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Kawamura S, Goto H, Kikuchi T, Okabe T, Hasegawa Y, Sugita Y, Fujitsuka H, Kataoka R, Katsumata K, Goto R, Suzuki Y, Hayashi JI, Umemura M, Mitani A. IL-35 May Prevent the Exacerbation of Aspiration Pneumonia Involving Porphyromonas gingivalis by Suppressing IL-17 Production. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:652-662. [PMID: 39725293 DOI: 10.1016/j.ajpath.2024.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 12/28/2024]
Abstract
Periodontitis is associated with aspiration pneumonia. However, the relationship between periodontitis and aspiration pneumonia remains unclear. This study investigated the virulence factor of Porphyromonas gingivalis, which exacerbates aspiration pneumonia, and the role of IL-35, an inhibitory heterodimeric cytokine of Epstein-Barr virus-induced gene 3 (EBI3) and p35, in aspiration pneumonia using Ebi3 knockout (KO) mice. Aspiration pneumonia was induced by the intratracheal injection of Streptococcus pneumoniae and P. gingivalis culture supernatant (mixed infection). Leupeptin was used to inhibit gingipain, a virulence factor of P. gingivalis. Four days after infection, lung tissues were collected for analyses. The percentage of interstitium in the group with mixed infection and leupeptin treatment was significantly reduced compared with the nonleupeptin administration group. Additionally, the percentage of interstitium in the field of Ebi3 KO mice was significantly increased compared with wild-type (WT) mice in mixed infection. IL-35 production in WT mice with mixed infection was significantly increased compared with the control group. IL-17 production in Ebi3 KO mice was significantly increased compared with WT mice with mixed infection. These findings suggest that gingipain exacerbates aspiration pneumonia and that IL-35 may contribute to suppressing the exacerbation of aspiration pneumonia.
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Affiliation(s)
- Shotaro Kawamura
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Hisashi Goto
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.
| | - Takeshi Kikuchi
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Teppei Okabe
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Yoshiaki Hasegawa
- Department of Microbiology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Yoshihiko Sugita
- Department of Oral Pathology and Forensic Odontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Hirotaka Fujitsuka
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Ryosuke Kataoka
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Koudai Katsumata
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Ryoma Goto
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Yuiko Suzuki
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Jun-Ichiro Hayashi
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Masayuki Umemura
- Molecular Microbiology Group, Department of Infectious Diseases, Tropical Biosphere Research Center, University of the Ryukyus, Okinawa, Japan
| | - Akio Mitani
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
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Jia M, Fu H, Jiang X, Wang L, Xu J, Barnes PJ, Adcock IM, Liu Y, He S, Zhang F, Yao L, Sun P, Yao X. DEL-1, as an anti-neutrophil transepithelial migration molecule, inhibits airway neutrophilic inflammation in asthma. Allergy 2024; 79:1180-1194. [PMID: 37681299 DOI: 10.1111/all.15882] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 08/05/2023] [Accepted: 08/22/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND Neutrophil migration into the airways is a key process in neutrophilic asthma. Developmental endothelial locus-1 (DEL-1), an extracellular matrix protein, is a neutrophil adhesion inhibitor that attenuates neutrophilic inflammation. METHODS Levels of DEL-1 were measured in exhaled breath condensate (EBC) and serum in asthma patients by ELISA. DEL-1 modulation of neutrophil adhesion and transepithelial migration was examined in a co-culture model in vitro. The effects of DEL-1-adenoviral vector-mediated overexpression on ovalbumin/lipopolysaccharide (OVA/LPS)-induced neutrophilic asthma were studied in mice in vivo. RESULTS DEL-1 was primarily expressed in human bronchial epithelial cells and was decreased in asthma patients. Serum DEL-1 concentrations were reduced in patients with severe asthma compared with normal subjects (567.1 ± 75.3 vs. 276.8 ± 29.36 pg/mL, p < .001) and were negatively correlated to blood neutrophils (r = -0.2881, p = .0384) and neutrophil-to-lymphocyte ratio (NLR) (r = -0.5469, p < .0001). DEL-1 concentrations in the EBC of severe asthmatic patients (113.2 ± 8.09 pg/mL) were also lower than normal subjects (193.0 ± 7.61 pg/mL, p < .001) and were positively correlated with the asthma control test (ACT) score (r = 0.3678, p = .0035) and negatively related to EBC IL-17 (r = -0.3756, p = .0131), myeloperoxidase (MPO) (r = -0.5967, p = .0055), and neutrophil elastase (NE) (r = -0.5488, p = .0009) expression in asthma patients. Neutrophil adhesion and transepithelial migration in asthma patients were associated with LFA-1 binding to ICAM-1 and inhibited by DEL-1. DEL-1 mRNA and protein expression in human bronchial epithelial cells were regulated by IL-17. Exogenous DEL-1 inhibited IL-17-enhanced neutrophil adhesion and migration. DEL-1 expression was decreased while neutrophil infiltration was increased in the airway of a murine model of neutrophilic asthma. This was prevented by DEL-1 overexpression. CONCLUSIONS DEL-1 down-regulation leads to increased neutrophil migration across bronchial epithelial cells and is associated with neutrophilic airway inflammation in asthma.
