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Farag A, Hendawy H, Emam MH, Hasegawa M, Mandour AS, Tanaka R. Stem Cell Therapies in Canine Cardiology: Comparative Efficacy, Emerging Trends, and Clinical Integration. Biomolecules 2025; 15:371. [PMID: 40149907 PMCID: PMC11940628 DOI: 10.3390/biom15030371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/26/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Cardiovascular diseases are a leading cause of morbidity and mortality in dogs, with limited options available for reversing myocardial damage. Stem cell therapies have shown significant potential for cardiac repair, owing to their immunomodulatory, antifibrotic, and regenerative properties. This review evaluates the therapeutic applications of mesenchymal stem cells (MSCs) derived from bone marrow, adipose tissue, and Wharton's jelly with a focus on their role in canine cardiology and their immunoregulatory properties. Preclinical studies have highlighted their efficacy in enhancing cardiac function, reducing fibrosis, and promoting angiogenesis. Various delivery methods, including intracoronary and intramyocardial injections, are assessed for their safety and efficacy. Challenges such as low cell retention, differentiation efficiency, and variability in therapeutic responses are also discussed. Emerging strategies, including genetic modifications and combination therapies, aim to enhance the efficacy of MSCs. Additionally, advances in delivery systems and regulatory frameworks are reviewed to support clinical translation. This comprehensive evaluation underscores the potential of stem cell therapies to revolutionize canine cardiovascular disease management while identifying critical areas for future research and clinical integration.
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Affiliation(s)
- Ahmed Farag
- Faculty of Agriculture, Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Hanan Hendawy
- Department of Veterinary Surgery, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Mahmoud H. Emam
- Animal Medicine Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mizuki Hasegawa
- Faculty of Agriculture, Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
| | - Ahmed S. Mandour
- Department of Animal Medicine (Internal Medicine), Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Ryou Tanaka
- Faculty of Agriculture, Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
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Oh SJ, Nguyen TT, Seo Y, Park HJ, Ahn JS, Shin YY, Kang BJ, Jang M, Park J, Jeong JH, Kim HS. Sustained release of stem cell secretome from nano-villi chitosan microspheres for effective treatment of atopic dermatitis. Int J Biol Macromol 2024; 277:134344. [PMID: 39089545 DOI: 10.1016/j.ijbiomac.2024.134344] [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: 11/06/2023] [Revised: 07/01/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
Canine atopic dermatitis (AD) arises from hypersensitive immune reactions. AD symptoms entail severe pruritus and skin inflammation, with frequent relapses. Consequently, AD patients require continuous management, imposing financial burdens and mental fatigue on pet owners. In this study, we aimed to investigate the therapeutic relevance of secretome from canine adipose tissue-derived mesenchymal stem cells (MSCs), especially after encapsulation in nano-villi chitosan microspheres (CS-MS) to expect improved efficacy. Conditioned media (CM) from MSCs significantly inhibited the proliferation of splenocytes, induced the generation of regulatory T cells, and decreased mast cell degranulation. We found that beneficial soluble factors known to reduce AD symptoms, including transforming growth factor-beta 1, were detectable after sequential concentration and lyophilization of CM. The CS-MS, developed by a phase inversion regeneration method, showed high loading and sustained release of the secretome. Local injection of secretome-loaded CS-MS (ST/SC-MS) effectively reduced clinical severity compared to groups treated with secretome. Histological analysis revealed that ST/SC-MS potently suppressed epidermal hyperplasia, immunocyte infiltration and mast cell activation in the lesion. Taken together, this study presents a novel therapeutic approach exhibiting more potent and prolonged immunoregulatory efficacy of MSC secretome for canine AD treatment.
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Affiliation(s)
- Su-Jeong Oh
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Tiep Tien Nguyen
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea; Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Yoojin Seo
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hee-Jeong Park
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ji-Su Ahn
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ye Young Shin
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Seoul 08590, Republic of Korea
| | - Byung-Jae Kang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea; BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul, 08826, Republic of Korea
| | - Min Jang
- Department of Veterinary Surgery, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Junhyeung Park
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea.
| | - Hyung-Sik Kim
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea.
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Rusch RM, Inagaki E, Taniguchi H, Sakakura S, Tamai R, Nonaka H, Shimizu S, Sato S, Ogawa Y, Masatoshi H, Negishi K, Okano H, Shimmura S. Adipose-derived mesenchymal stromal cells: A study on safety and efficacy in ocular inflammation. Ocul Surf 2024; 34:523-534. [PMID: 39542088 DOI: 10.1016/j.jtos.2024.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/28/2024] [Accepted: 11/02/2024] [Indexed: 11/17/2024]
Abstract
PURPOSE This study explores the application of adipose-derived mesenchymal stromal cells (adMSCs) as a therapy for ocular inflammatory diseases utilizing a chronic GVHD model. METHODS Human adMSCs were administered via subconjunctival injection into mice with chronic ocular GVHD. Clinical scores and changes in T cell populations were analyzed. RESULTS The study showed significant improvement in corneal integrity, including epithelial damage, opacity, thickness, and structure, after subconjunctival adMSC transplantation. Additionally, adMSC transplantation increased CD45+ and Foxp3+ Tregs while decreasing CD4+ T cells, 1IL17A+ Th17 cells, and IFNγ+ Th1 cells in local cervical lymph nodes. Moreover, adMSC-conditioned media enhanced wound closure and cell migration toward the wound bed in vitro. The cells disappeared within a week suggesting that trophic factors were involved. CONCLUSION The dual benefit of adMSCs in immune-related ocular disorders underscores their potential for clinical application. This study focuses on subconjunctival delivery, effects of adMSCs and migration post-injection, with implications for optimizing cellular therapy application. The observed dual action, combining immunomodulation and tissue repair enhancement, underscores holistic approach of adMSC therapy in regenerative medicine, making it a potent treatment for diseases involving inflammation and tissue damage in the ocular surface.
