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Zhang Z, Wu W, Li M, Du L, Li J, Yin X, Zhang W. Mesenchymal stem cell–derived extracellular vesicles: A novel nanoimmunoregulatory tool in musculoskeletal diseases. NANO TODAY 2024; 57:102343. [DOI: 10.1016/j.nantod.2024.102343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Darwish M, El Hajj R, Khayat L, Alaaeddine N. Stem Cell Secretions as a Potential Therapeutic Agent for Autism Spectrum Disorder: A Narrative Review. Stem Cell Rev Rep 2024; 20:1252-1272. [PMID: 38630359 DOI: 10.1007/s12015-024-10724-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2024] [Indexed: 07/04/2024]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental illness characterized by impaired social interaction and restricted repetitive behaviors or interests. The rising prevalence of ASD diagnosis has triggered a surge in research into investigating the underlying neuropathological processes and finding new therapeutic approaches. ASD is characterized by neuroinflammation and dysregulation of neuro-immune cross-talk, which suggests that stem cell treatment might be a potential therapeutic approach. The beneficial and restorative effects of stem cells are mainly due to their paracrine activity, in which stem cells generate and release extracellular vesicles such as exosomes and distinct secreted non-vesicle soluble proteins, including, growth factors, chemokines, cytokines, and immunomodulatory molecules referred to as the Secretome. In this paper, we reviewed the existing research exploring the therapeutic potential of stem cell secretome focusing on their role in addressing ASD pathology. Furthermore, we proposed a comprehensive mechanism of action for stem cell secretions, encompassing the broader secretome as well as the specific contribution of exosomes, in alleviating ASD neuropathology. Across the reviewed studies, exosomes and secreted soluble factors of the transplanted stem cell demonstrate a potential efficacy in ameliorating autistic-like behaviors. The proposed mechanism of action involves the modulation of signaling pathways implicated in neuroinflammation, angiogenesis, cellular apoptosis, and immunomodulation.
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Affiliation(s)
- Mariam Darwish
- Faculty of Medical Sciences, Neuroscience Research Center, Lebanese University, Beirut, Lebanon
| | | | | | - Nada Alaaeddine
- Dean of Health Sciences, Modern University for Business & Science, Beirut, Lebanon.
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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Summers BS, Thomas Broome S, Pang TWR, Mundell HD, Koh Belic N, Tom NC, Ng ML, Yap M, Sen MK, Sedaghat S, Weible MW, Castorina A, Lim CK, Lovelace MD, Brew BJ. A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease. Int J Tryptophan Res 2024; 17:11786469241248287. [PMID: 38757094 PMCID: PMC11097742 DOI: 10.1177/11786469241248287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 04/03/2024] [Indexed: 05/18/2024] Open
Abstract
Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.
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Affiliation(s)
- Benjamin Sebastian Summers
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Sarah Thomas Broome
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | | | - Hamish D Mundell
- Faculty of Medicine and Health, New South Wales Brain Tissue Resource Centre, School of Medical Sciences, Charles Perkins Centre, University of Sydney, NSW, Australia
| | - Naomi Koh Belic
- School of Life Sciences, University of Technology, Sydney, NSW, Australia
| | - Nicole C Tom
- Formerly of the Department of Physiology, University of Sydney, NSW, Australia
| | - Mei Li Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maylin Yap
- Formerly of the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Monokesh K Sen
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- School of Medicine, Western Sydney University, NSW, Australia
- Faculty of Medicine and Health, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Sara Sedaghat
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Michael W Weible
- School of Environment and Science, Griffith University, Brisbane, QLD, Australia
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia
| | - Alessandro Castorina
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | - Chai K Lim
- Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
| | - Michael D Lovelace
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Bruce J Brew
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
- Departments of Neurology and Immunology, St. Vincent’s Hospital, Sydney, NSW, Australia
- University of Notre Dame, Darlinghurst, Sydney, NSW, Australia
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Chen L, Zhang N, Huang Y, Zhang Q, Fang Y, Fu J, Yuan Y, Chen L, Chen X, Xu Z, Li Y, Izawa H, Xiang C. Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside. Stem Cell Rev Rep 2023; 19:2192-2224. [PMID: 37498509 DOI: 10.1007/s12015-023-10583-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
Liver diseases impose a huge burden worldwide. Although hepatocyte transplantation has long been considered as a potential strategy for treating liver diseases, its clinical implementation has created some obvious limitations. As an alternative strategy, cell therapy, particularly mesenchymal stem cell (MSC) transplantation, is widely used in treating different liver diseases, including acute liver disease, acute-on-chronic liver failure, hepatitis B/C virus, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Here, we summarize the status of MSC transplantation in treating liver diseases, focusing on the therapeutic mechanisms, including differentiation into hepatocyte-like cells, immunomodulating function with a variety of immune cells, paracrine effects via the secretion of various cytokines and extracellular vesicles, and facilitation of homing and engraftment. Some improved perspectives and current challenges are also addressed. In summary, MSCs have great potential in the treatment of liver diseases based on their multi-faceted characteristics, and more accurate mechanisms and novel therapeutic strategies stemming from MSCs will facilitate clinical practice.
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Affiliation(s)
- Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Lu Chen
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Xin Chen
- Department of Hematology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310027, People's Republic of China
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Hiromi Izawa
- Jingugaien Woman Life Clinic, Jingu-Gaien 3-39-5 2F, Shibuya-Ku, Tokyo, Japan
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China.
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Wang YH, Chen EQ. Mesenchymal Stem Cell Therapy in Acute Liver Failure. Gut Liver 2023; 17:674-683. [PMID: 36843422 PMCID: PMC10502502 DOI: 10.5009/gnl220417] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 02/28/2023] Open
Abstract
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Kandeel M, Morsy MA, Alkhodair KM, Alhojaily S. Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities. Biomolecules 2023; 13:1250. [PMID: 37627315 PMCID: PMC10452295 DOI: 10.3390/biom13081250] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a type of versatile adult stem cells present in various organs. These cells give rise to extracellular vesicles (EVs) containing a diverse array of biologically active elements, making them a promising approach for therapeutics and diagnostics. This article examines the potential therapeutic applications of MSC-derived EVs in addressing neurodegenerative disorders such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Furthermore, the present state-of-the-art for MSC-EV-based therapy in AD, HD, PD, ALS, and MS is discussed. Significant progress has been made in understanding the etiology and potential treatments for a range of neurodegenerative diseases (NDs) over the last few decades. The contents of EVs are carried across cells for intercellular contact, which often results in the control of the recipient cell's homeostasis. Since EVs represent the therapeutically beneficial cargo of parent cells and are devoid of many ethical problems connected with cell-based treatments, they offer a viable cell-free therapy alternative for tissue regeneration and repair. Developing innovative EV-dependent medicines has proven difficult due to the lack of standardized procedures in EV extraction processes as well as their pharmacological characteristics and mechanisms of action. However, recent biotechnology and engineering research has greatly enhanced the content and applicability of MSC-EVs.
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Affiliation(s)
- Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Mohamed A. Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Khalid M. Alkhodair
- Department of Anatomy, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Sameer Alhojaily
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
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Pavlovic D, Miloradovic D, Stojanovic MD, Harrell CR, Polosa R, Rust S, Volti GL, Caruso M, Jakovljevic V, Djonov V, Volarevic V. Cigarette smoke attenuates mesenchymal stem cell-based suppression of immune cell-driven acute liver failure. Toxicol Lett 2023; 385:12-20. [PMID: 37572970 DOI: 10.1016/j.toxlet.2023.08.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/22/2023] [Accepted: 08/09/2023] [Indexed: 08/14/2023]
Abstract
Detrimental effects of smoking on mesenchymal stem cell (MSC)-dependent immunosuppression and hepatoprotection are unknown. Herewith, by using α-galactosylceramide (α-GalCer)-induced liver injury, a well-established murine model of fulminant hepatitis, we examined molecular mechanisms which were responsible for negative effects of cigarette smoke on MSC-dependent immunomodulation. MSC which were grown in cigarette smoke-exposed medium (MSCWS-CM) obtained pro-inflammatory phenotype, were not able to optimally produce hepatoprotective and immunosuppressive cytokines (TGF-β, HGF, IL-10, NO, KYN), and secreted significantly higher amounts of inflammatory cytokines (IFN-γ, TNF-α, IL-17, IL-6) than MSC that were cultured in standard medium never exposed to cigarette smoke (MSCCM). In contrast to MSCCM, which efficiently attenuated α-GalCer-induced hepatitis, MSCWS-CM were not able to prevent hepatocyte injury and liver inflammation. MSCWS-CM had reduced capacity for the suppression of liver-infiltrated inflammatory macrophages, dendritic cells (DCs) and lymphocytes. Although significantly lower number of IL-12-producing macrophages and DCs, TNF-α, IFN-γ or IL-17-producing CD4 + and CD8 +T lymphocytes, NK and NKT cells were noticed in the livers of α-GalCer+MSCCM-treated mice compared to α-GalCer+saline-treated animals, this phenomenon was not observed in α-GalCer-injured mice that received MSCWS-CM. MSCWS-CM could not induce expansion of anti-inflammatory IL-10-producing FoxP3 +CD4 + and CD8 + T regulatory cells and were not able to create immunosuppressive microenvironment in the liver as MSCCM. Similarly as it was observed in mice, MSCWS-CM were not able to optimally inhibit production of inflammatory and hepatototoxic cytokines in activated human Th1/Th17 and NKT1/NKT17 cells, confirming the hypothesis that cigarette smoke significantly attenuates therapeutic potential of MSC in cell-based immunotherapy of inflammatory liver diseases.