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Affiliation(s)
- Man Jia
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Heng Fu
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinyu Jiang
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lina Wang
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiayan Xu
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Peter J Barnes
- Airway Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK
| | - Ian M Adcock
- Airway Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK
| | - Yi Liu
- Department of Allergy, Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infections Respiratory Disease, Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Shujuan He
- Department of Respiratory Medicine, Nanjing Red Cross Hospital, Nanjing, China
| | - Fan Zhang
- Department of Respiratory Medicine, Nanjing Red Cross Hospital, Nanjing, China
| | - Lei Yao
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Peng Sun
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Yao
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Hasanzadeh A, Ebadati A, Dastanpour L, Aref AR, Sahandi Zangabad P, Kalbasi A, Dai X, Mehta G, Ghasemi A, Fatahi Y, Joshi S, Hamblin MR, Karimi M. Applications of Innovation Technologies for Personalized Cancer Medicine: Stem Cells and Gene-Editing Tools. ACS Pharmacol Transl Sci 2023; 6:1758-1779. [PMID: 38093832 PMCID: PMC10714436 DOI: 10.1021/acsptsci.3c00102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 02/16/2024]
Abstract
Personalized medicine is a new approach toward safer and even cheaper treatments with minimal side effects and toxicity. Planning a therapy based on individual properties causes an effective result in a patient's treatment, especially in a complex disease such as cancer. The benefits of personalized medicine include not only early diagnosis with high accuracy but also a more appropriate and effective therapeutic approach based on the unique clinical, genetic, and epigenetic features and biomarker profiles of a specific patient's disease. In order to achieve personalized cancer therapy, understanding cancer biology plays an important role. One of the crucial applications of personalized medicine that has gained consideration more recently due to its capability in developing disease therapy is related to the field of stem cells. We review various applications of pluripotent, somatic, and cancer stem cells in personalized medicine, including targeted cancer therapy, cancer modeling, diagnostics, and drug screening. CRISPR-Cas gene-editing technology is then discussed as a state-of-the-art biotechnological advance with substantial impacts on medical and therapeutic applications. As part of this section, the role of CRISPR-Cas genome editing in recent cancer studies is reviewed as a further example of personalized medicine application.
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Affiliation(s)
- Akbar Hasanzadeh
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Arefeh Ebadati
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Lida Dastanpour
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Amir R. Aref
- Department
of Medical Oncology and Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States
| | - Parham Sahandi Zangabad
- Monash
Institute of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical
Sciences, Monash University, Parkville, Melbourne, Victoria 3052, Australia
| | - Alireza Kalbasi
- Department
of Medical Oncology, Dana-Farber Cancer
Institute, Boston, Massachusetts 02115, United States
| | - Xiaofeng Dai
- School of
Biotechnology, Jiangnan University, Wuxi 214122, China
- National
Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China
- Jiangsu Provincial
Research Center for Bioactive Product Processing Technology, Jiangnan University, Wuxi 214122, China
| | - Geeta Mehta
- Department
of Biomedical Engineering, University of
Michigan, Ann Arbor, Michigan 48109, United States
- Department
of Materials Science and Engineering, University
of Michigan, Ann Arbor, Michigan 48109, United States
- Macromolecular
Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
- Rogel Cancer
Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Precision
Health, University of Michigan, Ann Arbor, Michigan 48105, United States
| | - Amir Ghasemi
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Department
of Materials Science and Engineering, Sharif
University of Technology, Tehran 14588, Iran
| | - Yousef Fatahi
- Nanotechnology
Research Centre, Faculty of Pharmacy, Tehran
University of Medical Sciences, Tehran 14166, Iran
- Department
of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14166, Iran
- Universal
Scientific Education and Research Network (USERN), Tehran 14166, Iran
| | - Suhasini Joshi
- Chemical
Biology Program, Memorial Sloan Kettering
Cancer Center, New York, New York 10065, United States
| | - Michael R. Hamblin
- Laser Research
Centre, Faculty of Health Science, University
of Johannesburg, Doornfontein 2028, South Africa
- Radiation
Biology Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
| | - Mahdi Karimi
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Oncopathology
Research Center, Iran University of Medical
Sciences, Tehran 14535, Iran
- Research
Center for Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran 14166, Iran
- Applied
Biotechnology Research Centre, Tehran Medical Science, Islamic Azad University, Tehran 14166, Iran