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Affiliation(s)
- Robert M Rusch
- Department of Clinical Regenerative Medicine, Fujita Health University, Japan
| | - Emi Inagaki
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
| | - Hiroko Taniguchi
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
| | - Saki Sakakura
- Department of Clinical Regenerative Medicine, Fujita Health University, Japan
| | | | | | - Shota Shimizu
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
| | - Shinri Sato
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
| | - Hirayama Masatoshi
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
| | - Kazuno Negishi
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Japan
| | - Shigeto Shimmura
- Department of Clinical Regenerative Medicine, Fujita Health University, Japan.
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Buyl K, Merimi M, Rodrigues RM, Rahmani S, Fayyad-Kazan M, Bouhtit F, Boukhatem N, Vanhaecke T, Fahmi H, De Kock J, Najar M. The Immunological Profile of Adipose Mesenchymal Stromal/Stem Cells after Cell Expansion and Inflammatory Priming. Biomolecules 2024; 14:852. [PMID: 39062566 PMCID: PMC11275169 DOI: 10.3390/biom14070852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/28/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND AT-MSCs display great immunoregulatory features, making them potential candidates for cell-based therapy. This study aimed to evaluate the "RBC lysis buffer" isolation protocol and immunological profiling of the so-obtained AT-MSCs. METHODS We established an immune-comparative screening of AT-MSCs throughout in vitro cell expansion (PM, P1, P2, P3, P4) and inflammatory priming regarding the expression of 28 cell-surface markers, 6 cytokines/chemokines, and 10 TLR patterns. FINDINGS AT-MSCs were highly expandable and sensitive to microenvironment challenges, hereby showing plasticity in distinct expression profiles. Both cell expansion and inflammation differentially modulated the expression profile of CD34, HLA-DR, CD40, CD62L, CD200 and CD155, CD252, CD54, CD58, CD106, CD274 and CD112. Inflammation resulted in a significant increase in the expression of the cytokines IL-6, IL-8, IL-1β, IL-1Ra, CCL5, and TNFα. Depending on the culture conditions, the expression of the TLR pattern was distinctively altered with TLR1-4, TLR7, and TLR10 being increased, whereas TLR6 was downregulated. Protein network and functional enrichment analysis showed that several trophic and immune responses are likely linked to these immunological changes. CONCLUSIONS AT-MSCs may sense and actively respond to tissue challenges by modulating distinct and specific pathways to create an appropriate immuno-reparative environment. These mechanisms need to be further characterized to identify and assess a molecular target that can enhance or impede the therapeutic ability of AT-MSCs, which therefore will help improve the quality, safety, and efficacy of the therapeutic strategy.
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Affiliation(s)
- Karolien Buyl
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Makram Merimi
- LBBES Laboratory, Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco (F.B.); (N.B.)
| | - Robim M. Rodrigues
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Saida Rahmani
- LBBES Laboratory, Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco (F.B.); (N.B.)
| | - Mohammad Fayyad-Kazan
- Department of Natural and Applied Sciences, College of Arts and Sciences, The American University of Iraq-Baghdad (AUIB), Baghdad 10001, Iraq
| | - Fatima Bouhtit
- LBBES Laboratory, Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco (F.B.); (N.B.)
- Hematology Department, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium
- Laboratoire d’Hématologie, CHU Mohammed VI, Faculté de Médecine et de Pharmacie d’Oujda, University Mohammed Premier, Oujda 60000, Morocco
| | - Noureddine Boukhatem
- LBBES Laboratory, Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco (F.B.); (N.B.)
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Joery De Kock
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Mehdi Najar
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
- Faculty of Medicine, ULB721, Université Libre de Bruxelles, 1070 Brussels, Belgium
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Taheri M, Tehrani HA, Dehghani S, Alibolandi M, Arefian E, Ramezani M. Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle. Med Res Rev 2024; 44:1596-1661. [PMID: 38299924 DOI: 10.1002/med.22023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 11/28/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Dehghani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Taeb S, Rostamzadeh D, Mafi S, Mofatteh M, Zarrabi A, Hushmandi K, Safari A, Khodamoradi E, Najafi M. Update on Mesenchymal Stem Cells: A Crucial Player in Cancer Immunotherapy. Curr Mol Med 2024; 24:98-113. [PMID: 36573062 DOI: 10.2174/1566524023666221226143814] [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: 05/17/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 12/28/2022]
Abstract
The idea of cancer immunotherapy has spread, and it has made tremendous progress with the advancement of new technology. Immunotherapy, which serves to assist the natural defenses of the body in eradicating cancerous cells, is a remarkable achievement that has revolutionized both cancer research and cancer treatments. Currently, the use of stem cells in immunotherapy is widespread and shares a special characteristic, including cancer cell migration, bioactive component release, and immunosuppressive activity. In the context of cancer, mesenchymal stem cells (MSCs) are rapidly being identified as vital stromal regulators of tumor progression. MSCs therapy has been implicated in treating a wide range of diseases, including bone damage, autoimmune diseases, and particularly hematopoietic abnormalities, providing stem cell-based therapy with an extra dimension. Moreover, the implication of MSCs does not have ethical concerns, and the complications known in pluripotent and totipotent stem cells are less common in MSCs. MSCs have a lot of distinctive characteristics that, when coupled, make them excellent for cellular-based immunotherapy and as vehicles for gene and drug delivery in a variety of inflammations and malignancies. MSCs can migrate to the inflammatory site and exert immunomodulatory responses via cell-to-cell contacts with lymphocytes by generating soluble substances. In the current review, we discuss the most recent research on the immunological characteristics of MSCs, their use as immunomodulatory carriers, techniques for approving MSCs to adjust their immunological contour, and their usages as vehicles for delivering therapeutic as well as drugs and genes engineered to destroy tumor cells.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Sahar Mafi
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohammad Mofatteh
- Sir William Dunn School of Pathology, Medical Sciences Division, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom
- Lincoln College, University of Oxford, Turl Street, Oxford OX1 3DR, United Kingdom
| | - Ali Zarrabi
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Arash Safari
- Department of Radiology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ehsan Khodamoradi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Abinti M, Favi E, Alfieri CM, Zanoni F, Armelloni S, Ferraresso M, Cantaluppi V, Castellano G. Update on current and potential application of extracellular vesicles in kidney transplantation. Am J Transplant 2023; 23:1673-1693. [PMID: 37517555 DOI: 10.1016/j.ajt.2023.07.010] [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: 05/02/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/01/2023]
Abstract
Kidney transplantation (KT) is the best treatment for end-stage kidney disease. However, early diagnosis of graft injury remains challenging, mainly because of the lack of accurate and noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as is the development of innovative therapies. Many research efforts are focusing on extracellular vesicles, cellular particles free in each body fluid that have shown promising results as precise markers of damage and potential therapeutic targets in many diseases, including the renal field. In fact, through their receptors and cargo, they act in damage response and immune modulation. In transplantation, they may be used to determine organ quality and aging, the presence of delayed graft function, rejection, and many other transplant-related pathologies. Moreover, their low immunogenicity and safe profile make them ideal for drug delivery and the development of therapies to improve KT outcomes. In this review, we summarize current evidence about extracellular vesicles in KT, starting with their characteristics and major laboratory techniques for isolation and characterization. Then, we discuss their use as potential markers of damage and as therapeutic targets, discussing their promising use in clinical practice as a form of liquid biopsy.
