang, Y., Zhang, Y. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. FASEB J. 33, 1695–1710 (2019). www.fasebj.org