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Lopes-Pacheco M, Rocco PRM. Functional enhancement strategies to potentiate the therapeutic properties of mesenchymal stromal cells for respiratory diseases. Front Pharmacol 2023; 14:1067422. [PMID: 37007034 PMCID: PMC10062457 DOI: 10.3389/fphar.2023.1067422] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Respiratory diseases remain a major health concern worldwide because they subject patients to considerable financial and psychosocial burdens and result in a high rate of morbidity and mortality. Although significant progress has been made in understanding the underlying pathologic mechanisms of severe respiratory diseases, most therapies are supportive, aiming to mitigate symptoms and slow down their progressive course but cannot improve lung function or reverse tissue remodeling. Mesenchymal stromal cells (MSCs) are at the forefront of the regenerative medicine field due to their unique biomedical potential in promoting immunomodulation, anti-inflammatory, anti-apoptotic and antimicrobial activities, and tissue repair in various experimental models. However, despite several years of preclinical research on MSCs, therapeutic outcomes have fallen far short in early-stage clinical trials for respiratory diseases. This limited efficacy has been associated with several factors, such as reduced MSC homing, survival, and infusion in the late course of lung disease. Accordingly, genetic engineering and preconditioning methods have emerged as functional enhancement strategies to potentiate the therapeutic actions of MSCs and thus achieve better clinical outcomes. This narrative review describes various strategies that have been investigated in the experimental setting to functionally potentiate the therapeutic properties of MSCs for respiratory diseases. These include changes in culture conditions, exposure of MSCs to inflammatory environments, pharmacological agents or other substances, and genetic manipulation for enhanced and sustained expression of genes of interest. Future directions and challenges in efficiently translating MSC research into clinical practice are discussed.
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Affiliation(s)
- Miquéias Lopes-Pacheco
- Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
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5
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Li R, Zeng J, Ren T. Expression of DEL-1 in alveolar epithelial cells prevents lipopolysaccharide-induced inflammation, oxidative stress, and eosinophil recruitment in acute lung injury. Int Immunopharmacol 2022; 110:108961. [PMID: 35764019 DOI: 10.1016/j.intimp.2022.108961] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 11/05/2022]
Abstract
Bacterial infection is a major cause of acute lung injury (ALI). Developmental endothelial locus-1 (DEL-1) is an immunomodulatory mediator secreted by the endothelial cells. This study aimed to investigate the role of DEL-1 in lipopolysaccharide (LPS)-induced ALI in mouse models and its ability to regulate on eosinophil recruitment. Male C57BL/6 mice were administered an adeno-associated virus (AAV)-mediated DEL-1 overexpression vector via intratracheal injection. Twenty-one days after vector instillation, mice were challenged with LPS (5 mg/kg body weight). Lung injury was evaluated using haematoxylin-eosin staining, flow cytometry, enzyme-linked immunosorbnent assay, quantitative real-time polymerase chain reaction, western blotting, immunohistochemistry and immunofluorescence analyses. DEL-1 was expressed in alveolar epithelial cells of mice. Compared with that in the control group, DEL-1 was expressed at low levels in the lungs of LPS-challenged mice. LPS injured the lungs in mice, as evidenced by an increase in alveolar wall thickness, inflammatory cell infiltration in the stroma, and alveolar collapse. AAV-mediated DEL-1 overexpression attenuated LPS-induced lung injury and inhibited the release of TNF-α, IL-6, and IL-1β. DEL-1 overexpression also attenuated LPS-induced oxidative stress by decreasing lactic dehydrogenase (LDH), myeloperoxidase (MPO), malondialdehyde (MDA), and reactive oxygen species (ROS) activities and increasing superoxide dismutase (SOD) activity. In addition, DEL-1 prevented eosinophil recruitment into lung tissues and inhibited eotaxin production. This study revealed the beneficial role of DEL-1 in preventing LPS-induced ALI in mice. Therefore, DEL-1 can protect lung tissues against LPS-induced inflammation, oxidative stress, and eosinophil recruitment.
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Affiliation(s)
- Ruirui Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Shihezi University School of Medicine, Shihezi, Xinjiang Uygur Autonomous Region, 832008, P.R. China.
| | - Jianqiong Zeng
- Cardiovascular Surgery CCU, Foshan First People's Hospital, Foshan, Guangdong, 528000, P.R. China
| | - Tao Ren
- Three departments of cardiology, The First Affiliated Hospital of Shihezi University School of Medicine, Shihezi, Xinjiang Uygur Autonomous Region, 832008, P.R. China
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Sharma A, Chakraborty A, Jaganathan BG. Review of the potential of mesenchymal stem cells for the treatment of infectious diseases. World J Stem Cells 2021; 13:568-593. [PMID: 34249228 PMCID: PMC8246252 DOI: 10.4252/wjsc.v13.i6.568] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/07/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating the levels of pro-inflammatory cytokines, and inhibiting the excessive recruitment of neutrophils and proliferation of T cells at the site of injury. MSCs aid in the regeneration of damaged tissue by differentiating into the damaged cell types or by releasing paracrine factors that direct tissue regeneration, differentiation, and wound healing. In this review, we discuss in detail the various mechanisms by which MSCs help combat pathogens, tissue damage associated with infectious diseases, and challenges in utilizing MSCs for therapy.