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Affiliation(s)
- Matteo Abinti
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Evaldo Favi
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Carlo Maria Alfieri
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Francesca Zanoni
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Silvia Armelloni
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Mariano Ferraresso
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplant Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), "Maggiore della Carita" University Hospital, Novara, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
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8
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Zhu X, Ma D, Yang B, An Q, Zhao J, Gao X, Zhang L. Research progress of engineered mesenchymal stem cells and their derived exosomes and their application in autoimmune/inflammatory diseases. Stem Cell Res Ther 2023; 14:71. [PMID: 37038221 PMCID: PMC10088151 DOI: 10.1186/s13287-023-03295-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 03/22/2023] [Indexed: 04/12/2023] Open
Abstract
Autoimmune/inflammatory diseases affect many people and are an important cause of global incidence and mortality. Mesenchymal stem cells (MSCs) have low immunogenicity, immune regulation, multidifferentiation and other biological characteristics, play an important role in tissue repair and immune regulation and are widely used in the research and treatment of autoimmune/inflammatory diseases. In addition, MSCs can secrete extracellular vesicles with lipid bilayer structures under resting or activated conditions, including exosomes, microparticles and apoptotic bodies. Among them, exosomes, as the most important component of extracellular vesicles, can function as parent MSCs. Although MSCs and their exosomes have the characteristics of immune regulation and homing, engineering these cells or vesicles through various technical means, such as genetic engineering, surface modification and tissue engineering, can further improve their homing and other congenital characteristics, make them specifically target specific tissues or organs, and improve their therapeutic effect. This article reviews the advanced technology of engineering MSCs or MSC-derived exosomes and its application in some autoimmune/inflammatory diseases by searching the literature published in recent years at home and abroad.
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Affiliation(s)
- Xueqing Zhu
- School of Basic Medicine, Shanxi Medical University, Taiyuan, China
| | - Dan Ma
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Baoqi Yang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Qi An
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Jingwen Zhao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Xinnan Gao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Liyun Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China.
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Sheikholeslami A, Fazaeli H, Kalhor N, Khoshandam M, Eshagh Hoseini SJ, Sheykhhasan M. Use of Mesenchymal Stem Cells in Crohn's Disease and Perianal Fistulas: A Narrative Review. Curr Stem Cell Res Ther 2023; 18:76-92. [PMID: 34530720 DOI: 10.2174/1574888x16666210916145717] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/08/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
Crohn's Disease (CD), which usually leads to anal fistulas among patients, is the most important inflammatory bowel disease that causes morbidity in many people around the world. This review article proposes using MSCs as a hopeful therapeutic strategy for CD and anal fistula treatment in both preclinical and clinical conditions. Finally, darvadstrocel, a cell-based medication to treat complex anal fistulas in adults, as the only European Medicines Agency (EMA)-approved product for the treatment of anal fistulas in CD is addressed. Although several common therapies, such as surgery and anti-tumor necrosis factor-alpha (TNF-α) drugs as well as a combination of these methods is used to improve this disease, however, due to the low effectiveness of these treatments, the use of new strategies with higher efficiency is still recommended. Cell therapy is among the new emerging therapeutic strategies that have attracted great attention from clinicians due to its unique capabilities. One of the most widely used cell sources administrated in cell therapy is mesenchymal stem cell (MSC). This review article will discuss preclinical and clinical studies about MSCs as a potent and promising therapeutic option in the treatment of CD and anal fistula.