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Affiliation(s)
- Dragica Pavlovic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Dragana Miloradovic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Milica Dimitrijevic Stojanovic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Carl Randall Harrell
- Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, FL 34684, USA
| | - Riccardo Polosa
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Sonja Rust
- ECLAT Srl, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Giovanni Li Volti
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Massimo Caruso
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Vladimir Jakovljevic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland
| | - Vladislav Volarevic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia; Departments of Genetics and Department of Microbiology and Immunology, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences University of Kragujevac, Serbia.
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Chen Q, Jin M, Wang S, Wang K, Chen L, Zhu X, Zhang Y, Wang Y, Li Y, Li S, Zeng Y, Feng L, Yang W, Gao Y, Zhou S, Peng Q. Establishing an hTERT-driven immortalized umbilical cord-derived mesenchymal stem cell line and its therapeutic application in mice with liver failure. J Tissue Eng 2023; 14:20417314231200328. [PMID: 37736245 PMCID: PMC10510347 DOI: 10.1177/20417314231200328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/25/2023] [Indexed: 09/23/2023] Open
Abstract
Acute liver failure (ALF) is characterized by rapid liver cell destruction. It is a multi-etiological and fulminant complication with a clinical mortality of over 80%. Therapy using mesenchymal stem cells (MSCs) or MSCs-derived exosomes can alleviate acute liver injury, which has been demonstrated in animal experiments and clinical application. However, similar to other stem cells, different cell sources, poor stability, cell senescence and other factors limit the clinical application of MSCs. To achieve mass production and quality control on stem cells and their exosomes, transfecting umbilical cord mesenchymal stem cell (UCMSC) with lentivirus overexpressing human telomerase reverse transcriptase (hTERT) gene, the hTERT-UCMSC was constructed as an immortalized MSC cell line. Compared with the primary UCMSC (P3) and immortalized cell line hTERT-UCMSC at early passage (P10), the hTERT-UCMSC retained the key morphological and physiological characteristics of UCMSC at the 35th passage (P35), and showed no signs of carcinogenicity and toxic effect in mice. There was no difference in either exosome production or characteristics of exosomes among cultures from P3 primary cells, P10 and P35 immortalized hTERT-UCMSCs. Inoculation of either hTERT-UCMSC (P35) or its exosomes improved the survival rate and liver function of ALF mice induced by thioacetamide (TAA). Our findings suggest that this immortalized cell line can maintain its characteristics in long-term culture. Inoculation of hTERT-UCMSC and its exosomes could potentially be used in clinics for the treatment of liver failure in the future.
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Affiliation(s)
- Qi Chen
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Meixian Jin
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Simin Wang
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Kexin Wang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Liqin Chen
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaojuan Zhu
- Department of Anesthesiology, The First People’ s Hospital of Kashi, Kashgar, Xinjiang, China
| | - Ying Zhang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Wang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yang Li
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shao Li
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Youmin Zeng
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Feng
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Wanren Yang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Gao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shuqin Zhou
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qing Peng
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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11
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Abdolmohammadi K, Mahmoudi T, Alimohammadi M, Tahmasebi S, Zavvar M, Hashemi SM. Mesenchymal stem cell-based therapy as a new therapeutic approach for acute inflammation. Life Sci 2023; 312:121206. [PMID: 36403645 DOI: 10.1016/j.lfs.2022.121206] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/12/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022]
Abstract
Acute inflammatory diseases such as acute colitis, kidney injury, liver failure, lung injury, myocardial infarction, pancreatitis, septic shock, and spinal cord injury are significant causes of death worldwide. Despite advances in the understanding of its pathophysiology, there are many restrictions in the treatment of these diseases, and new therapeutic approaches are required. Mesenchymal stem cell-based therapy due to immunomodulatory and regenerative properties is a promising candidate for acute inflammatory disease management. Based on preclinical results, mesenchymal stem cells and their-derived secretome improved immunological and clinical parameters. Furthermore, many clinical trials of acute kidney, liver, lung, myocardial, and spinal cord injury have yielded promising results. In this review, we try to provide a comprehensive view of mesenchymal stem cell-based therapy in acute inflammatory diseases as a new treatment approach.
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Affiliation(s)
- Kamal Abdolmohammadi
- Department of Immunology, School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Tayebeh Mahmoudi
- 17 Shahrivar Hospital, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Zavvar
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanothechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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12
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Sorokina EV, Bisheva IV. The role of cells of the innate immune system in psoriasis. VESTNIK DERMATOLOGII I VENEROLOGII 2022. [DOI: 10.25208/vdv1330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Psoriasis is an immune-mediated disease with a complex pathogenesis. The close relationship between the development of psoriasis and the adaptive immune response is already known. However, recent data have shown that innate immune cells also play an important role in the development of psoriasis. Congenital lymphoid cells, dendritic cells, T cells, NK cells, and NKT lymphocytes are activated in psoriasis, contributing to disease pathology through IL-17-dependent and independent mechanisms. During disease progression, T cells secrete proinflammatory cytokines that induce and exacerbate the course of psoriasis. T cells have memory cell properties that respond rapidly to secondary stimulation, which contributes to disease relapse. This article presents an overview of recent findings demonstrating the role of innate immunity in psoriasis.
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13
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Pozzobon M, D’Agostino S, Roubelakis MG, Cargnoni A, Gramignoli R, Wolbank S, Gindraux F, Bollini S, Kerdjoudj H, Fenelon M, Di Pietro R, Basile M, Borutinskaitė V, Piva R, Schoeberlein A, Eissner G, Giebel B, Ponsaerts P. General consensus on multimodal functions and validation analysis of perinatal derivatives for regenerative medicine applications. Front Bioeng Biotechnol 2022; 10:961987. [PMID: 36263355 PMCID: PMC9574482 DOI: 10.3389/fbioe.2022.961987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/01/2022] [Indexed: 11/26/2022] Open
Abstract
Perinatal tissues, such as placenta and umbilical cord contain a variety of somatic stem cell types, spanning from the largely used hematopoietic stem and progenitor cells to the most recently described broadly multipotent epithelial and stromal cells. As perinatal derivatives (PnD), several of these cell types and related products provide an interesting regenerative potential for a variety of diseases. Within COST SPRINT Action, we continue our review series, revising and summarizing the modalities of action and proposed medical approaches using PnD products: cells, secretome, extracellular vesicles, and decellularized tissues. Focusing on the brain, bone, skeletal muscle, heart, intestinal, liver, and lung pathologies, we discuss the importance of potency testing in validating PnD therapeutics, and critically evaluate the concept of PnD application in the field of tissue regeneration. Hereby we aim to shed light on the actual therapeutic properties of PnD, with an open eye for future clinical application. This review is part of a quadrinomial series on functional/potency assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer, anti-inflammation, wound healing, angiogenesis, and regeneration.
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Affiliation(s)
- Michela Pozzobon
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Stefania D’Agostino
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Maria G. Roubelakis
- Laboratory of Biology, Medical School of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, The Research Center in Cooperation with AUVA Trauma Research Center, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Florelle Gindraux
- Service de Chirurgie Orthopédique, Traumatologique et plastique, CHU Besançon, Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, University Bourgogne Franche-Comté, Besançon, France
| | - Sveva Bollini
- Department of Experimental Medicine (DIMES), School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | - Halima Kerdjoudj
- University of Reims Champagne Ardenne, EA 4691 BIOS “Biomatériaux et Inflammation en Site Osseux”, UFR d’Odontologie, Reims, France
| | | | - Roberta Di Pietro
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Mariangela Basile
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Veronika Borutinskaitė
- Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Vilnius, Lithuania
| | - Roberta Piva
- Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Guenther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
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14
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Harrell CR, Pavlovic D, Djonov V, Volarevic V. Therapeutic potential of mesenchymal stem cells in the treatment of acute liver failure. World J Gastroenterol 2022; 28:3627-3636. [PMID: 36161038 PMCID: PMC9372816 DOI: 10.3748/wjg.v28.i28.3627] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/08/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
Acute liver failure (ALF) is a severe and life-threatening condition in which rapid deterioration of liver function develops in a patient who has no preexisting liver disease. Mesenchymal stem cells (MSCs) are immunoregulatory stem cells which are able to modulate phenotype and function of all immune cells that play pathogenic role in the development and progression of ALF. MSCs in juxtacrine and paracrine manner attenuate antigen-presenting properties of dendritic cells and macrophages, reduce production of inflammatory cytokines in T lymphocytes, suppress hepatotoxicity of natural killer T (NKT) cells and promote generation and expansion of immunosuppressive T, B and NKT regulatory cells in acutely inflamed liver. Due to their nano-sized dimension and lipid envelope, intravenously injected MSC-derived exosomes (MSC-Exos) may by-pass all biological barriers to deliver MSC-sourced immunoregulatoy factors directly into the liver-infiltrated immune cells and injured hepatocytes. Results obtained by us and others revealed that intravenous administration of MSCs and MSC-Exos efficiently attenuated detrimental immune response and acute inflammation in the liver, suggesting that MSCs and MSC-Exos could be considered as potentially new remedies in the immunotherapy of ALF. In this review, we emphasize the current knowledge about molecular and cellular mechanisms which are responsible for MSC-based modulation of liver-infiltrated immune cells and we discuss different insights regarding the therapeutic potential of MSCs in liver regeneration.