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Affiliation(s)
- Amit Sharma
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Anuja Chakraborty
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Bithiah Grace Jaganathan
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
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7
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Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell 2020; 11:707-722. [PMID: 32519302 PMCID: PMC7282699 DOI: 10.1007/s13238-020-00738-2] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/12/2020] [Indexed: 01/08/2023] Open
Abstract
The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
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Affiliation(s)
- Hua Qin
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China.
| | - Andong Zhao
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China
- Tianjin Medical University, Tianjin, 300070, China
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8
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Sadeghian Chaleshtori S, Mokhber Dezfouli MR, Jabbari Fakhr M. Mesenchymal stem/stromal cells: the therapeutic effects in animal models of acute pulmonary diseases. Respir Res 2020; 21:110. [PMID: 32393278 PMCID: PMC7213547 DOI: 10.1186/s12931-020-01373-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
The pulmonary diseases are one of the most important causes of death in the world. The successful therapies in the field of lung diseases are very limited and the medical treatments available are ineffective in many of the lung diseases. Many studies have evaluated the new therapies in the acute pulmonary diseases, and the transplantation of mesenchymal stem/stromal cells (MSCs), which is a branch of cell therapy, has a special place among the new medical techniques. The MSCs are present throughout the body and are thought to play a role in tissue regeneration and inflammation control. In the event of injury, the local MSCs traverse the shortest possible distance from the tissue or blood vessels to reach the affected site. But, there are few undifferentiated cells in the tissues. The exogenous MSCs are used to immunity modify or regenerative treatments in preclinical models of acute pulmonary diseases. Several studies have shown the positive effects of MSCs replacement in the acute lung disorders. The effection mechanism of the MSCs include the differentiation ability and the secretion of paracrine agents such as the anti-inflammatory mediators. Many studies suggest that this treatment method is safe and is probably to be widely used in future clinical trials. This review will describe the therapeutic effects of the MSCs in the experimental models of the acute pulmonary diseases for use as a method of treatment in clinical trials in future.
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Affiliation(s)
- Sirous Sadeghian Chaleshtori
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.,Institute of Biomedical Research, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mohammad Reza Mokhber Dezfouli
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran. .,Institute of Biomedical Research, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Massoumeh Jabbari Fakhr
- Institute of Biomedical Research, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.,Department of Tissue Engineering, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
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9
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Strategies to Enhance Mesenchymal Stem Cell-Based Therapies for Acute Respiratory Distress Syndrome. Stem Cells Int 2019; 2019:5432134. [PMID: 31885615 PMCID: PMC6893276 DOI: 10.1155/2019/5432134] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 10/28/2019] [Indexed: 02/07/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a multifaced disease characterized by the acute onset of hypoxemia, worsened pulmonary compliance, and noncardiogenic pulmonary edema. Despite over five decades of research, specific treatments for established ARDS are still lacking. MSC-based therapies have the advantage of targeting nearly all pathophysiological components of ARDS by means of a variety of secreted trophic factors, exerting anti-inflammatory, antioxidative, immunomodulatory, antiapoptotic, and proangiogenic effects, resulting in significant structural and functional recovery following ARDS in various preclinical models. However, the therapeutic efficacy of transplanted MSCs is limited by their poor engraftment and low survival rate in the injured tissues, major barriers to clinical translation. Accordingly, several strategies have been explored to improve MSC retention in the lung and enhance the innate properties of MSCs in preclinical models of ARDS. To provide a comprehensive and updated view, we summarize a large body of experimental evidence for a variety of strategies directed towards strengthening the therapeutic potential of MSCs in ARDS.