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Affiliation(s)
- Azar Sheikholeslami
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Hoda Fazaeli
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom,Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Mohadeseh Khoshandam
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | | | - Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
- Department of Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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10
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Eshghi F, Tahmasebi S, Alimohammadi M, Soudi S, Khaligh SG, Khosrojerdi A, Heidari N, Hashemi SM. Study of immunomodulatory effects of mesenchymal stem cell-derived exosomes in a mouse model of LPS induced systemic inflammation. Life Sci 2022; 310:120938. [PMID: 36150466 DOI: 10.1016/j.lfs.2022.120938] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/19/2022] [Accepted: 09/04/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Sepsis is a debilitating systemic inflammation that resulted from infection or injury. Despite many advances in treatment, the resulting mortality rate has remained high due to increasing antibiotic resistance and aging communities. The present study investigated the effects of stem cell-derived exosomes in a mouse model of LPS-induced systemic inflammation. MATERIALS AND METHODS To induce sepsis, the LPS model was used. Mice were divided into three groups: normal, patient group (LPS + PBS), and treatment group (LPS + exosome). The treatment group received an intravenous exosome 1 h after induction of the model. Patient and treatment groups were sacrificed at 4, 6, 24, and 48 h after induction of the model, and their tissues were isolated. Blood samples were taken from animal hearts to perform biochemical and immunological tests. The study results were analyzed using Graph Pad Prism software version 9. RESULTS Mesenchymal stem cell-derived exosomes decreased serum levels of ALT and AST liver enzymes, decreased neutrophil to lymphocyte ratio (NLR), and improved kidney, liver, and lung tissue damage at 4, 6, and 24 h after model induction. At 24 h, the exosomes were able to reduce serum urea levels. This study revealed decreased levels of inflammatory cytokines such as IL-6, IL-1β, and TNF-α after exosome injection. CONCLUSION Our findings suggest that treating mice with stem cell-derived exosomes can ameliorate the destructive effects of inflammation caused by sepsis by reducing inflammatory factors and tissue damage.
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Affiliation(s)
- Fateme Eshghi
- 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
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Arezou Khosrojerdi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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11
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Faraj JA, Al-Athari AJH, Mohie SED, Kadhim IK, Jawad NM, Abbas WJ, Jalil AT. Reprogramming the tumor microenvironment to improve the efficacy of cancer immunotherapies. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:239. [PMID: 36175691 DOI: 10.1007/s12032-022-01842-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/01/2022] [Indexed: 10/14/2022]
Abstract
The immunotherapeutic approaches based on checkpoint inhibitors, tumor vaccination, immune cell-based therapy, and cytokines were developed to engage the patient's immune system against cancer and better survival of them. While potent, however, preclinical and clinical data have identified that abnormalities in the tumor microenvironment (TME) can affect the efficacy of immunotherapies in some cancers. It is therefore imperative to develop new therapeutic interventions that will enable to overcome tumor-supportive TME and restrain anti-tumor immunity in patients that acquire resistance to current immunotherapies. Therefore, recognition of the essential nature of the tolerogenic TME may lead to a shift from the immune-suppressive TME to an immune-stimulating phenotype. Here, we review the composition of the TME and its effect on tumor immunoediting and then present how targeted monotherapy or combination therapies can be employed for reprogramming educated TME to improve current immunotherapies outcomes or elucidate potential therapeutic targets.
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Affiliation(s)
- Jabar A Faraj
- Department of Pharmacy, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq
| | | | - Sharaf El Din Mohie
- Department of Pharmacy, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq
| | - Iman Kareem Kadhim
- Department of Pharmacy, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq
| | - Noor Muhsen Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq
| | - Weaam J Abbas
- Department of Pharmacy, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq.
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12
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Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs). Int J Mol Sci 2022; 23:ijms23169274. [PMID: 36012544 PMCID: PMC9409099 DOI: 10.3390/ijms23169274] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.
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13
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Fang Y, Bouari S, Hoogduijn MJ, Ijzermans JNM, de Bruin RWF, Minnee RC. Therapeutic efficacy of extracellular vesicles to suppress allograft rejection in preclinical kidney transplantation models: A systematic review and meta-analysis. Transplant Rev (Orlando) 2022; 36:100714. [PMID: 35853384 DOI: 10.1016/j.trre.2022.100714] [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: 05/21/2022] [Revised: 07/07/2022] [Accepted: 07/10/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Kidney transplantation is the optimal treatment of end-stage renal disease. Extracellular vesicles (EVs) have tremendous therapeutic potential, but their role in modulating immune responses in kidney transplantation remains unclear. METHODS We performed a systematic review and meta-analysis to investigate the therapeutic efficacy of EVs in preclinical kidney transplant models. Outcomes for meta-analysis were graft survival and renal function. Subgroup analysis was conducted between immune cell derived EVs (immune cell-EVs) and mesenchymal stromal cell derived EVs (MSC-EVs). RESULTS Seven studies published from 2013 to 2021 were included. The overall effects showed that EVs had a positive role in prolonging allograft survival (standardized mean difference (SMD) = 2.00; 95% confidence interval (CI), 0.79 to 3.21; P < 0.01; I2 = 94%), reducing serum creatinine (SCr) (SMD = -2.19; 95%CI, -3.35 to -1.04; P < 0.01; I2 = 93%) and blood urea nitrogen (BUN) concentrations (SMD = -1.69; 95%CI, -2.98 to -0.40; P = 0.01; I2 = 94%). Subgroup analyses indicated that only immune cell-EVs significantly prolonged graft survival and improve renal function but not MSC-EVs. CONCLUSIONS EVs are promising candidates to suppress allograft rejection and improve kidney transplant outcome. Immune cell-EVs showed their superiority over MSC-EVs in prolonging graft survival and improving renal function. For interpretation of the outcomes, additional studies are needed to validate these findings.