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Affiliation(s)
| | - Dragica Pavlovic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Bern 3012, Switzerland
| | - Vladislav Volarevic
- Department of Medical Genetics and Microbiology and Immunology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
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15
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Psaraki A, Ntari L, Karakostas C, Korrou-Karava D, Roubelakis MG. Extracellular vesicles derived from mesenchymal stem/stromal cells: The regenerative impact in liver diseases. Hepatology 2022; 75:1590-1603. [PMID: 34449901 DOI: 10.1002/hep.32129] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/04/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023]
Abstract
Liver dysfunctions are classified into acute and chronic diseases, which comprise a heterogeneous group of pathological features and a high mortality rate. Liver transplantation remains the gold-standard therapy for most liver diseases, with concomitant limitations related to donor organ shortage and lifelong immunosuppressive therapy. A concept in liver therapy intends to overcome these limitations based on the secreted extracellular vesicles (EVs; microvesicles and exosomes) by mesenchymal stem/stromal cells (MSCs). A significant number of studies have shown that factors released by MSCs could induce liver repair and ameliorate systemic inflammation through paracrine effects. It is well known that this paracrine action is based not only on the secretion of cytokines and growth factors but also on EVs, which regulate pathways associated with inflammation, hepatic fibrosis, integrin-linked protein kinase signaling, and apoptosis. Herein, we extensively discuss the differential effects of MSC-EVs on different liver diseases and on cellular and animal models and address the complex molecular mechanisms involved in the therapeutic potential of EVs. In addition, we cover the crucial information regarding the type of molecules contained in MSC-EVs that can be effective in the context of liver diseases. In conclusion, outcomes on MSC-EV-mediated therapy are expected to lead to an innovative, cell-free, noninvasive, less immunogenic, and nontoxic alternative strategy for liver treatment and to provide important mechanistic information on the reparative function of liver cells.
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Affiliation(s)
- Adriana Psaraki
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Lydia Ntari
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Christos Karakostas
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Despoina Korrou-Karava
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Maria G Roubelakis
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
- Centre of Basic ResearchBiomedical Research Foundation of the Academy of AthensAthensGreece
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16
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Yang Y, Dong G, Bi Y, Zhang X, Yao X, Jin G, Zhang K, Shu Z, Hong F. Human liver stem cells alleviate Con-A induced liver injury by regulating the balance of Treg/Th17 cells. Transpl Immunol 2022; 74:101632. [PMID: 35623594 DOI: 10.1016/j.trim.2022.101632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Liver injury is a serious threat to human health that has become a worldwide problem. To date, there is still no effective treatment strategy. In the present study, we examined the protective effects of Human liver stem cells (HLSCs) against concanavalin A (Con A)-induced acute liver injury. METHODS Isolated HLSCs were characterized by microscopy, functional assays, and gene expression. HLSCs or HLSCs culture medium were transplanted in mice for 12 h and subsequently challenged with Con A via tail-vein injection. The effects were evaluated through survival rate, histology, blood tests, TUNEL assay, quantitative RT-PCR and flow cytometry. CellTracker™ CM-Dil labled HLSCs were tracked by fluorescence microscope. RESULTS Transplantation of HLSCs reduced the mortality rate, reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), narrowed the area of liver necrosis, and inhibited hepatocyte apoptosis induced by Con A. Injection of HLSCs culture medium could also alleviate Con A-induced liver injury. Of note, HLSCs-transplanted mice exhibited lower frequencies of Th17 cells and higher frequencies of Tregs in their liver and spleen following Con A injection. Moreover, transplantation of HLSCs significantly reduced the expression of IL-17A, IL-17F and ROR-γt induced by Con A, while reversed Con A-induced downregulation of Foxp3 expression and IL-10. CONCLUSIONS HLSCs protect mice from immune-mediated liver injury by regulating the balance of Treg/Th17 cells, suggesting that transplantation of HLSCs is a potential and effective therapeutic method for amelioration of liver injury.
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Affiliation(s)
- Yonghong Yang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Guanjun Dong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, PR China
| | - Yanzhen Bi
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao, PR China
| | - Xiaobei Zhang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Xiaoying Yao
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Guiyuan Jin
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Kai Zhang
- Jilin University No 3 Hospital, Jilin, PR China
| | - Zhenfeng Shu
- Shanghai Meifeng Biotechnology Co., Ltd, Shanghai, PR China
| | - Feng Hong
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China; Institute of Liver Diseases, Affiliated Hospital of Jining Medical University, Jining, PR China.
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17
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Shokravi S, Borisov V, Zaman BA, Niazvand F, Hazrati R, Khah MM, Thangavelu L, Marzban S, Sohrabi A, Zamani A. Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review. Stem Cell Res Ther 2022; 13:192. [PMID: 35527304 PMCID: PMC9080215 DOI: 10.1186/s13287-022-02825-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Recently, mesenchymal stromal cells (MSCs) and their derivative exosome have become a promising approach in the context of liver diseases therapy, in particular, acute liver failure (ALF). In addition to their differentiation into hepatocytes in vivo, which is partially involved in liver regeneration, MSCs support liver regeneration as a result of their appreciated competencies, such as antiapoptotic, immunomodulatory, antifibrotic, and also antioxidant attributes. Further, MSCs-secreted molecules inspire hepatocyte proliferation in vivo, facilitating damaged tissue recovery in ALF. Given these properties, various MSCs-based approaches have evolved and resulted in encouraging outcomes in ALF animal models and also displayed safety and also modest efficacy in human studies, providing a new avenue for ALF therapy. Irrespective of MSCs-derived exosome, MSCs-based strategies in ALF include administration of native MSCs, genetically modified MSCs, pretreated MSCs, MSCs delivery using biomaterials, and also MSCs in combination with and other therapeutic molecules or modalities. Herein, we will deliver an overview regarding the therapeutic effects of the MSCs and their exosomes in ALF. As well, we will discuss recent progress in preclinical and clinical studies and current challenges in MSCs-based therapies in ALF, with a special focus on in vivo reports.
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Affiliation(s)
- Samin Shokravi
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Vitaliy Borisov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Burhan Abdullah Zaman
- Basic Sciences Department, College of Pharmacy, University of Duhok, Duhok, Kurdistan Region Iraq
| | - Firoozeh Niazvand
- School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Raheleh Hazrati
- Department of Medicinal Chemistry, Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Meysam Mohammadi Khah
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Sima Marzban
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Armin Sohrabi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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18
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Hazrati A, Malekpour K, Soudi S, Hashemi SM. Mesenchymal Stromal/Stem Cells and Their Extracellular Vesicles Application in Acute and Chronic Inflammatory Liver Diseases: Emphasizing on the Anti-Fibrotic and Immunomodulatory Mechanisms. Front Immunol 2022; 13:865888. [PMID: 35464407 PMCID: PMC9021384 DOI: 10.3389/fimmu.2022.865888] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/15/2022] [Indexed: 12/21/2022] Open
Abstract
Various factors, including viral and bacterial infections, autoimmune responses, diabetes, drugs, alcohol abuse, and fat deposition, can damage liver tissue and impair its function. These factors affect the liver tissue and lead to acute and chronic liver damage, and if left untreated, can eventually lead to cirrhosis, fibrosis, and liver carcinoma. The main treatment for these disorders is liver transplantation. Still, given the few tissue donors, problems with tissue rejection, immunosuppression caused by medications taken while receiving tissue, and the high cost of transplantation, liver transplantation have been limited. Therefore, finding alternative treatments that do not have the mentioned problems is significant. Cell therapy is one of the treatments that has received a lot of attention today. Hepatocytes and mesenchymal stromal/stem cells (MSCs) are used in many patients to treat liver-related diseases. In the meantime, the use of mesenchymal stem cells has been studied more than other cells due to their favourable characteristics and has reduced the need for liver transplantation. These cells increase the regeneration and repair of liver tissue through various mechanisms, including migration to the site of liver injury, differentiation into liver cells, production of extracellular vesicles (EVs), secretion of various growth factors, and regulation of the immune system. Notably, cell therapy is not entirely excellent and has problems such as cell rejection, undesirable differentiation, accumulation in unwanted locations, and potential tumorigenesis. Therefore, the application of MSCs derived EVs, including exosomes, can help treat liver disease and prevent its progression. Exosomes can prevent apoptosis and induce proliferation by transferring different cargos to the target cell. In addition, these vesicles have been shown to transport hepatocyte growth factor (HGF) and can promote the hepatocytes'(one of the most important cells in the liver parenchyma) growths.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Medovic MV, Jakovljevic VL, Zivkovic VI, Jeremic NS, Jeremic JN, Bolevich SB, Ravic Nikolic AB, Milicic VM, Srejovic IM. Psoriasis between Autoimmunity and Oxidative Stress: Changes Induced by Different Therapeutic Approaches. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2249834. [PMID: 35313642 PMCID: PMC8934232 DOI: 10.1155/2022/2249834] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/15/2022] [Indexed: 12/15/2022]
Abstract
Psoriasis is defined as chronic, immune-mediated disease. Regardless of the development of new therapeutic approaches, the precise etiology of psoriasis remains unknown and speculative. The aim of this review was to systematize the results of previous research on the role of oxidative stress and aberrant immune response in the pathogenesis of psoriasis, as well as the impact of certain therapeutic modalities on the oxidative status in patients with psoriasis. Complex immune pathways of both the innate and adaptive immune systems appear to be major pathomechanisms in the development of psoriasis. Oxidative stress represents another important contributor to the pathophysiology of disease, and the redox imbalance in psoriasis has been reported in skin cells and, systemically, in plasma and blood cells, and more recently, also in saliva. Current immune model of psoriasis begins with activation of immune system in susceptible person by some environmental factor and loss of immune tolerance to psoriasis autoantigens. Increased production of IL-17 appears to be the most prominent role in psoriasis pathogenesis, while IL-23 is recognized as master regulator in psoriasis having a specific role in cross bridging the production of IL-17 by innate and acquired immunity. Other proinflammatory cytokines, including IFN-γ, TNF-α, IL-1β, IL-6, IL-22, IL-26, IL-29, or IL-36, have also been reported to play important roles in the development of psoriasis. Oxidative stress can promote inflammation through several signaling pathways. The most noticeable and most powerful antioxidative effects exert various biologics compared to more convenient therapeutic modalities, such as methotrexate or phototherapy. The complex interaction of redox, immune, and inflammatory signaling pathways should be focused on further researches tackling the pathophysiology of psoriasis, while antioxidative supplementation could be the solution in some refractory cases of the disease.