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10
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Kamm JL, Parlane NA, Riley CB, Gee EK, Dittmer KE, McIlwraith CW. Blood type and breed-associated differences in cell marker expression on equine bone marrow-derived mesenchymal stem cells including major histocompatibility complex class II antigen expression. PLoS One 2019; 14:e0225161. [PMID: 31747418 PMCID: PMC6867698 DOI: 10.1371/journal.pone.0225161] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Accepted: 10/28/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND As the search for an immune privileged allogeneic donor mesenchymal stem cell (MSC) line continues in equine medicine, the characterization of the cells between different sources becomes important. Our research seeks to more clearly define the MSC marker expression of different equine MSC donors. METHODS The bone marrow-derived MSCs from two equine breeds and different blood donor-types were compared over successive culture passages to determine the differential expression of important antigens. Eighteen Thoroughbreds and 18 Standardbreds, including 8 blood donor (erythrocyte Aa, Ca, and Qa antigen negative) horses, were evaluated. Bone marrow was taken from each horse for isolation and culture of MSCs. Samples from passages 2, 4, 6, and 8 were labelled and evaluated by flow cytometry. The cell surface expression of CD11a/18, CD44, CD90 and MHC class II antigens were assessed. Trilineage assays for differentiation into adipogenic, chondrogenic and osteogenic lines were performed to verify characterization of the cells as MSCs. FINDINGS There were significant differences in mesenchymal stem cell marker expression between breeds and blood antigen-type groups over time. Standardbred horses showed a significantly lower expression of MHC class II than did Thoroughbred horses at passages 2, 4 and 6. CD90 was significantly higher in universal blood donor Standardbreds as compared to non-blood donor Standardbreds over all time points. All MSC samples showed high expression of CD44 and low expression of CD11a/18. CONCLUSIONS Universal blood donor- type Standardbred MSCs from passages 2-4 show the most ideal antigen expression pattern of the horses and passages that we characterized for use as a single treatment of donor bone marrow-derived MSCs. Further work is needed to determine the significance of this differential expression along with the effect of the expression of MHC I on equine bone marrow-derived MSCs.
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Affiliation(s)
- J. Lacy Kamm
- Massey University, School of Veterinary Science, Massey University, Palmerston North, New Zealand
- Veterinary Associates, Karaka, Auckland, New Zealand
- * E-mail:
| | - Natalie A. Parlane
- AgResearch, Hopkirk Research Institute, Massey University, Palmerston North, New Zealand
| | - Christopher B. Riley
- Massey University, School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Erica K. Gee
- Massey University, School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Keren E. Dittmer
- Massey University, School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - C. Wayne McIlwraith
- Massey University, School of Veterinary Science, Massey University, Palmerston North, New Zealand
- Colorado State University, Orthopaedic Research Center, Fort Collins, Colorado, United States of America
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11
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Hajishengallis G, Chavakis T. DEL-1-Regulated Immune Plasticity and Inflammatory Disorders. Trends Mol Med 2019; 25:444-459. [PMID: 30885428 DOI: 10.1016/j.molmed.2019.02.010] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/18/2019] [Accepted: 02/20/2019] [Indexed: 12/16/2022]
Abstract
In contrast to traditional immune cell-centered viewpoints, recent studies suggest that tissues are not passive recipients of immunity but have a 'regulatory say' over the host inflammatory response. Identification of tissue-derived homeostatic molecules regulating immune plasticity is seminal for understanding the inherent regulatory potential of different organs in the immune response. DEL-1 (developmental endothelial locus-1) is a secreted multidomain protein interacting with integrins and phospholipids and regulates, depending on its expression location, distinct stages of the host inflammatory response (from myelopoiesis over leukocyte recruitment to efferocytosis and resolution of inflammation). Here we synthesize recent evidence of DEL-1 as an exemplar local regulatory factor in the context of tissue immune plasticity and inflammatory disorders (such as periodontitis, multiple sclerosis, and pulmonary disorders), and discuss its potential as a therapeutic agent.
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Affiliation(s)
- George Hajishengallis
- Penn Dental Medicine, Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.
| | - Triantafyllos Chavakis
- Faculty of Medicine, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
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12
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Chen X, Tang L, Feng J, Wang Y, Han Z, Meng J. Downregulation of Paralemmin-3 Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Rats by Regulating Inflammatory Response and Inhibiting Formation of TLR4/MyD88 and TLR4/TRIF Complexes. Inflammation 2018; 40:1983-1999. [PMID: 28801798 PMCID: PMC7102376 DOI: 10.1007/s10753-017-0639-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Previous studies have demonstrated paralemmin-3 (PALM3) participates in Toll-like receptor (TLR) signaling. This study investigated the effect of PALM3 knockdown on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its underlying mechanisms. We constructed a recombinant adenoviral vector containing short hairpin RNA for PALM3 to knockdown PALM3 expression. A transgene-free adenoviral vector was used as a negative control. The ALI rat model was established by LPS peritoneal injection at 48-h post-transfection. Results showed that downregulation of PALM3 improved the survival rate, attenuated lung pathological changes, alleviated pulmonary edema, lung vascular leakage and neutrophil infiltration, inhibited the production of proinflammatory cytokines and activation of nuclear factor κB and interferon β regulatory factor 3, and promoted the secretion of anti-inflammatory cytokine interleukin-10 and expression of suppressor of cytokine signaling-3 in the ALI rat model. However, PALM3 knockdown had no effect on TLR4, myeloid differentiation factor 88 (MyD88), and Toll-interleukin-1 receptor domain-containing adaptor inducing interferon β (TRIF) expression. Moreover, PALM3 knockdown reduced the interaction of TLR4 with MyD88 or TRIF induced by LPS in rat lungs. Therefore, the downregulation of PALM3 protected rats from LPS-induced ALI and its mechanisms were partially associated with the modulation of inflammatory responses and inhibition of TLR4/MyD88 and TLR4/TRIF complex formation.