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Affiliation(s)
- Yitian Fang
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Sarah Bouari
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Martin J Hoogduijn
- Erasmus MC Transplant Institute, Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Jan N M Ijzermans
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Ron W F de Bruin
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Robert C Minnee
- Erasmus MC Transplant Institute, Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
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14
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Parikh UM, Mentz J, Collier I, Davis MJ, Abu-Ghname A, Colchado D, Short WD, King A, Buchanan EP, Balaji S. Strategies to Minimize Surgical Scarring: Translation of Lessons Learned from Bedside to Bench and Back. Adv Wound Care (New Rochelle) 2022; 11:311-329. [PMID: 34416825 DOI: 10.1089/wound.2021.0010] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Significance: An understanding of the physiology of wound healing and scarring is necessary to minimize surgical scar formation. By reducing tension across the healing wound, eliminating excess inflammation and infection, and encouraging perfusion to healing areas, surgeons can support healing and minimize scarring. Recent Advances: Preoperatively, newer techniques focused on incision placement to minimize tension, skin sterilization to minimize infection and inflammation, and control of comorbid factors to promote a healing process with minimal scarring are constantly evolving. Intraoperatively, measures like layered closure, undermining, and tissue expansion can be taken to relieve tension across the healing wound. Appropriate suture technique and selection should be considered, and finally, there are new surgical technologies available to reduce tension across the closure. Postoperatively, the healing process can be supported as proliferation and remodeling take place within the wound. A balance of moisture control, tension reduction, and infection prevention can be achieved with dressings, ointments, and silicone. Vitamins and corticosteroids can also affect the scarring process by modulating the cellular factors involved in healing. Critical Issues: Healing with no or minimal scarring is the ultimate goal of wound healing research. Understanding how mechanical tension, inflammation and infection, and perfusion and hypoxia impact profibrotic pathways allows for the development of therapies that can modulate cytokine response and the wound extracellular microenvironment to reduce fibrosis and scarring. Future Directions: New tension-off loading topical treatments, laser, and dermabrasion devices are under development, and small molecule therapeutics have demonstrated scarless wound healing in animal models, providing a promising new direction for future research aimed to minimize surgical scarring.
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Affiliation(s)
- Umang M. Parikh
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - James Mentz
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Ian Collier
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Matthew J. Davis
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Amjed Abu-Ghname
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Daniel Colchado
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Walker D. Short
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Alice King
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Edward P. Buchanan
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Swathi Balaji
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
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15
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Behm C, Zhao Z, Andrukhov O. Immunomodulatory Activities of Periodontal Ligament Stem Cells in Orthodontic Forces-Induced Inflammatory Processes: Current Views and Future Perspectives. FRONTIERS IN ORAL HEALTH 2022; 3:877348. [PMID: 35601817 PMCID: PMC9114308 DOI: 10.3389/froh.2022.877348] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/13/2022] [Indexed: 12/25/2022] Open
Abstract
Orthodontic tooth movement (OTM) is induced by applying active mechanical forces, causing a local non-infectious inflammatory response in the periodontal ligament (PDL). As a prerequisite for OTM, the inflammation status is associated with increased levels of various cytokines and involves the interaction between immune cells and periodontal ligament stem cells (hPDLSCs). It is well established that hPDLSCs respond to orthodontic forces in several ways, such as by secreting multiple inflammatory factors. Another essential feature of hPDLSCs is their immunomodulatory activities, which are executed through cytokine (e.g., TNF-α and IL-1β)-induced production of various soluble immunomediators (e.g., indoleamine-2,3-dioxygenase-1, tumor necrosis factor-inducible gene 6 protein, prostaglandin E2) and direct cell-to-cell contact (e.g., programmed cell death ligand 1, programmed cell death ligand 2). It is well known that these immunomodulatory abilities are essential for local periodontal tissue homeostasis and regeneration. So far, only a handful of studies provides first hints that hPDLSCs change immunological processes during OTM via their immunomodulatory activities. These studies demonstrate the pro-inflammatory aspect of immunomodulation by hPDLSCs. However, no studies exist which investigate cytokine and cell-to-cell contact mediated immunomodulatory activities of hPDLSCs. In this perspective article, we will discuss the potential role of the immunomodulatory potential of hPDLSCs in establishing and resolving the OTM-associated non-infectious inflammation and hence its potential impact on periodontal tissue homeostasis during OTM.
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Affiliation(s)
- Christian Behm
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
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16
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Combination of stem cell therapy and acupuncture to treat ischemic stroke: a prospective review. Stem Cell Res Ther 2022; 13:87. [PMID: 35241146 PMCID: PMC8896103 DOI: 10.1186/s13287-022-02761-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 01/17/2022] [Indexed: 12/03/2022] Open
Abstract
Stroke is the second leading cause globally that leads to severe disability and death. Stem cell therapy has been developed over the recent years to treat stroke and diminish the mortality and disability rate of brain injuries. Acupuncture, which can activate endogenous recovery via physical stimuli, has been applied to enhance the recovery and rehabilitation of stroke patients. Attempts have been made to combine stem cell therapy and acupuncture to treat stroke patients and have shown the promising results. This prospective review will look into the possible mechanisms of stem cell therapy and acupuncture and intend to undercover the potential benefit of the combined therapy. It intends to bridge the modern emerging stem cell therapy and traditional acupuncture at cellular and molecular levels and to demonstrate the potential benefit to improve clinical outcomes.
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17
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Henriques-Pons A, Beghini DG, Silva VDS, Iwao Horita S, da Silva FAB. Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration. Front Immunol 2022; 12:780900. [PMID: 35095855 PMCID: PMC8793136 DOI: 10.3389/fimmu.2021.780900] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/17/2021] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the "cytokine storm" observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.
