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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression
Zhuo Chen, Meng-Wei Yao, Zhi-Lin Shen, Shi-Dan Li, Wei Xing, Wei Guo, Zhan Li, Xiao-Feng Wu, Luo-Quan Ao, Wen-Yong Lu, Qi-Zhou Lian, Xiang Xu, Xiang Ao
Zhuo Chen, Meng-Wei Yao, Zhi-Lin Shen, Wei Xing, Wei Guo, Zhan Li, Xiao-Feng Wu, Luo-Quan Ao, Xiang Xu, Xiang Ao, Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
Zhuo Chen, College of Basic Medical Sciences, Army Medical University, Chongqing 400038, China
Shi-Dan Li, Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing 400042, China
Wen-Yong Lu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, The South of Shangcai Village, Wenzhou 325005, Zhejiang Province, China
Qi-Zhou Lian, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
Xiang Ao, Department of Orthopedics, 953 Hospital of PLA Army, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse 857000, Tibet Autonomous Region, China
Author contributions: Chen Z and Yao MW contributed equally to this work; Chen Z and Yao MW designed all the project and the experiment; Chen Z, Ao X, Guo W, Xing W, Shen ZL, and Lian QZ developed the methodology; Chen Z, Yao MW, and Ao LQ performed the in vivo experiments; Chen Z, Yao MW, Li Z, Li SD, and Lu WY performed the in vitro experiments; Chen Z and Ao X wrote the manuscript; Xu X, Ao X, and Chen Z reviewed and edited the paper; and all authors read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81871568 and No. 32100643; and COVID-19 Infection and Prevention Emergency Special Project of Chongqing Education Commission, No. KYYJ202009.
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 Army Medical University (SYXK2022-0018).
Conflict-of-interest statement: The authors confirm that this article has no conflict of interest to report.
Data sharing statement: Data sets used or analyzed during the current study can be obtained reasonably request of the corresponding authors.
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: Xiang Ao, PhD, Researcher, Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Changjiang Road, Yuzhong District, Chongqing 40042, China. ax_syd@163.com
Received: March 13, 2023
Peer-review started: March 13, 2023
First decision: June 6, 2023
Revised: June 20, 2023
Accepted: July 24, 2023
Article in press: July 24, 2023
Published online: August 26, 2023
ARTICLE HIGHLIGHTS
Research background
The immunosuppressive capacity of Mesenchymal stem cells (MSCs) is dependent on the “license” of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α), but this; however, the mechanism is unclear.
Research motivation
The efficacy of MSCs transplantation (MSCT) is limited by the expression of immunosuppressive molecules of MSCs, including PD-L1. However, the mechanism of IFN-γ alone or in combination with TNF-α inducing MSCs high expression of PD-L1 remains unclear.
Research objectives
To reveal the mechanism of high PD-L1 expression in MSCs pretreated with IFN-γ and TNF-α and explore the application prospects of MSCs with high PD-L1 expression in ulcerative colitis.
Research methods
We assessed PD-L1 expression in human umbilical cord-MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signaling inhibition and RNA interference experiments to elucidate the specific cross-talk signaling pathways between IFN-γ and TNF-α. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium (DSS)-induced acute colitis.
Research results
Our results showed that IFN-γ upregulated PD-L1 expression in hUC-MSCs to enhance their immunosuppressive activities through the JAK/STAT1/interferon regulatory factor 1 (IRF1) pathway. TNF-α synergistically enhanced IFN-γ-induced PD-L1 expression in hUC-MSCs by upregulating nuclear factor kappa-B (NF-κB)-mediated expression of IFN-γ receptor 1 to activate JAK/STAT1/IRF1 signaling. Furthermore, high PD-L1 expression in hUC-MSCs induced by IFN-γ and TNF-α significantly attenuated DSS-induced acute colitis in mice.
Research conclusions
Our study revealed that IFN-γ and TNF-α synergistically induce the high PD-L1 expression of hUC-MSCs through the JAK/STAT1/IRF1 pathway and the NF-κB pathway, which effectively improves the immunosuppressive capacity of hUC-MSCs.
Research perspectives
The results of the present study could facilitate the optimization of clinical application strategies of MSCT.