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Affiliation(s)
- Xuxin Chen
- Department of Respiratory Medicine, Navy General Hospital of the PLA, No. 6 Fucheng Road, Beijing, 100037, China
| | - Lu Tang
- Department of Neurology, The First Hospital of Changsha, Changsha, 430100, People's Republic of China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yi Wang
- Department of Respiratory Medicine, The Sixth People's Hospital of Jinan City Affiliated to Jining Medical College, Jinan, 250200, People's Republic of China
| | - Zhihai Han
- Department of Respiratory Medicine, Navy General Hospital of the PLA, No. 6 Fucheng Road, Beijing, 100037, China.
| | - Jiguang Meng
- Department of Respiratory Medicine, Navy General Hospital of the PLA, No. 6 Fucheng Road, Beijing, 100037, China.
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13
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Yan S, Chen L, Zhao Q, Liu YN, Hou R, Yu J, Zhang H. Developmental endothelial locus-1 (Del-1) antagonizes Interleukin-17-mediated allergic asthma. Immunol Cell Biol 2018; 96:526-535. [PMID: 29437247 DOI: 10.1111/imcb.12023] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 02/08/2018] [Accepted: 02/08/2018] [Indexed: 01/13/2023]
Abstract
Interleukin (IL)-17 is a major contributor to the pathogenesis of allergic asthma. Developmental endothelial locus-1 (Del-1) is an endothelial cell-secreted protein known to inhibit IL-17 expression. However, little is known about the association between Del-1 and IL-17 in the pathogenesis of allergic asthma. Using bronchoalveolar lavage fluid (BALF) and peripheral blood samples collected from allergic asthmatic patients and controls, we explored the role of Del-1 in relation to IL-17 in allergic asthma. We found that the negative correlation between Del-1 and IL-17 was significant in BALF of allergic asthmatics. Del-1 treatment inhibited the expression of IL-17, the differentiation of IL-17-secreting leukocytes and associated cytokines. Contrarily, IL-17 levels were increased after treatment with anti-Del-1 mAb. Consistent with this, Del-1 treatment led to downregulation of IL-5, CCL5 and IL-4, thus reducing secretion of eosinophil cationic protein. Furthermore, Del-1 significantly downregulated the expression of ICAM-1 and may have the potential to reduce leukocyte transendothelial migration. Our data demonstrate that Del-1 can negatively regulate IL-17 and its proinflammatory function, thereby limiting airway inflammation in allergic asthmatics, and suggest Del-1 as a potential candidate for prevention and treatment of allergic asthma.
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Affiliation(s)
- Shu Yan
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Li Chen
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Zhao
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ya-Nan Liu
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Rui Hou
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Yu
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hong Zhang
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
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14
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Silva LHA, Antunes MA, Dos Santos CC, Weiss DJ, Cruz FF, Rocco PRM. Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases. Stem Cell Res Ther 2018; 9:45. [PMID: 29482654 PMCID: PMC5828113 DOI: 10.1186/s13287-018-0802-8] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Due to their anti-inflammatory, antiapoptotic, antimicrobial, and antifibrotic properties, mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of respiratory diseases. Nevertheless, even though MSC administration has been demonstrated to be safe in clinical trials, to date, few studies have shown evidence of MSC efficacy in respiratory diseases. The present review describes strategies to enhance the beneficial effects of MSCs, including preconditioning (under hypoxia, oxidative stress, heat shock, serum deprivation, and exposure to inflammatory biological samples) and genetic manipulation. These strategies can variably promote increases in MSC survival rates, by inducing expression of cytoprotective genes, as well as increase MSC potency by improving secretion of reparative factors. Furthermore, these strategies have been demonstrated to enhance the beneficial effects of MSCs in preclinical lung disease models. However, there is still a long way to go before such strategies can be translated from bench to bedside.
