Exosomes derived from human umbilical cord mesenchymal stem cells attenuate hepatic ischaemia-reperfusion injury via the let-7i-5p/Faslg axis

doi:10.3748/wjg.v31.i33.108653

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Sep 7, 2025 (publication date) through Sep 4, 2025

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World Journal of Gastroenterology

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1007-9327

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World J Gastroenterol. Sep 7, 2025; 31(33): 108653
Published online Sep 7, 2025. doi: 10.3748/wjg.v31.i33.108653

Exosomes derived from human umbilical cord mesenchymal stem cells attenuate hepatic ischaemia-reperfusion injury via the let-7i-5p/Faslg axis

Yao Gao, Min He, Cong-Wen Bian, Rui Yu, Jia-Jiao Luo, Yin-Ming Xiang, Yun-Xin Yang, Han-Fei Huang, Zhong Zeng

Yao Gao, Cong-Wen Bian, Rui Yu, Jia-Jiao Luo, Yin-Ming Xiang, Yun-Xin Yang, Han-Fei Huang, Zhong Zeng, The Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China

Min He, Department of Hepatic, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou 510440, Guangdong Province, China

Co-corresponding authors: Han-Fei Huang and Zhong Zeng.

Author contributions: Gao Y, Huang HF, Zeng Z, He M, and Bian CW contributed to project design; Gao Y, He M, Bian CW, Yu R, Luo JJ, Xiang YM, and Yang YX contributed to the experimental execution; Gao Y was responsible for data analysis and drafting of the initial manuscript; Yu R, Luo JJ, Xiang YM, and Yang YX contributed to the and data organization; Huang HF and Zeng Z contributed to the provided experimental guidance and research resources, participated in revision and proofreading, and made equal contributions as co-corresponding authors; and all authors reviewed and approved the final manuscript.

Supported by Natural Science Foundation Project of Yunnan Province, No. 202302AA310025 and No. 202449CE340016; and Health Research Project of Yunnan Province, No. 300068.

Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Kunming Medical University, No. KMMU20241598.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: All data generated during this study are available from the corresponding authors upon reasonable request.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Han-Fei Huang, Professor, The Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wuhua District, Kunming 650032, Yunnan Province, China. huanghanfei@kmmu.edu.cn

Received: April 27, 2025
Revised: July 5, 2025
Accepted: August 5, 2025
Published online: September 7, 2025
Processing time: 128 Days and 0.1 Hours

Abstract

BACKGROUND

Hepatic ischaemia-reperfusion injury (HIRI) is an unavoidable process in liver transplantation, where apoptosis plays a critical role. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-exos), which constitute a cell-free therapeutic approach, have garnered extensive attention in alleviating HIRI. However, the potential of hucMSC-exos in mitigating apoptosis and their underlying mechanisms remain largely unknown.

AIM

To investigate the effects of hucMSC-exos on apoptosis after HIRI and explore the underlying mechanisms.

METHODS

The therapeutic effects of hucMSC-exos on HIRI and hypoxia/reoxygenation injury in L02 cells were investigated. RNA sequencing was used to detect differentially expressed genes in L02 cells after hucMSC-exo treatment, and the expression of apoptosis markers in L02 cells was analyzed. MicroRNA (miRNA) sequencing was performed to analyse the miRNA expression profiles of hucMSC-exos and L02 cells after hucMSC-exo treatment. Through a miRNA-mRNA integrated analysis, candidate miRNAs and their regulated target genes were identified. We subsequently studied the roles of these candidate miRNAs in mouse HIRI and L02 cell hypoxia/reoxygenation injury.

RESULTS

Fluorescence confocal microscopy revealed that hucMSC-exos effectively homed to the liver and were taken up by hepatocytes, likely due to the presence of anti-very late antigen-4 and anti-lymphocyte function-associated antigen-1 on the surface of hucMSC-exos. HucMSC-exos alleviate hepatocyte damage by inhibiting apoptosis. Specifically, let-7i-5p within hucMSC-exos inhibited the expression of the factor-related apoptosis ligand protein in L02 cells, leading to the upregulation of B-cell lymphoma-2 and the downregulation of B-cell lymphoma-2-associated X protein and cysteinyl aspartate specific proteinase-3, thereby inhibiting L02 cell apoptosis and enhancing cell proliferation activity. The overexpression of let-7i-5p effectively enhanced the antiapoptotic effects of hucMSC-exos both in vitro and in vivo.

CONCLUSION

Our findings indicate that hucMSC-exos alleviate HIRI by inhibiting apoptosis. We demonstrated that hucMSC-exos target apoptosis in L02 cells and mediate the let-7i-5p/factor-related apoptosis ligand pathway, thereby ameliorating HIRI. This study provides new insights into the role of hucMSC-exos in hepatocyte apoptosis and highlights the potential of hucMSC-exos as a therapeutic strategy for HIRI.

Keywords: Mesenchymal stem cells; Exosomes; Let-7i-5p; Ischaemia-reperfusion injury; Liver

Core Tip: Human umbilical cord mesenchymal stem cell-derived exosomes mitigate hepatic ischaemia-reperfusion injury by targeting damaged hepatocytes via very late activation antigen-4/vascular cell adhesion molecule-1 and lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 interactions. Their membrane proteins crucially mediate this specific protection, suppressing both the extrinsic and intrinsic apoptotic pathways. Central to this mechanism is the let-7i-5p/factor-related apoptosis ligand signaling axis.