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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
Interferon-γ priming enhances the therapeutic effects of menstrual blood-derived stromal cells in a mouse liver ischemia-reperfusion model
Qi Zhang, Si-Ning Zhou, Jia-Min Fu, Li-Jun Chen, Yang-Xin Fang, Zhen-Yu Xu, Hui-Kang Xu, Yin Yuan, Yu-Qi Huang, Ning Zhang, Yi-Fei Li, Charlie Xiang
Qi Zhang, Si-Ning Zhou, Jia-Min Fu, Li-Jun Chen, Yang-Xin Fang, Hui-Kang Xu, Yin Yuan, Yu-Qi Huang, Ning Zhang, Yi-Fei Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Qi Zhang, Si-Ning Zhou, Jia-Min Fu, Li-Jun Chen, Yang-Xin Fang, Hui-Kang Xu, Yin Yuan, Yu-Qi Huang, Ning Zhang, Yi-Fei Li, Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
Zhen-Yu Xu, Innovative Precision Medicine Group, Shulan Hospital, Hangzhou 311215, Zhejiang Province, China
Charlie Xiang, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Author contributions: Zhang Q, Zhou SN, Chen LJ, Xu ZY, and Xiang C designed the research study; Zhang Q, Zhou SN, Fu JM, Fang YX, Xu HK, Yuan Y, Huang YQ, Zhang N, and Li YF performed the research; Zhang Q, Zhou SN, and Chen LJ analyzed the data and wrote the manuscript; and all authors have read and approved the final manuscript.
Supported by National Key R&D Program of China, No. 2022YFA1105603 and 2022YFC2304405; Hangzhou Science and Technology Project, China, No. 20200224; National Natural Science Foundation of China, No. 81900563; Key Research & Development Plan of Zhejiang Province, China, No. 2019C03015 and 2020C04016.
Institutional review board statement: The study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Zhejiang University Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Laboratory Animal Welfare and Ethics Committee of Zhejiang University (ZJU-IACUC), and the ethics code is ZJU20210299.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data mentioned in the article can be obtained by contacting the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
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: Charlie Xiang, PhD, Director, Professor, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. cxiang@zju.edu.cn
Received: April 20, 2023
Peer-review started: April 20, 2023
First decision: June 7, 2023
Revised: June 21, 2023
Accepted: July 18, 2023
Article in press: July 18, 2023
Published online: September 26, 2023
ARTICLE HIGHLIGHTS
Research background
Ischemia-reperfusion injury (IRI) and immune rejection are two important factors that affect the prognosis of liver transplantation. Mesenchymal stem cells (MSCs) have been used in liver transplantation and showed certain beneficial effects.
Research motivation
Some studies have indicated that the effects of MSCs are not very significant. Therefore, there is an urgent to find a new way to make MSCs exert better therapeutic effect.
Research objectives
In this study, we attempted to enhance the therapeutic potential of human menstrual blood-derived stromal cells (MenSCs) in a mouse liver ischemia-reperfusion (I/R) model through interferon-γ (IFN-γ) priming strategies and explore the specific mechanisms.
Research methods
After determining the appropriate priming strategies, we applied MenSCs and primed MenSCs in the short-term and long-term mouse liver I/R models, and compared their therapeutic effects. In order to further explore the specific mechanism, we performed a metabolomic analysis of mouse liver samples.
Research results
IFN-γ-primed MenSCs secreted higher levels of indoleamine 2,3-dioxygenase (IDO), attenuated liver injury, and increased regulatory T cell (Treg) numbers in the mouse spleens to greater degrees than untreated MenSCs. Metabolomics and autophagy analyses proved that primed MenSCs more strongly induced protective autophagy in the mouse livers. Further experiments proved that IDO enhanced the protective autophagy by inhibiting the mammalian target of rapamycin (mTOR) pathway and activating the AMPK pathway.
Research conclusions
IFN-γ-primed MenSCs exerted better therapeutic effects in the liver I/R model through secreting higher IDO levels. IDO, on the one hand, increased Treg numbers in the spleen; on the other hand, activated the AMPK-mTOR-autophagy axis to reduce IRI.
Research perspectives
Our study suggests that IFN-γ-primed MenSCs may be a novel and superior MSC product for liver transplantation in the future, and the specific mechanism of how MSCs or IDO enhance autophagy in recipient cells is still worth further study.