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Affiliation(s)
- Andrea Henriques-Pons
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
| | - Daniela Gois Beghini
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
| | | | - Samuel Iwao Horita
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
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18
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Najar M, Melki R, Khalife F, Lagneaux L, Bouhtit F, Moussa Agha D, Fahmi H, Lewalle P, Fayyad-Kazan M, Merimi M. Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization. Front Cell Dev Biol 2022; 9:716853. [PMID: 35096805 PMCID: PMC8795900 DOI: 10.3389/fcell.2021.716853] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022] Open
Abstract
Cellular therapy aims to replace damaged resident cells by restoring cellular and molecular environments suitable for tissue repair and regeneration. Among several candidates, mesenchymal stem/stromal cells (MSCs) represent a critical component of stromal niches known to be involved in tissue homeostasis. In vitro, MSCs appear as fibroblast-like plastic adherent cells regardless of the tissue source. The therapeutic value of MSCs is being explored in several conditions, including immunological, inflammatory and degenerative diseases, as well as cancer. An improved understanding of their origin and function would facilitate their clinical use. The stemness of MSCs is still debated and requires further study. Several terms have been used to designate MSCs, although consensual nomenclature has yet to be determined. The presence of distinct markers may facilitate the identification and isolation of specific subpopulations of MSCs. Regarding their therapeutic properties, the mechanisms underlying their immune and trophic effects imply the secretion of various mediators rather than direct cellular contact. These mediators can be packaged in extracellular vesicles, thus paving the way to exploit therapeutic cell-free products derived from MSCs. Of importance, the function of MSCs and their secretome are significantly sensitive to their environment. Several features, such as culture conditions, delivery method, therapeutic dose and the immunobiology of MSCs, may influence their clinical outcomes. In this review, we will summarize recent findings related to MSC properties. We will also discuss the main preclinical and clinical challenges that may influence the therapeutic value of MSCs and discuss some optimization strategies.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Rahma Melki
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Ferial Khalife
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Fatima Bouhtit
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Douaa Moussa Agha
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Mohammad Fayyad-Kazan
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Hadath, Lebanon
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Lebanon
| | - Makram Merimi
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
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Miao J, Ren Z, Zhong Z, Yan L, Xia X, Wang J, Yang J. Mesenchymal Stem Cells: Potential Therapeutic Prospect of Paracrine Pathways in Neonatal Infection. J Interferon Cytokine Res 2021; 41:365-374. [PMID: 34672801 DOI: 10.1089/jir.2021.0094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Infection is the leading cause of admission and mortality in neonatal intensive care units. Immature immune function and antibiotic resistance make the treatment more difficult. However, there is no effective prevention for it. Recently, more and more researches are focusing on stem cell therapy, especially mesenchymal stem cells (MSCs); their potential paracrine effect confer MSCs with a major advantage to treat the immune and inflammatory disorders associated with neonatal infection. In this review, we summarize the basal properties and preclinical evidence of MSCs and explore the potential mechanisms of paracrine factors of MSCs for neonatal infection.
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Affiliation(s)
- Jiayu Miao
- Department of Pediatrics, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Zhuxiao Ren
- Department of Neonatology, and Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Zhicheng Zhong
- Department of Prenatal Diagnosis Center, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Longli Yan
- Department of Neonatology, and Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xin Xia
- Department of Neonatology, and Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Jianlan Wang
- Department of Neonatology, and Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Jie Yang
- Department of Neonatology, and Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
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Mesenchymal Stem Cells in the Treatment of COVID-19, a Promising Future. Cells 2021; 10:cells10102588. [PMID: 34685567 PMCID: PMC8533906 DOI: 10.3390/cells10102588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/11/2021] [Accepted: 09/17/2021] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells’ differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.
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Inhibition of Allogeneic and Autologous T Cell Proliferation by Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients. Stem Cells Int 2021; 2021:6637328. [PMID: 33777148 PMCID: PMC7979299 DOI: 10.1155/2021/6637328] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/17/2021] [Accepted: 02/15/2021] [Indexed: 01/14/2023] Open
Abstract
Background In ankylosing spondylitis (AS), accompanied by chronic inflammation, T cell expansion plays a pathogenic role; the immunoregulatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) are impaired, while functional characteristics of their adipose tissue-derived counterparts are (ASCs) unknown. Methods We evaluated the antiproliferative activity of AS/ASCs, obtained from 20 patients, towards allogeneic and autologous T lymphocytes, using ASCs from healthy donors (HD/ASCs) as the reference cell lines. The PHA-activated peripheral blood mononuclear cells (PBMCs) were cocultured in cell-cell contact and transwell conditions with untreated or TNF + IFNγ- (TI-) licensed ASCs, then analyzed by flow cytometry to identify proliferating and nonproliferating CD4+ and CD8+ T cells. The concentrations of kynurenines, prostaglandin E2 (PGE2), and IL-10 were measured in culture supernatants. Results In an allogeneic system, HD/ASCs and AS/ASCs similarly decreased the proliferation of CD4+ and CD8+ T cells and acted mainly via soluble factors. The concentrations of kynurenines and PGE2 inversely correlated with T cell proliferation, and selective inhibitors of these factors synthesis significantly restored T cell response. AS/ASCs exerted a similar antiproliferative impact also on autologous T cells. Conclusion We report for the first time that despite chronic in vivo exposure to inflammatory conditions, AS/ASCs retain the normal capability to restrain expansion of allogeneic and autologous CD4+ and CD8+ T cells, act primarily via kynurenines and PGE2, and thus may have potential therapeutic value. Some distinctions between the antiproliferative effects of AS/ASCs and HD/ASCs suggest in vivo licensing of AS/ASCs.
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Tootee A, Nikbin B, Ghahary A, Esfahani EN, Arjmand B, Aghayan H, Qorbani M, Larijani B. Immunopathology of Type 1 Diabetes and Immunomodulatory Effects of Stem Cells: A Narrative Review of the Literature. Endocr Metab Immune Disord Drug Targets 2021; 22:169-197. [PMID: 33538679 DOI: 10.2174/1871530321666210203212809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/11/2020] [Accepted: 10/27/2020] [Indexed: 11/22/2022]
Abstract
Type 1 Diabetes (T1D) is a complex autoimmune disorder which occurs as a result of an intricate series of pathologic interactions between pancreatic β-cells and a wide range of components of both the innate and the adaptive immune systems. Stem-cell therapy, a recently-emerged potentially therapeutic option for curative treatment of diabetes, is demonstrated to cause significant alternations to both different immune cells such as macrophages, natural killer (NK) cells, dendritic cells, T cells, and B cells and non-cellular elements including serum cytokines and different components of the complement system. Although there exists overwhelming evidence indicating that the documented therapeutic effects of stem cells on patients with T1D is primarily due to their potential for immune regulation rather than pancreatic tissue regeneration, to date, the precise underlying mechanisms remain obscure. On the other hand, immune-mediated rejection of stem cells remains one of the main obstacles to regenerative medicine. Moreover, the consequences of efferocytosis of stem-cells by the recipients' lung-resident macrophages have recently emerged as a responsible mechanism for some immune-mediated therapeutic effects of stem-cells. This review focuses on the nature of the interactions amongst different compartments of the immune systems which are involved in the pathogenesis of T1D and provides explanation as to how stem cell-based interventions can influence immune system and maintain the physiologic equilibrium.