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Affiliation(s)
- Luisa H A Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, s/n, Bloco G-014, Ilha do Fundão-, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Mariana A Antunes
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, s/n, Bloco G-014, Ilha do Fundão-, Rio de Janeiro, RJ, 21941-902, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Claudia C Dos Santos
- The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada
| | - Daniel J Weiss
- Department of Medicine, Vermont Lung Center, College of Medicine, University of Vermont, Burlington, USA
| | - Fernanda F Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, s/n, Bloco G-014, Ilha do Fundão-, Rio de Janeiro, RJ, 21941-902, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, s/n, Bloco G-014, Ilha do Fundão-, Rio de Janeiro, RJ, 21941-902, Brazil. .,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
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15
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McIntyre LA, Stewart DJ, Mei SHJ, Courtman D, Watpool I, Granton J, Marshall J, dos Santos C, Walley KR, Winston BW, Schlosser K, Fergusson DA. Cellular Immunotherapy for Septic Shock. A Phase I Clinical Trial. Am J Respir Crit Care Med 2018; 197:337-347. [DOI: 10.1164/rccm.201705-1006oc] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- Lauralyn A. McIntyre
- Division of Critical Care, Department of Medicine
- Department of Epidemiology and Community Medicine, and
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Duncan J. Stewart
- Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Shirley H. J. Mei
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - David Courtman
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Irene Watpool
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | | | - John Marshall
- Department of Surgery and Critical Care Medicine, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Claudia dos Santos
- Department of Surgery and Critical Care Medicine, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Keith R. Walley
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Brent W. Winston
- Department of Critical Care Medicine, Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Kenny Schlosser
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Dean A. Fergusson
- Department of Epidemiology and Community Medicine, and
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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16
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Yao Y, Zheng Z, Song Q. Mesenchymal stem cells: A double-edged sword in radiation-induced lung injury. Thorac Cancer 2017; 9:208-217. [PMID: 29235254 PMCID: PMC5792737 DOI: 10.1111/1759-7714.12573] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/10/2017] [Accepted: 11/10/2017] [Indexed: 01/06/2023] Open
Abstract
Radiation therapy is an important treatment modality for multiple thoracic malignancies. However, radiation‐induced lung injury (RILI), which is the term generally used to describe damage to the lungs caused by exposure to ionizing radiation, remains a critical issue affecting both tumor control and patient quality of life. Despite tremendous effort, there is no current consensus regarding the optimal treatment approach for RILI. Because of a number of functional advantages, including self‐proliferation, multi‐differentiation, injury foci chemotaxis, anti‐inflammation, and immunomodulation, mesenchymal stem cells (MSCs) have been a focus of research for many years. Accumulating evidence indicates the therapeutic potential of transplantation of MSCs derived from adipose tissue, umbilical cord blood, and bone marrow for inflammatory diseases, including RILI. However, reports have also shown that MSCs, including fibrocytes, lung hematopoietic progenitor cells, and ABCG2+ MSCs, actually enhance the progression of lung injuries. These contradictory results suggest that MSCs may have dual effects and that caution should be taken when using MSCs to treat RILI. In this review, we present and discuss recent evidence of the double‐edged function of MSCs and provide comments on the prospects of these findings.
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Affiliation(s)
- Yi Yao
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhongliang Zheng
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Qibin Song
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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17
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Mei SHJ, Dos Santos CC, Stewart DJ. Advances in Stem Cell and Cell-Based Gene Therapy Approaches for Experimental Acute Lung Injury: A Review of Preclinical Studies. Hum Gene Ther 2017; 27:802-812. [PMID: 27531647 DOI: 10.1089/hum.2016.063] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Given the failure of pharmacological interventions in acute respiratory distress syndrome (ARDS), researchers have been actively pursuing novel strategies to treat this devastating, life-threatening condition commonly seen in the intensive care unit. There has been considerable research on harnessing the reparative properties of stem and progenitor cells to develop more effective therapeutic approaches for respiratory diseases with limited treatment options, such as ARDS. This review discusses the preclinical literature on the use of stem and progenitor cell therapy and cell-based gene therapy for the treatment of preclinical animal models of acute lung injury (ALI). A variety of cell types that have been used in preclinical models of ALI, such as mesenchymal stem cells, endothelial progenitor cells, and induced pluripotent stem cells, were evaluated. At present, two phase I trials have been completed and one phase I/II clinical trial is well underway in order to translate the therapeutic benefit gleaned from preclinical studies in complex animal models of ALI to patients with ARDS, paving the way for what could potentially develop into transformative therapy for critically ill patients. As we await the results of these early cell therapy trials, future success of stem cell therapy for ARDS will depend on selection of the most appropriate cell type, route and timing of cell delivery, enhancing effectiveness of cells (i.e., potency), and potentially combining beneficial cells and genes (cell-based gene therapy) to maximize therapeutic efficacy. The experimental models and scientific methods exploited to date have provided researchers with invaluable knowledge that will be leveraged to engineer cells with enhanced therapeutic capabilities for use in the next generation of clinical trials.
