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Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2
Advanced Science ( IF 15.1 ) Pub Date : 2020-08-20 , DOI: 10.1002/advs.201903746
Jun Zheng 1 , Tongyu Lu 1 , Chaorong Zhou 2, 3 , Jianye Cai 1 , Xiaomei Zhang 4 , Jinliang Liang 4 , Xin Sui 5 , Xiaoyan Chen 6 , Liang Chen 1 , Yao Sun 5 , Jiebin Zhang 1 , Wenjie Chen 6 , Yingcai Zhang 1 , Jia Yao 1 , Guihua Chen 1 , Yang Yang 1
Affiliation  

As a cause of postoperative complications and early hepatic failure after liver transplantation, liver ischemia/reperfusion injury (IRI) still has no effective treatment during clinical administration. Although the therapeutic potential of mesenchymal stem cells (MSCs) for liver IRI has been previously shown, the underlying mechanisms are not completely clear. It is accepted that MSC‐derived extracellular vesicles (MSC‐EVs) are newly uncovered messengers for intercellular communication. Herein, it is reported that umbilical cord‐derived MSCs (UC‐MSCs) improve liver IRI in mice through their secreted EVs. It is also visualized that UC‐MSC‐EVs mainly concentrate in liver after 6 h of reperfusion. Furthermore, UC‐MSC‐EVs are found to significantly modulate the membranous expression of CD154 of intrahepatic CD4+ T cells, which is an initiation of inflammatory response in liver and can aggravate liver IRI. Mechanistically, protein mass spectrum analysis is performed and it is revealed that Chaperonin containing TCP1 subunit 2 (CCT2) enriches in UC‐MSC‐EVs, which regulates the calcium channels to affect Ca2+ influx and suppress CD154 synthesis in CD4+ T cells. In conclusion, these results highlight the therapeutic potential of UC‐MSC‐EVs in attenuating liver IRI. This finding suggests that CCT2 from UC‐MSC‐EVs can modulate CD154 expression of intrahepatic CD4+ T cells during liver IRI through the Ca2+‐calcineurin‐NFAT1 signaling pathway.

中文翻译:

人脐带间充质干细胞衍生的细胞外囊泡通过 CCT2 减少 CD4+ T 细胞上的 CD154 表达来保护肝脏缺血/再灌注损伤

肝脏缺血/再灌注损伤(IRI)作为肝移植术后并发症和早期肝功能衰竭的一个原因,在临床用药中尚无有效的治疗方法。尽管间充质干细胞 (MSC) 对肝脏 IRI 的治疗潜力先前已被证明,但其潜在机制尚不完全清楚。人们普遍认为,间充质干细胞衍生的细胞外囊泡(MSC-EV)是新发现的细胞间通讯信使。据报道,脐带间充质干细胞(UC-MSCs)通过其分泌的 EV 改善小鼠肝脏 IRI。还可以看出,再灌注 6 小时后 UC-MSC-EV 主要集中在肝脏中。此外,UC-MSC-EVs被发现能显着调节肝内CD4+T细胞的CD154的膜表达,这是肝脏炎症反应的启动,并会加重肝脏IRI。从机制上讲,进行蛋白质质谱分析后发现,含有 TCP1 亚基 2 (CCT2) 的 Chaperonin 在 UC-MSC-EV 中富集,可调节钙通道以影响 Ca 2+流入并抑制 CD4+ T 细胞中 CD154 的合成。总之,这些结果凸显了 UC-MSC-EV 在减轻肝脏 IRI 方面的治疗潜力。这一发现表明,UC-MSC-EV 中的 CCT2 可以通过 Ca 2+ -钙调神经磷酸酶-NFAT1 信号通路调节肝脏 IRI 期间肝内 CD4+ T 细胞的 CD154 表达。
更新日期:2020-09-23
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