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Affiliation(s)
- Ali Tootee
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Behrouz Nikbin
- Research Center of Molecular Immunology, Tehran University of Medical Sciences, Tehran, . Iran
| | - Aziz Ghahary
- British Columbia Professional Firefighters' Burn and Wound Healing Research Laboratory, Department of Surgery, Plastic Surgery, University of British Columbia, Vancouver, . Canada
| | - Ensieh Nasli Esfahani
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Babak Arjmand
- Cell therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Hamidreza Aghayan
- Cell therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Mostafa Qorbani
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, . Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
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Barati S, Tahmasebi F, Faghihi F. Effects of mesenchymal stem cells transplantation on multiple sclerosis patients. Neuropeptides 2020; 84:102095. [PMID: 33059244 DOI: 10.1016/j.npep.2020.102095] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 09/12/2020] [Accepted: 09/13/2020] [Indexed: 02/06/2023]
Abstract
Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) with symptoms such as neuroinflammation and axonal degeneration. Existing drugs help reduce inflammatory conditions and protect CNS from demyelination and axonal damage; however, these drugs are unable to enhance axonal repair and remyelination. In this regard, cell therapy is considered as a promising regenerative approach to MS treatment. High immunomodulatory capacity, neuro-differentiation and neuroprotection properties have made Mesenchymal Stem Cells (MSCs) particularly useful for regenerative medicine. There are scant studies on the role of MSCs in patients suffering from MS. The low number of MS patients and the lack of control groups in these studies may explain the lack of beneficial effects of MSC transplantation in cell therapies. In this review, we evaluated the beneficial effects of MSC transplantation in clinical studies in terms of immunomodulatory, remyelinating and neuroprotecting properties of MSCs.
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Affiliation(s)
- Shirin Barati
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Tahmasebi
- Department of Anatomy, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faeze Faghihi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Padnahad Co.Ltd, Tehran, Iran.
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Bajetto A, Thellung S, Dellacasagrande I, Pagano A, Barbieri F, Florio T. Cross talk between mesenchymal and glioblastoma stem cells: Communication beyond controversies. Stem Cells Transl Med 2020; 9:1310-1330. [PMID: 32543030 PMCID: PMC7581451 DOI: 10.1002/sctm.20-0161] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) can be isolated from bone marrow or other adult tissues (adipose tissue, dental pulp, amniotic fluid, and umbilical cord). In vitro, MSCs grow as adherent cells, display fibroblast-like morphology, and self-renew, undergoing specific mesodermal differentiation. High heterogeneity of MSCs from different origin, and differences in preparation techniques, make difficult to uniform their functional properties for therapeutic purposes. Immunomodulatory, migratory, and differentiation ability, fueled clinical MSC application in regenerative medicine, whereas beneficial effects are currently mainly ascribed to their secretome and extracellular vesicles. MSC translational potential in cancer therapy exploits putative anti-tumor activity and inherent tropism toward tumor sites to deliver cytotoxic drugs. However, controversial results emerged evaluating either the therapeutic potential or homing efficiency of MSCs, as both antitumor and protumor effects were reported. Glioblastoma (GBM) is the most malignant brain tumor and its development and aggressive nature is sustained by cancer stem cells (CSCs) and the identification of effective therapeutic is required. MSC dualistic action, tumor-promoting or tumor-targeting, is dependent on secreted factors and extracellular vesicles driving a complex cross talk between MSCs and GBM CSCs. Tumor-tropic ability of MSCs, besides providing an alternative therapeutic approach, could represent a tool to understand the biology of GBM CSCs and related paracrine mechanisms, underpinning MSC-GBM interactions. In this review, recent findings on the complex nature of MSCs will be highlighted, focusing on their elusive impact on GBM progression and aggressiveness by direct cell-cell interaction and via secretome, also facing the perspectives and challenges in treatment strategies.
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Affiliation(s)
- Adriana Bajetto
- Dipartimento di Medicina InternaUniversità di GenovaGenovaItaly
| | | | | | - Aldo Pagano
- Dipartimento di Medicina SperimentaleUniversità di GenovaGenovaItaly
- IRCCS Ospedale Policlinico San MartinoGenovaItaly
| | | | - Tullio Florio
- Dipartimento di Medicina InternaUniversità di GenovaGenovaItaly
- IRCCS Ospedale Policlinico San MartinoGenovaItaly
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25
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Çetin İ, Topçul M. Can mesenchymal stem cells be used to treat COVID-19-induced pneumonia? (Review). Biomed Rep 2020; 13:62. [PMID: 33194191 DOI: 10.3892/br.2020.1369] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 09/08/2020] [Indexed: 12/13/2022] Open
Abstract
The novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which has resulted in the COVID-19 pandemic, infection by which is commonly characterized by a sore throat, fever and cough, was first reported in Wuhan, China on 31st December 2019. This novel disease is mild in certain individuals, usually younger healthy individuals, whereas the elder and those with underlying health conditions develop severe symptoms and may die as a result of the disease or associated complications. Along with pneumonia, hypercytokinemia, also termed a cytokine storm, is one of the most common pathologies observed in patients with COVID-19. As patients react to the infection with the virus differently; in certain individuals, a cytokine storm may result in death. At present, there is no cure or widely available vaccine for the novel coronavirus. However, it has been hypothesized that mesenchymal stem cells may assist in the treatment/management of the cytokine storm due to their immunomodulating properties.