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Affiliation(s)
- Marija V. Medovic
- Department of Dermatovenerology, University of Kragujevac, Faculty of Medical Sciences, Svetozara Markovica 69, 34000 Kragujevac, Serbia
- University Clinical Center Kragujevac, Zmaj Jovina 30, 34000 Kragujevac, Serbia
| | - Vladimir Lj. Jakovljevic
- Department of Physiology, University of Kragujevac, Faculty of Medical Sciences, Svetozara Markovica 69, 34000 Kragujevac, Serbia
- I.M. Sechenov First Moscow State Medical University, Department of Human Pathophysiology, Moscow, Russian Federation, Trubetskaya Str. 2, 119992 Moscow, Russia
| | - Vladimir I. Zivkovic
- Department of Physiology, University of Kragujevac, Faculty of Medical Sciences, Svetozara Markovica 69, 34000 Kragujevac, Serbia
| | - Nevena S. Jeremic
- Department of Pharmacy, University of Kragujevac, Faculty of Medical Sciences, Svetozara Markovica 69, 34000 Kragujevac, Serbia
| | - Jovana N. Jeremic
- Department of Pharmacy, University of Kragujevac, Faculty of Medical Sciences, Svetozara Markovica 69, 34000 Kragujevac, Serbia
| | - Sergey B. Bolevich
- I.M. Sechenov First Moscow State Medical University, Department of Human Pathophysiology, Moscow, Russian Federation, Trubetskaya Str. 2, 119992 Moscow, Russia
| | - Ana B. Ravic Nikolic
- Department of Dermatovenerology, University of Kragujevac, Faculty of Medical Sciences, Svetozara Markovica 69, 34000 Kragujevac, Serbia
- University Clinical Center Kragujevac, Zmaj Jovina 30, 34000 Kragujevac, Serbia
| | - Vesna M. Milicic
- Department of Dermatovenerology, University of Kragujevac, Faculty of Medical Sciences, Svetozara Markovica 69, 34000 Kragujevac, Serbia
- University Clinical Center Kragujevac, Zmaj Jovina 30, 34000 Kragujevac, Serbia
| | - Ivan M. Srejovic
- Department of Physiology, University of Kragujevac, Faculty of Medical Sciences, Svetozara Markovica 69, 34000 Kragujevac, Serbia
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Lee C, Kim M, Han J, Yoon M, Jung Y. Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis. Biomedicines 2021; 9:1598. [PMID: 34829827 PMCID: PMC8615475 DOI: 10.3390/biomedicines9111598] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent stem cells derived from various post-natal organs. Therapeutic approaches involving MSCs have been studied extensively in various diseases, including liver disease. MSCs modulate hepatic inflammation and fibrosis and/or differentiate into hepatocytes by interacting directly with immune cells, HSCs, and hepatocytes and secreting modulators, thereby contributing to reduced liver fibrosis. Cell-free therapy including MSC-released secretomes and extracellular vesicles has elicited extensive attention because they could overcome MSC transplantation limitations. Herein, we provide basic information on hepatic fibrogenesis and the therapeutic potential of MSCs. We also review findings presenting the effects of MSC itself and MSC-based cell-free treatments in liver fibrosis, focusing on HSC activation. Growing evidence supports the anti-fibrotic function of either MSC itself or MSC modulators, although the mechanism underpinning their effects on liver fibrosis has not been established. Further studies are required to investigate the detailed mechanism explaining their functions to expand MSC therapies using the cell itself and cell-free treatments for liver fibrosis.
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Affiliation(s)
- Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Minju Kim
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Jinsol Han
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Myunghee Yoon
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Biomedical Research Institute, Pusan National University, Pusan 46241, Korea;
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
- Departments of Biological Sciences, Pusan National University, Pusan 46241, Korea
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21
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Mesenchymal Stem Cell Transplantation for the Treatment of Age-Related Musculoskeletal Frailty. Int J Mol Sci 2021; 22:ijms221910542. [PMID: 34638883 PMCID: PMC8508885 DOI: 10.3390/ijms221910542] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/16/2021] [Accepted: 09/24/2021] [Indexed: 12/16/2022] Open
Abstract
Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies leading to rapid growth of geriatric population. Thus, age-associated diseases especially in the musculoskeletal system are becoming more common. Loss of bone (osteoporosis) and muscle (sarcopenia) mass are conditions whose prevalence is increasing because of the change in population distribution in the world towards an older mean age. The deterioration in the bone and muscle functions can cause severe disability and seriously affects the patients’ quality of life. Currently, there is no treatment to prevent and reverse age-related musculoskeletal frailty. Existing interventions are mainly to slow down and control the signs and symptoms. Mesenchymal stem cell (MSC) transplantation is a promising approach to attenuate age-related musculoskeletal frailty. This review compiles the present knowledge of the causes and changes of the musculoskeletal frailty and the potential of MSC transplantation as a regenerative therapy for age-related musculoskeletal frailty.
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22
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Zhang N, Zhao L, Liu D, Hu C, Wang Y, He T, Bi Y, He Y. Characterization of Urine-Derived Stem Cells from Patients with End-Stage Liver Diseases and Application to Induced Acute and Chronic Liver Injury of Nude Mice Model. Stem Cells Dev 2021; 30:1126-1138. [PMID: 34549601 DOI: 10.1089/scd.2021.0137] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Urine-derived stem cells (USCs) are adult stem cells isolated from urine with strong proliferative ability and differentiation potentials. Cell transplantation of USCs could partly repair liver injury. It has been reported that the proliferative ability of bone mesenchymal stem cells in patients with chronic liver failure is significantly lower than in patients without liver disease. The aim of this study was therefore to evaluate the biological characteristics of USCs from end-stage liver disease patients (LD-USCs, USCs from patients with liver disease) compared with those from normal healthy individuals (N-USCs, USCs from normal individuals), with a view to determining whether autologous USCs can be applied to the treatment of liver disease. In this study USCs were isolated from urine samples of male patients with end-stage liver disease. Adherent USCs exhibit a spindle- or rice grain-like morphology, and express CD24, CD29, CD73, CD90, and CD146 surface markers, but not CD31, CD34, CD45, and CD105. We observed no differences in cell morphology or cell surface marker profile between LD-USCs and N-USCs. LD-USCs exhibited similar proliferative, colony-forming, apoptotic, and migratory abilities to N-USCs. Both USCs demonstrated similar capacities for osteogenic, adipogenic, and chondrogenic differentiation. When USCs were transplanted into CCl4 treatment-induced acute and chronic liver fibrosis mouse models, we observed a decrease in liver index, recovery of alanine aminotransferase and aspartate aminotransferase levels, alleviation of liver tissue injury, and dramatic improvement of liver tissue structure. USC transplantation can effectively recover liver function and improve liver tissue damage in acute or chronic liver injury mouse models. According to the results, we concluded that the biological characteristics of LD-USCs are not affected by basic liver disease. This study provides further evidence of the stem cell characteristics and liver repair function of LD-USCs, which may serve as a theoretical and experimental foundation for autologous USC transplantation technology in the treatment of liver failure and end-stage liver diseases.
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Affiliation(s)
- Nannan Zhang
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Li Zhao
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Daijiang Liu
- Department of Gastroenterology, Chongqing Emergency Medical Center, Chongqing, China
| | - Chaoqun Hu
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Wang
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Tongchuan He
- Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois, USA
| | - Yang Bi
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yun He
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
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23
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TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell-Cell Contact and Extracellular Vesicles. Int J Mol Sci 2021; 22:ijms22179531. [PMID: 34502453 PMCID: PMC8431422 DOI: 10.3390/ijms22179531] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/10/2021] [Accepted: 08/26/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of MSC immunoregulatory mechanisms. In addition, the importance of cell–cell contact for MSCs to efficiently modulate the immune response has recently been highlighted. Because these interactions would be difficult to achieve in the physiological context, the release of extracellular vesicles (EVs) and their participation as intermediaries of communication between MSCs and immune cells becomes relevant. Therefore, this article focuses on analyzing immunoregulatory mechanisms mediated by cell contact, highlighting the importance of intercellular adhesion molecule-1 (ICAM-1) and the participation of EVs. Moreover, the effects of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), the main cytokines involved in MSC activation, are examined. These cytokines, when used at the appropriate concentrations and times, would promote increases in the expression of immunoregulatory molecules in the cell and allow the acquisition of EVs enriched with these molecules. The establishment of certain in vitro activation guidelines will facilitate the design of conditioning protocols to obtain functional MSCs or EVs in different pathophysiological conditions.
