Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Dec 26, 2024; 16(12): 1022-1046
Published online Dec 26, 2024. doi: 10.4252/wjsc.v16.i12.1022
Exosomes derived from microRNA-540-3p overexpressing mesenchymal stem cells promote immune tolerance via the CD74/nuclear factor-kappaB pathway in cardiac allograft
Ji-Gang He, Xin-Xin Wu, Si Li, Dan Yan, Gao-Peng Xiao, Fu-Gang Mao
Ji-Gang He, Si Li, Department of Cardiovascular Surgery, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
Xin-Xin Wu, Yunnan University of Traditional Chinese Medicine, Kunming 650500, Yunnan Province, China
Dan Yan, Department of Medical Intensive Care Unit, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
Gao-Peng Xiao, Department of Anaesthesia, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
Fu-Gang Mao, Department of Ultrasonic, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
Author contributions: He JG and Mao FG contributed to the conceptualization of this manuscript; He JG and Wu XX participated in the software; He JG and Xiao GP were involved in the investigation of this study; He JG and Li S wrote the original draft; Li S contributed to the data curation; He JG participated in the methodology, funding acquisition, formal analysis of this manuscript; Li S and Yan D contributed to the visualization; Xiao GP and Mao FG were involved in the resources and supervision; Wu XX contributed to the validation; Yan D and Mao FG contributed to the writing - review & editing; Mao FG took part in resources and supervision.
Supported by the National Natural Science Foundation of China, No. 82060299; Medical Discipline Leader Project of Yunnan Provincial Health Commission, No. D-2019020; Yunnan Provincial Government Ten Thousand Person-Top Young Talents Project, No. KH-SWR-QNBJ-2019-002; Clinical Medical Center of the First People’s Hospital of Yunnan Province, No. 2021LCZXXF-XZ04 and No. 2022LCZXKF-HX05; Kunming Medical Joint Special Project - Outstanding Youth Cultivation Project, No. 202101AY070001-034; Kunming Medical Joint Special Project, No. 202101AY070001-272; Famous Doctor Project of “Xingdian Talent Support Plan” of Yunnan Province, No. XDYC-MY-2022-0037; and Yunnan Province 2023 Undergraduate Education and Teaching Reform Research Project, No. 2023BKXJJG-F04002.
Institutional animal care and use committee statement: All animal experiments were performed with the help of Yunan Labreal Biotech Ltd, co. in accordance with the ARRIVE principles and were approved by the Animal Care and Use Committee of the Yunan Labreal Biotech Ltd, co. Approval number: No. SL20220510.
Conflict-of-interest statement: The Yunan Labreal Biotech Ltd, co. provided the research materials in the animal experiment. Although the animal experiment was performed in the platform of a private company, they did not aware of or interfere the experimental propose and not participate in the writing, review, and publication of this manuscript. No economic interests were appeared.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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: Fu-Gang Mao, MD, Professor, Department of Ultrasonic, The First People’s Hospital of Yunnan Province, No. 157 Jinbi Road, Kunming 650032, Yunnan Province, China. maofugang666@163.com
Received: May 14, 2024
Revised: September 16, 2024
Accepted: November 12, 2024
Published online: December 26, 2024
Processing time: 212 Days and 19.2 Hours
Abstract
BACKGROUND

Heart transplantation is a crucial intervention for severe heart failure, yet the challenge of organ rejection is significant. Bone marrow mesenchymal stem cells (BMSCs) and their exosomes have demonstrated potential in modulating T cells, dendtitic cells (DCs), and cytokines to achieve immunomodulatory effects. DCs, as key antigen-presenting cells, play a critical role in shaping immune responses by influencing T-cell activation and cytokine production. Through this modulation, BMSCs and their exosomes enhance graft tolerance and prolonging survival.

AIM

To explore the immunomodulatory effects of exosomes derived from BMSCs overexpressing microRNA-540-3p (miR-540-3p) on cardiac allograft tolerance, focusing on how these exosomes modulating DCs and T cells activity through the CD74/nuclear factor-kappaB (NF-κB) pathway.

METHODS

Rat models were used to assess the impact of miR-540-3p-enhanced exosomes on immune tolerance in cardiac allografts. MiR-540-3p expression was manipulated in BMSCs, and derived exosomes were collected and administered to the rat models post-heart transplantation. The study monitored expression levels of major histocompatibility complex II, CD80, CD86, and CD274 in DCs, and quantified CD4+ and CD8+ T cells, T regulatory cells, and cytokine profiles.

RESULTS

Exosomes from miR-540-3p-overexpressing BMSCs lead to reduced expression of immune activation markers CD74 and NF-κB p65 in DCs and T cells. Rats treated with these exosomes showed decreased inflammation and improved cardiac function, indicated by lower levels of pro-inflammatory cytokines (interleukin-1β, interferon-γ) and higher levels of anti-inflammatory cytokines (interleukin-10, transforming growth factor β1). Additionally, miR-540-3p skewed the profiles of DCs and T cells towards immune tolerance, increasing the ratio of T regulatory cells and shifting cytokine secretion to favor graft acceptance.

CONCLUSION

Exosomes derived from BMSCs overexpressing miR-540-3p significantly enhance immune tolerance and prolong cardiac allograft survival by modulating the CD74/NF-κB pathway, which regulates activities of DCs and T cells. These findings highlight a promising therapeutic strategy to improve heart transplantation outcomes and potentially reduce the need for prolonged immunosuppression.

Keywords: Bone marrow mesenchymal stem cells; Exosomes; MicroRNA-540-3p; Cardiac allograft; Immune tolerance

Core Tip: This study explores the innovative use of exosomes from bone marrow mesenchymal stem cells overexpressing microRNA-540-3p to promote immune tolerance in heart transplantation. Demonstrating a significant modulation of the CD74/nuclear factor-kappaB pathway, these exosomes enhance graft survival and function by altering dendritic and T cell responses. Our findings suggest a promising therapeutic strategy that reduces the need for prolonged immunosuppression, offering a substantial advancement in transplant medicine. This approach underscores the potential of targeted exosomal therapies in improving outcomes for heart transplant patients.