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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators
Ying Gao, Mei-Fang Liu, Yang Li, Xi Liu, Yu-Jie Cao, Qian-Fa Long, Jun Yu, Jian-Ying Li
Ying Gao, Department of Respiratory and Critical Care Medicine, Shaanxi Provincial Rehabilitation Hospital, Xi’an 710000, Shaanxi Province, China
Mei-Fang Liu, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Ningxia Medical University (The First People’s Hospital of Yinchuan), Yinchuan 750001, Ningxia Hui Autonomous Region, China
Yang Li, School of Clinical Medicine, Xi’an Medical University, Xi’an 710021, Shaanxi Province, China
Xi Liu, Yu-Jie Cao, Jian-Ying Li, Department of Respiratory and Critical Care Medicine, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
Qian-Fa Long, Department of Neurosurgery, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
Jun Yu, Department of Emergency, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
Author contributions: Gao Y and Liu MF carried out the experiments, participated in the data collection, and drafted the manuscript; Li Y, Liu X, and Cao YJ performed the statistical analysis and participated in the study design; Long QF, Yu J, and Li JY helped draft the manuscript; and all authors read and approved the final manuscript.
Supported by Xi’an Science and Technology Plan Project, No. 20200001YX001(1); and Xi’an Talent Plan - Elite (Innovative Talents) Project, No. XAYC210062.
Institutional review board statement: This study was approved by the Ethics Committee guidelines of Xi’an Central Hospital, No. LW-2023-032.
Institutional animal care and use committee statement: All animal procedures were performed in accordance with the guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal procedures were approved by the hospital’s ethical committee for animals, No. IACUC-20210211.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data generated or analyzed during this study are included in this published article.
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: Jian-Ying Li, MD, Doctor, Department of Respiratory and Critical Care Medicine, Xi’an Central Hospital, No. 163 West Fifth Road, Xi’an 710000, Shaanxi Province, China. l13572168322@163.com
Received: January 6, 2024
Revised: March 22, 2024
Accepted: May 11, 2024
Published online: June 26, 2024
Processing time: 171 Days and 8 Hours
BACKGROUND
Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment.
AIM
To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model.
METHODS
The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.
RESULTS
Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF.
CONCLUSION
MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.
Core Tip: This study unveils the innovative potential of mesenchymal stem cells-extracellular vesicles (MSC-EVs) in mitigating pulmonary fibrosis (PF). MSC-EVs effectively countered transforming growth factor-β1-induced fibrosis in A549 cells, showcasing a significant reduction in collagen I and α-smooth muscle actin. The treatment exhibited a dual impact, alleviating oxidative stress and inflammatory responses in vitro. In PF mouse lungs, MSC-EVs demonstrated remarkable downregulation of fibrotic markers and modulation of oxidative stress and inflammation.