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Ghafouri-Fard S, Niazi V, Hussen BM, Omrani MD, Taheri M, Basiri A. The Emerging Role of Exosomes in the Treatment of Human Disorders With a Special Focus on Mesenchymal Stem Cells-Derived Exosomes. Front Cell Dev Biol 2021; 9:653296. [PMID: 34307345 PMCID: PMC8293617 DOI: 10.3389/fcell.2021.653296] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) are produced by diverse eukaryotic and prokaryotic cells. They have prominent roles in the modulation of cell-cell communication, inflammation versus immunomodulation, carcinogenic processes, cell proliferation and differentiation, and tissue regeneration. These acellular vesicles are more promising than cellular methods because of the lower risk of tumor formation, autoimmune responses and toxic effects compared with cell therapy. Moreover, the small size and lower complexity of these vesicles compared with cells have made their production and storage easier than cellular methods. Exosomes originated from mesenchymal stem cells has also been introduced as therapeutic option for a number of human diseases. The current review aims at summarization of the role of EVs in the regenerative medicine with a focus on their therapeutic impacts in liver fibrosis, lung disorders, osteoarthritis, colitis, myocardial injury, spinal cord injury and retinal injury.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mir Davood Omrani
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Basiri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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25
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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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26
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Luan Y, Kong X, Feng Y. Mesenchymal stem cells therapy for acute liver failure: Recent advances and future perspectives. LIVER RESEARCH 2021; 5:53-61. [PMID: 39959343 PMCID: PMC11791815 DOI: 10.1016/j.livres.2021.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/16/2021] [Accepted: 03/24/2021] [Indexed: 12/21/2022]
Abstract
Acute liver failure (ALF) is a life-threatening disease characterized by the rapid development of hepatocyte death and a systemic inflammatory response, which leads to high mortality. Despite the prevention of ALF complications, therapeutic effectiveness remains limited because of the rapid disease progression. Thus, there is a need to explore various therapeutic approaches. Currently, the only effective treatment is liver transplantation; However, the lack of donors, surgical complications, immunosuppression, and high medical costs limit its clinical application. Recently, mesenchymal stem cells (MSCs) have been found to exert hepatoprotective effects in ALF through suppression of inflammation, immunoregulation, promotion of mitosis, anti-apoptosis effects, and alleviation of the metabolic and oxidative stress imbalance. In this review, we summarize the advantages and disadvantages of MSCs from different sources and their molecular mechanisms in ALF treatment, along with future perspectives that may provide guidance to improve the current status of MSCs therapy for ALF.
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Affiliation(s)
- Yuling Luan
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Feng
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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27
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Harrell CR, Popovska Jovicic B, Djonov V, Volarevic V. Molecular Mechanisms Responsible for Mesenchymal Stem Cell-Based Treatment of Viral Diseases. Pathogens 2021; 10:pathogens10040409. [PMID: 33915728 PMCID: PMC8066286 DOI: 10.3390/pathogens10040409] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/16/2021] [Accepted: 03/26/2021] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are adult, immunomodulatory stem cells which reside in almost all postnatal tissues. Viral antigens and damage-associated molecular patterns released from injured and infected cells activate MSCs, which elicit strong antiviral immune response. MSC-sourced interferons and inflammatory cytokines modulate the cytotoxicity of NK cells and CTLs, enhance the antigen-presentation properties of DCs and macrophages, regulate cytokine synthesis in CD4+ T helper cells and promote antibody production in B cells. After the elimination of viral pathogens, MSCs produce immunoregulatory cytokines and trophic factors, prevent the over-activation of immune cells and promote tissue repair and regeneration. In this review article, we summarize the current knowledge on the molecular mechanisms that are responsible for the MSC-dependent elimination of virus-infected cells, and we emphasize the therapeutic potential of MSCs and their secretomes in the treatment of viral diseases.
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Affiliation(s)
- Carl Randall Harrell
- Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, FL 34684, USA;
| | - Biljana Popovska Jovicic
- Department of Infectious Diseases, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia
- Correspondence: (B.P.J.); (V.V.); Tel./Fax: +381-34306800 (V.V.)
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, 2 Baltzerstrasse, 3012 Bern, Switzerland;
| | - Vladislav Volarevic
- Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
- Correspondence: (B.P.J.); (V.V.); Tel./Fax: +381-34306800 (V.V.)
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28
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Zhou JH, Lu X, Yan CL, Sheng XY, Cao HC. Mesenchymal stromal cell-dependent immunoregulation in chemically-induced acute liver failure. World J Stem Cells 2021; 13:208-220. [PMID: 33815670 PMCID: PMC8006015 DOI: 10.4252/wjsc.v13.i3.208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 01/08/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI), which refers to liver damage caused by a drug or its metabolites, has emerged as an important cause of acute liver failure (ALF) in recent years. Chemically-induced ALF in animal models mimics the pathology of DILI in humans; thus, these models are used to study the mechanism of potentially effective treatment strategies. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties, and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF. Here, we summarize some of the existing research on the interaction between MSCs and immune cells, and discuss the possible mechanisms underlying the immuno-modulatory activity of MSCs in chemically-induced ALF. We conclude that MSCs can impact the phenotype and function of macrophages, as well as the differentiation and maturation of dendritic cells, and inhibit the proliferation and activation of T lymphocytes or B lymphocytes. MSCs also have immuno-modulatory effects on the production of cytokines, such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6, in animal models. Thus, MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.
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Affiliation(s)
- Jia-Hang Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xuan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Cui-Lin Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xin-Yu Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.
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29
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Kamm JL, Riley CB, Parlane N, Gee EK, McIlwraith CW. Interactions Between Allogeneic Mesenchymal Stromal Cells and the Recipient Immune System: A Comparative Review With Relevance to Equine Outcomes. Front Vet Sci 2021; 7:617647. [PMID: 33521090 PMCID: PMC7838369 DOI: 10.3389/fvets.2020.617647] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/02/2020] [Indexed: 12/27/2022] Open
Abstract
Despite significant immunosuppressive activity, allogeneic mesenchymal stromal cells (MSCs) carry an inherent risk of immune rejection when transferred into a recipient. In naïve recipients, this immune response is initially driven by the innate immune system, an immediate reaction to the foreign cells, and later, the adaptive immune system, a delayed response that causes cell death due to recognition of specific alloantigens by host cells and antibodies. This review describes the actions of MSCs to both suppress and activate the different arms of the immune system. We then review the survival and effectiveness of the currently used allogeneic MSC treatments.
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Affiliation(s)
- J Lacy Kamm
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Christopher B Riley
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Natalie Parlane
- Hopkirk Laboratory, AgResearch, Palmerston North, New Zealand
| | - Erica K Gee
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - C Wayne McIlwraith
- Orthopaedic Research Center, C. Wayne McIlwraith Translational Medical Institute, Colorado State University, Fort Collins, CO, United States
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30
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Mesenchymal Stem Cells Attenuate Acute Liver Failure by Promoting Expansion of Regulatory T Cells in an Indoleamine 2,3-Dioxygenase-Dependent Manner. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2020. [DOI: 10.2478/sjecr-2018-0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
The influence of mesenchymal stem cells (MSCs) on the phenotype and function of CD4+CD49b+FoxP3- regulatory cells has not been elucidated. We used Concanavalin A (ConA) - and α-galactosylceramide (α-GalCer)-induced acute liver injury to estimate the effects of MSCs on liver-infiltrating CD4+CD49b+FoxP3-regulatory cells. MSCs significantly reduced ConA- and α-GalCer-mediated liver injury in C57BL/6 mice, as demonstrated by biochemical tests, reduced influx of inflammatory CD4+ T cells, and increased presence of CD4+CD49b+FoxP3- regulatory cells in the injured livers. The number of CD4+CD49b+FoxP3-regulatory cells was also significantly increased in α-GalCer-treated mice that received MSC-derived conditioned medium (MSC-CM). The presence of 1-methyltryptophan, a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), in MSC-CM completely abrogated the hepatoprotective eff ect of MSCs and significantly decreased the total number of liver-infiltrated CD4+CD49b+FoxP3- regulatory cells, indicating the crucial importance of MSC-derived IDO for the expansion of CD4+CD49b+FoxP3- regulatory cells and the consequent MSC-dependent attenuation of acute liver injury.
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31
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Sato Y, Ogawa E, Okuyama R. Role of Innate Immune Cells in Psoriasis. Int J Mol Sci 2020; 21:ijms21186604. [PMID: 32917058 PMCID: PMC7554918 DOI: 10.3390/ijms21186604] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/08/2020] [Accepted: 09/08/2020] [Indexed: 12/13/2022] Open
Abstract
Psoriasis is a chronic inflammatory skin condition caused by a combination of hereditary and environmental factors. Its development is closely related to the adaptive immune response. T helper 17 cells are major IL-17-producing cells, a function that plays an important role in the pathogenesis of psoriasis. However, recent findings have demonstrated that innate immune cells also contribute to the development of psoriasis. Innate lymphoid cells, γδ T cells, natural killer T cells, and natural killer cells are activated in psoriasis, contributing to disease pathology through IL-17-dependent and -independent mechanisms. The present review provides an overview of recent findings, demonstrating a role for innate immunity in psoriasis.