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Affiliation(s)
- Shirley H J Mei
- 1 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Claudia C Dos Santos
- 2 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.,3 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Duncan J Stewart
- 1 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,4 Department of Medicine, University of Ottawa , Ottawa, Ontario, Canada
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18
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Cho RJ, Kim YS, Kim JY, Oh YM. Human adipose-derived mesenchymal stem cell spheroids improve recovery in a mouse model of elastase-induced emphysema. BMB Rep 2017; 50:79-84. [PMID: 27756443 PMCID: PMC5342870 DOI: 10.5483/bmbrep.2017.50.2.101] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Indexed: 01/24/2023] Open
Abstract
Emphysema, a pathologic component of the chronic obstructive pulmonary disease, causes irreversible destruction of lung. Many researchers have reported that mesenchymal stem cells can regenerate lung tissue after emphysema. We evaluated if spheroid human adipose-derived mesenchymal stem cells (ASCs) showed greater regenerative effects than dissociated ASCs in mice with elastase-induced emphysema. ASCs were administered via an intrapleural route. Mice injected with spheroid ASCs showed improved regeneration of lung tissues, increased expression of growth factors such as fibroblast growth factor-2 (FGF2) and hepatocyte growth factor (HGF), and a reduction in proteases with an induction of protease inhibitors when compared with mice injected with dissociated ASCs. Our findings indicate that spheroid ASCs show better regeneration of lung tissues than dissociated ACSs in mice with elastase-induced emphysema.
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Affiliation(s)
- Ryeon Jin Cho
- University of Ulsan College of Medicine, Seoul 05505, Korea
| | - You-Sun Kim
- University of Ulsan College of Medicine, Seoul 05505; Asan Institute for Life Science, Seoul 05505, Korea
| | - Ji-Young Kim
- Asan Institute for Life Science, Seoul 05505, Korea
| | - Yeon-Mok Oh
- University of Ulsan College of Medicine, Seoul 05505; Asan Institute for Life Science, Seoul 05505; Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Disease, Asan Medical Center, Seoul 05505, Korea
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19
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Cruz FF, Weiss DJ, Rocco PRM. Prospects and progress in cell therapy for acute respiratory distress syndrome. Expert Opin Biol Ther 2016; 16:1353-1360. [DOI: 10.1080/14712598.2016.1218845] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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20
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Yang N, Baban B, Isales CM, Shi XM. Crosstalk between bone marrow-derived mesenchymal stem cells and regulatory T cells through a glucocorticoid-induced leucine zipper/developmental endothelial locus-1-dependent mechanism. FASEB J 2015; 29:3954-63. [PMID: 26038125 DOI: 10.1096/fj.15-273664] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 05/26/2015] [Indexed: 12/31/2022]
Abstract
Bone marrow is a reservoir for regulatory T (T(reg)) cells, but how T(reg) cells are regulated in that environment remains poorly understood. We show that expression of glucocorticoid (GC)-induced leucine zipper (GILZ) in bone marrow mesenchymal lineage cells or bone marrow-derived mesenchymal stem cells (BMSCs) increases the production of T(reg) cells via a mechanism involving the up-regulation of developmental endothelial locus-1 (Del-1), an endogenous leukocyte-endothelial adhesion inhibitor. We found that the expression of Del-1 is increased ∼4-fold in the bone tissues of GILZ transgenic (Tg) mice, and this increase is coupled with a significant increase in the production of IL-10 (2.80 vs. 0.83) and decrease in the production of IL-6 (0.80 vs. 2.33) and IL-12 (0.25 vs. 1.67). We also show that GILZ-expressing BMSCs present antigen in a way that favors T(reg) cells. These results indicate that GILZ plays a critical role mediating the crosstalk between BMSCs and T(reg) in the bone marrow microenvironment. These data, together with our previous findings that overexpression of GILZ in BMSCs antagonizes TNF-α-elicited inflammatory responses, suggest that GILZ plays important roles in bone-immune cell communication and BMSC immune suppressive functions.
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Affiliation(s)
- Nianlan Yang
- *Department of Neuroscience and Regenerative Medicine, Department of Oral Biology, and Department of Orthopaedic Surgery, Georgia Regents University, Augusta, Georgia, USA
| | - Babak Baban
- *Department of Neuroscience and Regenerative Medicine, Department of Oral Biology, and Department of Orthopaedic Surgery, Georgia Regents University, Augusta, Georgia, USA
| | - Carlos M Isales
- *Department of Neuroscience and Regenerative Medicine, Department of Oral Biology, and Department of Orthopaedic Surgery, Georgia Regents University, Augusta, Georgia, USA
| | - Xing-Ming Shi
- *Department of Neuroscience and Regenerative Medicine, Department of Oral Biology, and Department of Orthopaedic Surgery, Georgia Regents University, Augusta, Georgia, USA
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