Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia-reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps

Tongyu Lu; Jiebin Zhang; Jianye Cai; Jiaqi Xiao; Xin Sui; Xiaofeng Yuan; Rong Li; Yang Li; Jia Yao; Guo Lv; Xiaoyan Chen; Haitian Chen; Kaining Zeng; Yasong Liu; Wenjie Chen; Guihua Chen; Yang Yang; Jun Zheng; Yingcai Zhang

doi:10.1016/j.biomaterials.2022.121486

Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia-reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps

Biomaterials. 2022 May:284:121486. doi: 10.1016/j.biomaterials.2022.121486. Epub 2022 Apr 2.

Authors

Tongyu Lu¹, Jiebin Zhang¹, Jianye Cai¹, Jiaqi Xiao¹, Xin Sui², Xiaofeng Yuan³, Rong Li⁴, Yang Li¹, Jia Yao¹, Guo Lv⁵, Xiaoyan Chen⁵, Haitian Chen¹, Kaining Zeng¹, Yasong Liu¹, Wenjie Chen⁵, Guihua Chen⁶, Yang Yang⁷, Jun Zheng⁸, Yingcai Zhang⁹

Affiliations

¹ 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.
² Surgical ICU, The Third Affiliated Hospital of Sun Yat-sen University, China.
³ General ICU, the Third Affiliated Hospital of Sun Yat-sen University, China.
⁴ Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, China.
⁵ Biological Treatment Center, The Third Affiliated Hospital of Sun Yat-sen University, China.
⁶ 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. Electronic address: chghua@mail.sysu.edu.cn.
⁷ 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. Electronic address: yysysu@163.com.
⁸ 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. Electronic address: zhengj67@mail2.sysu.edu.cn.
⁹ 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. Electronic address: zhangyc3@mail.sysu.edu.cn.

PMID: 35447404
DOI: 10.1016/j.biomaterials.2022.121486

Abstract

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.

Keywords: Extracellular vesicles; Liver ischaemia-reperfusion injury; Mesenchymal stromal cells; Mitochondria transfer; Nanotherapeutics; Neutrophils extracellular traps.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Extracellular Traps*
Extracellular Vesicles* / metabolism
Liver
Mesenchymal Stem Cells* / metabolism
Mitochondria
Reperfusion Injury* / metabolism
Reperfusion Injury* / therapy