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Affiliation(s)
| | | | - Ryuhei Okuyama
- Correspondence: ; Tel.: +81-263-37-2645; Fax: +81-263-37-2646
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32
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Moloudizargari M, Govahi A, Fallah M, Rezvanfar MA, Asghari MH, Abdollahi M. The mechanisms of cellular crosstalk between mesenchymal stem cells and natural killer cells: Therapeutic implications. J Cell Physiol 2020; 236:2413-2429. [PMID: 32892356 DOI: 10.1002/jcp.30038] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/11/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cells (MSCs) are mesenchymal precursors of various origins, with well-known immunomodulatory effects. Natural killer (NK) cells, the major cells of the innate immune system, are critical for the antitumor and antiviral defenses; however, in certain cases, they may be the main culprits in the pathogenesis of some NK-related conditions such as autoimmunities and hematological malignancies. On the other hand, these cells seem to be the major responders in beneficial phenomena like graft versus leukemia. Substantial data suggest that MSCs can variably affect NK cells and can be affected by these cells. Accordingly, acquiring a profound understanding of the crosstalk between MSCs and NK cells and the involved mechanisms seems to be a necessity to develop therapeutic approaches based on such interactions. Therefore, in this study, we made a thorough review of the existing literature on the interactions between MSCs and NK cells with a focus on the underlying mechanisms. The current knowledge herein suggests that MSCs possess a great potential to be used as tools for therapeutic targeting of NK cells in disease context and that preconditioning of MSCs, as well as their genetic manipulation before administration, may provide a wider variety of options in terms of eliciting more specific and desirable therapeutic outcomes. Nevertheless, our knowledge regarding the effects of MSCs on NK cells is still in its infancy, and further studies with well-defined conditions are warranted herein.
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Affiliation(s)
- Milad Moloudizargari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Govahi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marjan Fallah
- Department of Pharmacology and Toxicology, Medicinal Plant Research Centre, Faculty of Pharmacy, Islamic Azad University, Amol, Iran
| | - Mohammad A Rezvanfar
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mohammad H Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption. Int J Mol Sci 2020; 21:ijms21145169. [PMID: 32708317 PMCID: PMC7404053 DOI: 10.3390/ijms21145169] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/16/2020] [Accepted: 07/20/2020] [Indexed: 01/18/2023] Open
Abstract
The process of bone remodeling is the result of the regulated balance between bone cell populations, namely bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte, the mechanosensory cell type. Osteoclasts derived from the hematopoietic stem cell lineage are the principal cells involved in bone resorption. In osteolytic diseases such as rheumatoid arthritis, periodontitis, and osteoporosis, the balance is lost and changes in favor of bone resorption. Therefore, it is vital to elucidate the mechanisms of osteoclast formation and bone resorption. It has been reported that osteocytes express Receptor activator of nuclear factor κΒ ligand (RANKL), an essential factor for osteoclast formation. RANKL secreted by osteocytes is the most important factor for physiologically supported osteoclast formation in the developing skeleton and in pathological bone resorption such as experimental periodontal bone loss. TNF-α directly enhances RANKL expression in osteocytes and promotes osteoclast formation. Moreover, TNF-α enhances sclerostin expression in osteocytes, which also increases osteoclast formation. These findings suggest that osteocyte-related cytokines act directly to enhance osteoclast formation and bone resorption. In this review, we outline the most recent knowledge concerning bone resorption-related cytokines and discuss the osteocyte as the master regulator of bone resorption and effector in osteoclast formation.
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Kumar A, Hill TM, Gordy LE, Suryadevara N, Wu L, Flyak AI, Bezbradica JS, Van Kaer L, Joyce S. Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells. Proc Natl Acad Sci U S A 2020; 117:17156-17165. [PMID: 32611812 PMCID: PMC7382224 DOI: 10.1073/pnas.2001665117] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77tg) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Vα14-Jα18 TCR-α chain gene into the Nur77tg (Nur77tg;Vα14tg) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-γ-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.
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MESH Headings
- Animals
- Cell Differentiation/genetics
- Cell Differentiation/immunology
- Cells, Cultured
- Immune Tolerance/genetics
- Immune Tolerance/immunology
- Mice
- Mice, Knockout
- Natural Killer T-Cells/immunology
- Natural Killer T-Cells/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/immunology
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Receptors, Antigen, T-Cell
- Thymocytes
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Affiliation(s)
- Amrendra Kumar
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37232
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Timothy M Hill
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Chemistry and Life Science, US Military Academy, West Point, NY 10996
| | - Laura E Gordy
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Naveenchandra Suryadevara
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Lan Wu
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Andrew I Flyak
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Biology, Caltech, Pasadena, CA 91125
| | - Jelena S Bezbradica
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
- The Kennedy Institute of Rheumatology, University of Oxford, Oxford OX1 2JD, United Kingdom
| | - Luc Van Kaer
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Sebastian Joyce
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37232;
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
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Ng NN, Thakor AS. Locoregional delivery of stem cell-based therapies. Sci Transl Med 2020; 12:eaba4564. [PMID: 32522806 DOI: 10.1126/scitranslmed.aba4564] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/24/2020] [Accepted: 05/20/2020] [Indexed: 12/13/2022]
Abstract
Interventional regenerative medicine (IRM) uses image-guided, minimally invasive procedures for the targeted delivery of stem cell-based therapies to regenerate, replace, or repair damaged organs. Although many cellular therapies have shown promise in the preclinical setting, clinical results have been suboptimal. Most intravenously delivered cells become trapped in the lungs and reticuloendothelial system, resulting in little therapy reaching target tissues. IRM aims to increase the efficacy of cell-based therapies by locoregional stem cell delivery via endovascular, endoluminal, or direct injection into tissues. This review highlights routes of delivery, disease states, and mechanisms of action involved in the targeted delivery of stem cells.
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Affiliation(s)
- Nathan Norton Ng
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Avnesh Sinh Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304, USA.
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Sukhikh GT, Pekarev ОG, Maiborodin IV, Silachev DN, Shevtsova YА, Gоrуunоv KV, Onoprienko NV, Maiborodina VI, Galenok RV, Novikov AV, Pekareva ЕО. Preservation of Mesenchymal Stem Cell-Derived Extracellular Vesicles after Abdominal Delivery in the Experiment. Bull Exp Biol Med 2020; 169:122-129. [PMID: 32488786 DOI: 10.1007/s10517-020-04838-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Indexed: 01/08/2023]
Abstract
Light luminescent microscopy was used to study the distribution of extracellular microvesicles with PKH26-stained membranes secreted by placenta-derived mesenchymal stromal cells in the uterine tissues at different terms after injections to intact rats and after abdominal delivery (a model of cesarian section). Microvesicles migrated through the uterine tissues and were detected for at least 8 days after injection. In some cases, microvesicles were more numerous in the uterus after cesarian section modeling, which can be related to blockade of microcirculation and lymph flow due to inflammation accompanying surgical intervention. The content of microvesicles in the uterine tissues gradually declined due to macrophage phagocytosis and, probably, due to their migration into the vascular bed. Despite their size, properly stained extracellular microvesicles can be detected by light microscopy in tissues after injections.
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Affiliation(s)
- G T Sukhikh
- V. I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - О G Pekarev
- V. I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - I V Maiborodin
- Center of New Medical Technologies, Institute of Chemical Biology and Fundamental Medicine, Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia
| | - D N Silachev
- V. I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - Yu А Shevtsova
- V. I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - K V Gоrуunоv
- V. I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N V Onoprienko
- Novosibirsk State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - V I Maiborodina
- Institute of Molecular Pathology and Pathomorphology, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, Russia
| | - R V Galenok
- Novosibirsk State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - A V Novikov
- Novosibirsk State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Е О Pekareva
- Novosibirsk State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
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Topcu Sarica L, Zibandeh N, Genç D, Gül F, Akkoç T, Kombak EF, Cinel L, Akkoç T, Cinel I. Immunomodulatory and Tissue-preserving Effects of Human Dental Follicle Stem Cells in a Rat Cecal Ligation and Perforation Sepsis Model. Arch Med Res 2020; 51:397-405. [PMID: 32334851 DOI: 10.1016/j.arcmed.2020.04.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 03/19/2020] [Accepted: 04/10/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mesenchymal stem cells may be used for the treatment of sepsis. Dental follicle stem cells (DFSCs) are easily accessible but have not been studied in vivo or in clinical trials in sepsis models. AIM OF THE STUDY We aim to elucidate DFSC effects on host immunological functions in a rat cecal ligation and perforation (CLP) sepsis model. METHODS Adult male rats were categorized into group 1 (sham procedure SP), group 2 (SP + 1 × 106 DFSCs administered 0 h after SP), group 3 (CLP + saline), group 4 (CLP + 1 × 106 DFSCs administered 0 h after CLP), and group 5 (CLP + 1 × 106 DFSCs administered 4 h after CLP). Green fluorescent protein-labeled cells were used for imaging. Histopathological examination of ileal tissues was performed. RESULTS A significant increase in the percentage of CD4+/CD25+/Foxp3+ Treg cells in groups 4 and 5 occurred compared with that in group 3. No significant changes in CD3+/CD4+ helper T-cells and CD3+/CD8+ cytotoxic T-cells were observed. Treatment with DFSCs at 4 h significantly decreased the level of TNF-α compared with that in group 3. No significant changes in IL-10 levels and lymphocyte proliferation suppression were observed. During histopathological examination, no high scoring (Chiu scores: 3 or 4) rats were observed in the curative treatment group (group 5). CONCLUSIONS Treatment with DFSC after 4 h of sepsis induction downregulates tissue inflammatory responses by decreasing TNF-α levels and increasing Treg cell ratio. This also has a protective effect on intestinal tissues during sepsis.
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Affiliation(s)
- Leyla Topcu Sarica
- Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey
| | - Noushin Zibandeh
- Department of Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Deniz Genç
- Department of Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Fethi Gül
- Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey
| | - Tolga Akkoç
- TUBITAK MRC Genetic Engineering and Biotechnology Institute, Gebze, Turkey
| | - Erdem Faruk Kombak
- Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Leyla Cinel
- Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Tunç Akkoç
- Department of Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Ismail Cinel
- Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey.
