Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jun 26, 2024; 16(6): 690-707
Published online Jun 26, 2024. doi: 10.4252/wjsc.v16.i6.690
Outcomes of combined mitochondria and mesenchymal stem cells-derived exosome therapy in rat acute respiratory distress syndrome and sepsis
Kun-Chen Lin, Wen-Feng Fang, Jui-Ning Yeh, John Y Chiang, Hsin-Ju Chiang, Pei-Lin Shao, Pei-Hsun Sung, Hon-Kan Yip
Kun-Chen Lin, Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
Wen-Feng Fang, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
Jui-Ning Yeh, Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
John Y Chiang, Department of Computer Science and Engineering, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
John Y Chiang, Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Hsin-Ju Chiang, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
Pei-Lin Shao, Hon-Kan Yip, Department of Nursing, Asia University, Taichung 41354, Taiwan
Pei-Hsun Sung, Hon-Kan Yip, Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
Pei-Hsun Sung, Hon-Kan Yip, Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
Pei-Hsun Sung, Hon-Kan Yip, Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
Hon-Kan Yip, Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
Hon-Kan Yip, School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
Co-corresponding authors: Pei-Hsun Sung and Hon-Kan Yip.
Author contributions: Lin KC and Yeh JN performed the experiments; Fang WF, Chiang JY, Chiang HJ, and Shao PL performed the calculations and aided in interpreting the results; Sung PH and Yip HK conceived this study, drafted and revised the manuscript. Sung PH and Yip HK contributed equally to this work and should be considered co-corresponding authors.
Supported by the Ministry of Science and Technology, Taiwan, No. MOST 110-2314-B-182A-133-.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Committee at Kaohsiung Chang Gung Memorial Hospital (Affidavit of Approval of Animal Use Protocol No. 2020121604) and performed in accordance with the Guide for the Care and Use of Laboratory Animals, 8th edition (NIH publication No. 85-23, National Academy Press, Washington, DC, United States, revised 2011).
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 and its supplementary information files.
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: Hon-Kan Yip, MD, Chief Doctor, Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123 Dapi Road, Niaosung District, Kaohsiung 83301, Taiwan. han.gung@msa.hinet.net
Received: January 18, 2024
Revised: April 8, 2024
Accepted: May 9, 2024
Published online: June 26, 2024
Processing time: 159 Days and 7.5 Hours
Abstract
BACKGROUND

The treatment of acute respiratory distress syndrome (ARDS) complicated by sepsis syndrome (SS) remains challenging.

AIM

To investigate whether combined adipose-derived mesenchymal-stem-cells (ADMSCs)-derived exosome (EXAD) and exogenous mitochondria (mitoEx) protect the lung from ARDS complicated by SS.

METHODS

In vitro study, including L2 cells treated with lipopolysaccharide (LPS) and in vivo study including male-adult-SD rats categorized into groups 1 (sham-operated-control), 2 (ARDS-SS), 3 (ARDS-SS + EXAD), 4 (ARDS-SS + mitoEx), and 5 (ARDS-SS + EXAD + mitoEx), were included in the present study.

RESULTS

In vitro study showed an abundance of mitoEx found in recipient-L2 cells, resulting in significantly higher mitochondrial-cytochrome-C, adenosine triphosphate and relative mitochondrial DNA levels (P < 0.001). The protein levels of inflammation [interleukin (IL)-1β/tumor necrosis factor (TNF)-α/nuclear factor-κB/toll-like receptor (TLR)-4/matrix-metalloproteinase (MMP)-9/oxidative-stress (NOX-1/NOX-2)/apoptosis (cleaved-caspase3/cleaved-poly (ADP-ribose) polymerase)] were significantly attenuated in lipopolysaccharide (LPS)-treated L2 cells with EXAD treatment than without EXAD treatment, whereas the protein expressions of cellular junctions [occluding/β-catenin/zonula occludens (ZO)-1/E-cadherin] exhibited an opposite pattern of inflammation (all P < 0.001). Animals were euthanized by 72 h post-48 h-ARDS induction, and lung tissues were harvested. By 72 h, flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflammatory cells (Ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+) and albumin were lowest in group 1, highest in group 2, and significantly higher in groups 3 and 4 than in group 5 (all P < 0.0001), whereas arterial oxygen-saturation (SaO2%) displayed an opposite pattern of albumin among the groups. Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers (CD68+/γ-H2AX) displayed an identical pattern of SaO2% among the groups (all P < 0.0001). The protein expressions of inflammatory (TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress (NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged (cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic (beclin-1/Atg-5/ratio of LC3B-II/LC3B-I) biomarkers exhibited a similar manner, whereas antioxidants [nuclear respiratory factor (Nrf)-1/Nrf-2]/cellular junctions (ZO-1/E-cadherin)/mitochondrial electron transport chain (complex I-V) exhibited an opposite manner of albumin among the groups (all P < 0.0001).

CONCLUSION

Combined EXAD-mitoEx therapy was better than merely one for protecting the lung against ARDS-SS induced injury.

Keywords: Acute respiratory distress syndrome, Sepsis syndrome, Exosomes, Mitochondria, Adipose tissue-derived mesenchymal stem cells, Inflammation

Core Tip: To investigate whether combined adipose-derived mesenchymal-stem-cells-derived exosome (EXAD) and exogenous mitochondria (mitoEx) protect the lung from acute respiratory distress syndrome complicated by sepsis syndrome. The results of this study showed that combined EXAD and mitoEx exerted a synergic effect on protecting the lung from acute respiratory distress syndrome complicated by sepsis syndrome mainly by suppressing inflammatory reaction and oxidative stress, resulting in improved respiratory system and outcomes.