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Cao Y, Ji C, Lu L. Mesenchymal stem cell therapy for liver fibrosis/cirrhosis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:562. [PMID: 32775363 PMCID: PMC7347778 DOI: 10.21037/atm.2020.02.119] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Liver fibrosis represents a common outcome of most chronic liver diseases. Advanced fibrosis leads to cirrhosis for which no effective treatment is available except liver transplantation. Because of the limitations of liver transplantation, alternative therapeutic strategies are an urgent need to find. Recently, mesenchymal stem cells (MSCs) based therapy has been suggested as an attractive therapeutic option for liver fibrosis and cirrhosis, based on the promising results from preclinical and clinical studies. Although the precise mechanisms of MSC transplantation are still not fully understood, accumulating evidence has indicated that MSCs eliminate the progression of fibrosis due to their immune-modulatory properties. In this review, we summarise the properties of MSCs and their clinical application in the treatment of liver fibrosis and cirrhosis. We also discuss the mechanisms involved in MSC-dependent regulation of immune microenvironment in the context of liver fibrosis and cirrhosis.
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Affiliation(s)
- Yan Cao
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, China
| | - Chenbo Ji
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, China
| | - Ling Lu
- Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing 210029, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 210029, China
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Zhang S, Yang Y, Fan L, Zhang F, Li L. The clinical application of mesenchymal stem cells in liver disease: the current situation and potential future. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:565. [PMID: 32775366 PMCID: PMC7347776 DOI: 10.21037/atm.2020.03.218] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver disease is a major health issue which present poor clinical treatment performance. Cirrhosis and liver failure are common clinical manifestations of liver diseases. Liver transplantation is recognized as the ultimate and most efficient therapy to the end stage of liver disease. But it was limited by the shortage of honor organs and high cost. Nowadays, stem cell therapy gained more and more attention due to its attractive efficacy in treating liver disease especially in cirrhosis during the clinical trials. Mesenchymal stem cell (MSC) can be differentiated into hepatocytes, promote liver regeneration, inhibit liver fibrosis and induce liver apoptosis, particularly via paracrine mechanisms. This review will highlight recent clinical applications of MSC, providing the available evidence and discussing some unsolved questions in treating liver disease.
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Affiliation(s)
- Sainan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Linxiao Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Mesenchymal stem/stromal cells stably transduced with an inhibitor of CC chemokine ligand 2 ameliorate bronchopulmonary dysplasia and pulmonary hypertension. Cytotherapy 2020; 22:180-192. [PMID: 32139242 DOI: 10.1016/j.jcyt.2020.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/21/2020] [Accepted: 01/22/2020] [Indexed: 12/20/2022]
Abstract
Perinatal bronchopulmonary dysplasia (BPD) is defined as lung injury in preterm infants caused by various factors, resulting in serious respiratory dysfunction and high mortality. The administration of mesenchymal stem/stromal cells (MSCs) to treat/prevent BPD has proven to have certain therapeutic effects. However, MSCs can only weakly regulate macrophage function, which is strongly involved in the development of BPD. 7ND-MSCs are MSCs transfected with 7ND, a truncated version of CC chemokine ligand 2 (CCL2) that promotes macrophage activation, using a lentiviral vector. In the present study, we show in a BPD rat model that 7ND-MSC administration, but not MSCs alone, ameliorated the impaired alveolarization evaluated by volume density and surface area in the lung tissue, as well as pulmonary artery remodeling and pulmonary hypertension induced by BPD. In addition, 7ND-MSCs, but not MSCs alone, reduced M1 macrophages and the messenger RNA expressions of interleukin-6 and CCL2 in the lung tissue. Thus, the present study showed the treatment effect of 7ND-MSCs in a BPD rat model, which was more effective than that of MSCs alone.
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Harrell CR, Markovic BS, Fellabaum C, Arsenijevic N, Djonov V, Volarevic V. The role of Interleukin 1 receptor antagonist in mesenchymal stem cell-based tissue repair and regeneration. Biofactors 2020; 46:263-275. [PMID: 31755595 DOI: 10.1002/biof.1587] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/27/2019] [Accepted: 10/19/2019] [Indexed: 12/13/2022]
Abstract
Interleukin (IL)-1 receptor antagonist (IL-1Ra), a naturally occurring antagonist of IL-1α/IL-1β signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL-1Ra-dependent manner, suppressed production of IL-1β in dermal macrophages, induced their polarization in anti-inflammatory M2 phenotype, attenuated antigen-presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL-1β in macrophages were mainly responsible for beneficial effects of MSC-derived IL-1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL-1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL-1Ra-dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL-1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC-treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL-1Ra-dependent inhibition of IL-1α/IL-1β-signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC-derived IL-1Ra before IL-1Ra-overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.
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Affiliation(s)
| | - Bojana Simovic Markovic
- Faculty of Medical Sciences, Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia
| | | | - Nebojsa Arsenijevic
- Faculty of Medical Sciences, Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia
| | | | - Vladislav Volarevic
- Faculty of Medical Sciences, Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia
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Hu C, Wu Z, Li L. Mesenchymal stromal cells promote liver regeneration through regulation of immune cells. Int J Biol Sci 2020; 16:893-903. [PMID: 32071558 PMCID: PMC7019139 DOI: 10.7150/ijbs.39725] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023] Open
Abstract
The liver is sensitive to pathogen-induced acute or chronic liver injury, and liver transplantation (LT) is the only effective strategy for end-stage liver diseases. However, the clinical application is limited by a shortage of liver organs, immunological rejection and high cost. Mesenchymal stromal cell (MSC)-based therapy has gradually become a hot topic for promoting liver regeneration and repairing liver injury in various liver diseases, since MSCs are reported to migrate toward injured tissues, undergo hepatogenic differentiation, inhibit inflammatory factor release and enhance the proliferation of liver cells in vivo. MSCs exert immunoregulatory effects through cell-cell contact and the secretion of anti-inflammatory factors to inhibit liver inflammation and promote liver regeneration. In addition, MSCs are reported to effectively inhibit the activation of cells of the innate immune system, including macrophages, natural killer (NK) cells, dendritic cells (DCs), monocytes and other immune cells, and inhibit the activation of cells of the adaptive immune system, including T lymphocytes, B lymphocytes and subsets of T cells or B cells. In the current review, we mainly focus on the potential effects and mechanisms of MSCs in inhibiting the activation of immune cells to attenuate liver injury in models or patients with acute liver failure (ALF), nonalcoholic fatty liver disease (NAFLD), and liver fibrosis and in patients or models after LT. We highlight that MSC transplantation may replace general therapies for eliminating acute or chronic liver injury in the near future.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Zhongwen Wu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
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Development of TPGS/F127/F68 mixed polymeric micelles: Enhanced oral bioavailability and hepatoprotection of syringic acid against carbon tetrachloride-induced hepatotoxicity. Food Chem Toxicol 2020; 137:111126. [PMID: 31954714 DOI: 10.1016/j.fct.2020.111126] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 12/12/2019] [Accepted: 01/09/2020] [Indexed: 12/26/2022]
Abstract
Syringic acid (SA), a natural polyphenol found in fruits and vegetables, is claimed to show notable hepatoprotection. Nevertheless, low solubility and bioavailability hamper the application of SA. This study aimed to investigate the potential of TPGS/F127/F68 mixed polymeric micelles as a sustained and liver-targeting nanocarrier for SA. Herein, the prepared SA-loaded TPGS/F127/F68 mixed polymeric micelles (SA-TPGS-Ms) were spherically-shaped and homogeneously-distributed nanoparticles with high entrapment efficiency (94.67 ± 2.05%) and sustained release. Besides, in-vitro cell culture studies revealed that SA-TPGS-Ms substantially promoted cellular uptake with excellent biocompatibility. After oral administration, SA-TPGS-Ms demonstrated an increased bioavailability (2.3-fold) and delayed in-vivo elimination compared with the free SA. Furthermore, the alleviation of oxidative stress and amelioration of hepatic injury in CCl4-induced hepatotoxicity mice further demonstrated the excellent hepatoprotection of SA-TPGS-Ms. Collectively, SA-TPGS-Ms could be a promising nanocarrier for the utilization of SA in functional foods, with enhanced bioavailability and hepatoprotection.
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Jiang W, Xu J. Immune modulation by mesenchymal stem cells. Cell Prolif 2020; 53:e12712. [PMID: 31730279 PMCID: PMC6985662 DOI: 10.1111/cpr.12712] [Citation(s) in RCA: 380] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/11/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) can be derived from various adult tissues with multipotent and self-renewal abilities. The characteristics of presenting no major ethical concerns, having low immunogenicity and possessing immune modulation functions make MSCs promising candidates for stem cell therapies. MSCs could promote inflammation when the immune system is underactivated and restrain inflammation when the immune system is overactivated to avoid self-overattack. These cells express many immune suppressors to switch them from a pro-inflammatory phenotype to an anti-inflammatory phenotype, resulting in immune effector cell suppression and immune suppressor cell activation. We would discuss the mechanisms governing the immune modulation function of these cells in this review, especially the immune-suppressive effects of MSCs.
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Affiliation(s)
- Wei Jiang
- Guangdong Provincial Key Laboratory of Regional Immunity and DiseasesHealth Science CenterShenzhen UniversityShenzhenChina
- Department of Anatomy, Histology & Developmental BiologyHealth Science CenterShenzhen UniversityShenzhenChina
| | - Jianyong Xu
- Guangdong Provincial Key Laboratory of Regional Immunity and DiseasesHealth Science CenterShenzhen UniversityShenzhenChina
- Department of Anatomy, Histology & Developmental BiologyHealth Science CenterShenzhen UniversityShenzhenChina
- Department of ImmunologyHealth Science CenterShenzhen UniversityShenzhenChina
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Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases. Cells 2019; 8:cells8121605. [PMID: 31835680 PMCID: PMC6952783 DOI: 10.3390/cells8121605] [Citation(s) in RCA: 502] [Impact Index Per Article: 83.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/24/2019] [Accepted: 12/05/2019] [Indexed: 12/12/2022] Open
Abstract
There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.
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Harrell CR, Gazdic M, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties. Curr Stem Cell Res Ther 2019; 14:327-336. [PMID: 30806325 DOI: 10.2174/1574888x14666190222201749] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/30/2018] [Accepted: 01/23/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. OBJECTIVE In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. METHODS An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: "amniotic fluid derived mesenchymal stem cells", "cell-therapy", "degenerative diseases", "inflammatory diseases", "regeneration", "immunosuppression". Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. RESULTS AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. CONCLUSION Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.
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Affiliation(s)
- Carl R Harrell
- Regenerative Processing Plant-RPP, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, FL, United States
| | - Marina Gazdic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Crissy Fellabaum
- Regenerative Processing Plant-RPP, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, FL, United States
| | - Nemanja Jovicic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Valentin Djonov
- Institute of Anatomy University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Vladislav Volarevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
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Eleuteri S, Fierabracci A. Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications. Int J Mol Sci 2019; 20:4597. [PMID: 31533317 PMCID: PMC6770239 DOI: 10.3390/ijms20184597] [Citation(s) in RCA: 200] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/09/2019] [Accepted: 09/11/2019] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have regenerative, immunoregulatory properties and can be easily isolated and expanded in vitro. Despite being a powerful tool for clinical applications, they present limitations in terms of delivery, safety, and variability of therapeutic response. Interestingly, the MSC secretome composed by cytokines, chemokines, growth factors, proteins, and extracellular vesicles, could represent a valid alternative to their use. It is noteworthy that MSC-derived extracellular vesicles (MSC-EVs) have the same effect and could be advantageous compared to the parental cells because of their specific miRNAs load. MiRNAs could be useful both in diagnostic procedures such as "liquid biopsy" to identify early pathologies and in the therapeutic field. Not only are MSC-EVs' preservation, transfer, and production easier, but their administration is also safer, hence some clinical trials are ongoing. However, much effort is required to improve the characterization of EVs to avoid artifacts and guarantee reproducibility of the studies.
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Affiliation(s)
- Sharon Eleuteri
- Infectivology and Clinical Trials Area, Children's Hospital Bambino Gesù, Viale San Paolo 15, 00146 Rome, Italy.
| | - Alessandra Fierabracci
- Infectivology and Clinical Trials Area, Children's Hospital Bambino Gesù, Viale San Paolo 15, 00146 Rome, Italy.
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Zilberman-Itskovich S, Abu-Hamad R, Zarura R, Sova M, Hachmo Y, Stark M, Neuman S, Slavin S, Efrati S. Human mesenchymal stromal cells ameliorate complement induced inflammatory cascade and improve renal functions in a rat model of ischemia-reperfusion induced acute kidney injury. PLoS One 2019; 14:e0222354. [PMID: 31513644 PMCID: PMC6741994 DOI: 10.1371/journal.pone.0222354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 08/27/2019] [Indexed: 01/24/2023] Open
Abstract
Introduction The primary rational for using mesenchymal stromal cells (MSCs) to rejuvenate damaged tissue is mostly based on their capacity to trans-differentiate and repair injured organs. However, previous studies have demonstrated that MSCs are beneficial even at very early stages, before differentiation and proliferation can be expected. The aim of the current study was to investigate the multifaceted immunological effects of systemically administrating MSCs in the setting of acute kidney injury (AKI) induced by ischemic-reperfusion (I/R). Methods A rat model of I/R induced AKI was used. The rats underwent a unilateral nephrectomy with simultaneously clamping the contralateral kidney for 60 minutes. Four treatment groups received intravenously, increasing doses of human MSCs and after 48 hours, the rats were sacrificed. Blood was taken to evaluate renal functions and to measure systemic inflammatory markers. Kidneys were taken for histopathologic examinations and evaluations of intra-renal complement activation and inflammatory mediators. Results Renal functions improved in U shaped dose dependent manner. Mean serum creatinine levels were 4.5, 2.9, 2.6, 1.7 and 4.1 mg/dL in I/R + placebo, I/R + 150x103 cells, I/R + 250x103 cells, I/R + 500x103 cells and I/R + 1,000x103 cells respectfully (p-values<0.05). Urea demonstrated consistent results with the same U shape improvement manner. The extensive activation of the complement system was ameliorated in the MSCs treatment groups. In addition, MSCs significantly decreased intra-renal levels of IL-1β and TNF-α. It should be noted that the highest doses of MSCs induced renal hypoxia, marked by the Hypoxy-probe staining. Conclusions The early beneficial effect of MSCs in the setting of AKI may be attributed to their immunomodulatory effects. Safe treatment with MSCs can block the deleterious activation of the complement cascade and alleviate the hazardous inflammatory mediator-related cascade.
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Affiliation(s)
- Shani Zilberman-Itskovich
- Nephrology Division, Assaf-Harofeh Medical Center, Zerifin, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- * E-mail:
| | - Ramzia Abu-Hamad
- Nephrology Division, Assaf-Harofeh Medical Center, Zerifin, Israel
| | - Rina Zarura
- Nephrology Division, Assaf-Harofeh Medical Center, Zerifin, Israel
| | - Marina Sova
- Nephrology Division, Assaf-Harofeh Medical Center, Zerifin, Israel
| | - Yafit Hachmo
- Nephrology Division, Assaf-Harofeh Medical Center, Zerifin, Israel
| | - Moshe Stark
- Nephrology Division, Assaf-Harofeh Medical Center, Zerifin, Israel
| | - Sara Neuman
- Biotherapy International, The Center for Innovative Cancer Immunotherapy & Regenerative Medicine, Weizmann Center, Tel Aviv, Israel
| | - Shimon Slavin
- Biotherapy International, The Center for Innovative Cancer Immunotherapy & Regenerative Medicine, Weizmann Center, Tel Aviv, Israel
| | - Shai Efrati
- Nephrology Division, Assaf-Harofeh Medical Center, Zerifin, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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Abstract
Invariant natural killer T cells (iNKT cells) are an innate-like T cell subset that expresses an invariant T cell receptor (TCR) α-chain and recognizes lipids presented on CD1d. They secrete diverse cytokines and can influence many types of immune responses. Despite having highly similar TCR specificities, iNKT cells differentiate in the thymus into distinct subsets that are analogous to T helper 1 (TH1), TH2 and TH17 cell subsets. Additional iNKT cell subsets that may require peripheral activation have also been described, including one that produces IL-10. In general, iNKT cells are non-circulating, tissue-resident lymphocytes, but the prevalence of different iNKT cell subsets differs markedly between tissues. Here, we summarize the functions of iNKT cells in four tissues in which they are prevalent, namely, the liver, the lungs, adipose tissue and the intestine. Importantly, we explain how local iNKT cell responses at each site contribute to tissue homeostasis and protection from infection but can also contribute to tissue inflammation and damage.
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Lu D, Ma T, Zhou X, Jiang Y, Han Y, Li H. B Lymphocytes Are the Target of Mesenchymal Stem Cells Immunoregulatory Effect in a Murine Graft-versus-Host Disease Model. Cell Transplant 2019; 28:1279-1288. [PMID: 31257911 PMCID: PMC6767898 DOI: 10.1177/0963689719860127] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
There is growing clinical interest in the utilization of mesenchymal stem cells (MSCs) in the management of acute graft-versus-host disease (aGvHD), yet the effect of major histocompatibility complexes (MHCs) on B lymphocytes in this process has been less well documented. Working in an MHC fully mismatched murine aGvHD model, we found that MSC co-transfer significantly prolonged the survival time of the recipients. More interestingly, analysis on immunophenotypic profiles of posttransplant splenocytes showed that surface expression of CD69 (an early activation marker) and CD86 (a costimulatory molecule) was suppressed predominantly on donor derived B lymphocytes by MSC infusion. Additionally, mRNA level of interleukin-4, a potent B lymphocyte stimulator, was strikingly reduced from MSC-treated mice, while interleukin-10, the regulatory B lymphocytes inductor, was increased; these may underlie the lesser activation of B lymphocytes. In consistence, depletion of B lymphocytes in the transfusion inoculum further prolonged the survival time of aGvHD mice regardless of MSC administration. Therefore, B lymphocytes played an important role in the development of aGvHD, and they are targets in MSC-regulated immune response cascade in vivo. This study may provide a mechanistic clue for the treatment of human clinical aGvHD.
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Affiliation(s)
- Di Lu
- Department of Plastic and Reconstructive Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, China.,Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, China.,Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Beijing, China
| | - Tian Ma
- Department of Plastic and Reconstructive Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - XiangBin Zhou
- Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, China.,Department of Stomatology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - YanMing Jiang
- Department of Ophthalmology, Rocket Force General Hospital, Beijing, China
| | - Yan Han
- Department of Plastic and Reconstructive Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Hong Li
- Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, China.,Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Beijing, China
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