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Affiliation(s)
- İdil Çetin
- Department of Biology, Faculty of Science, Istanbul University, Istanbul 34459, Turkey
| | - Mehmet Topçul
- Department of Biology, Faculty of Science, Istanbul University, Istanbul 34459, Turkey
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26
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Wesch D, Kabelitz D, Oberg HH. Tumor resistance mechanisms and their consequences on γδ T cell activation. Immunol Rev 2020; 298:84-98. [PMID: 33048357 DOI: 10.1111/imr.12925] [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: 08/03/2020] [Revised: 08/28/2020] [Accepted: 09/03/2020] [Indexed: 12/22/2022]
Abstract
Human γδ T lymphocytes are predominated by two major subsets, defined by the variable domain of the δ chain. Both, Vδ1 and Vδ2 T cells infiltrate in tumors and have been implicated in cancer immunosurveillance. Since the localization and distribution of tumor-infiltrating γδ T cell subsets and their impact on survival of cancer patients are not completely defined, this review summarizes the current knowledge about this issue. Different intrinsic tumor resistance mechanisms and immunosuppressive molecules of immune cells in the tumor microenvironment have been reported to negatively influence functional properties of γδ T cell subsets. Here, we focus on selected tumor resistance mechanisms including overexpression of cyclooxygenase (COX)-2 and indolamine-2,3-dioxygenase (IDO)-1/2, regulation by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-R4 pathway and the release of galectins. These inhibitory mechanisms play important roles in the cross-talk of γδ T cell subsets and tumor cells, thereby influencing cytotoxicity or proliferation of γδ T cells and limiting a successful γδ T cell-based immunotherapy. Possible future directions of a combined therapy of adoptively transferred γδ T cells together with γδ-targeting bispecific T cell engagers and COX-2 or IDO-1/2 inhibitors or targeting sialoglycan-Siglec pathways will be discussed and considered as attractive therapeutic options to overcome the immunosuppressive tumor microenvironment.
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Affiliation(s)
- Daniela Wesch
- Institute of Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Dieter Kabelitz
- Institute of Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Hans-Heinrich Oberg
- Institute of Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
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Shahir M, Mahmoud Hashemi S, Asadirad A, Varahram M, Kazempour‐Dizaji M, Folkerts G, Garssen J, Adcock I, Mortaz E. Effect of mesenchymal stem cell-derived exosomes on the induction of mouse tolerogenic dendritic cells. J Cell Physiol 2020; 235:7043-7055. [PMID: 32043593 PMCID: PMC7496360 DOI: 10.1002/jcp.29601] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022]
Abstract
Dendritic cells (DCs) orchestrate innate inflammatory responses and adaptive immunity through T-cell activation via direct cell-cell interactions and/or cytokine production. Tolerogenic DCs (tolDCs) help maintain immunological tolerance through the induction of T-cell unresponsiveness or apoptosis, and generation of regulatory T cells. Mesenchymal stromal cells (MSCs) are adult multipotent cells located within the stroma of bone marrow (BM), but they can be isolated from virtually all organs. Extracellular vesicles and exosomes are released from inflammatory cells and act as messengers enabling communication between cells. To investigate the effects of MSC-derived exosomes on the induction of mouse tolDCs, murine adipose-derived MSCs were isolated from C57BL/6 mice and exosomes isolated by ExoQuick-TC kits. BM-derived DCs (BMDCs) were prepared and cocultured with MSCs-derived exosomes (100 μg/ml) for 72 hr. Mature BMDCs were derived by adding lipopolysaccharide (LPS; 0.1μg/ml) at Day 8 for 24 hr. The study groups were divided into (a) immature DC (iDC, Ctrl), (b) iDC + exosome (Exo), (c) iDC + LPS (LPS), and (d) iDC + exosome + LPS (EXO + LPS). Expression of CD11c, CD83, CD86, CD40, and MHCII on DCs was analyzed at Day 9. DC proliferation was assessed by coculture with carboxyfluorescein succinimidyl ester-labeled BALB/C-derived splenocytes p. Interleukin-6 (IL-6), IL-10, and transforming growth factor-β (TGF-β) release were measured by enzyme-linked immunosorbent assay. MSC-derived exosomes decrease DC surface marker expression in cells treated with LPS, compared with control cells ( ≤ .05). MSC-derived exosomes decrease IL-6 release but augment IL-10 and TGF-β release (p ≤ .05). Lymphocyte proliferation was decreased (p ≤ .05) in the presence of DCs treated with MSC-derived exosomes. CMSC-derived exosomes suppress the maturation of BMDCs, suggesting that they may be important modulators of DC-induced immune responses.
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Affiliation(s)
- Mehri Shahir
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Ali Asadirad
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Mohammad Varahram
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD)Shahid Beheshti University of Medical SciencesTehranIran
| | - Mehdi Kazempour‐Dizaji
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD)Shahid Beheshti University of Medical SciencesTehranIran
| | - Gert Folkerts
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
| | - Johan Garssen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
- Immunology Platform for Specialized NutritionDanone Nutricia ResearchUtrechtThe Netherlands
| | - Ian Adcock
- Experimental Studies and Cell and Molecular Biology, Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research UnitRoyal Brompton HospitalLondonUK
- Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research InstituteUniversity of NewcastleNewcastleNew South WalesAustralia
| | - Esmaeil Mortaz
- Department of Immunology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
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Bedoui Y, Lebeau G, Guillot X, Dargai F, Guiraud P, Neal JW, Ralandison S, Gasque P. Emerging Roles of Perivascular Mesenchymal Stem Cells in Synovial Joint Inflammation. J Neuroimmune Pharmacol 2020; 15:838-851. [PMID: 32964324 DOI: 10.1007/s11481-020-09958-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/10/2020] [Indexed: 02/06/2023]
Abstract
In contrast to the significant advances in our understanding of the mesenchymal stem cell (MSC) populations in bone marrow (BM), little is known about the MSCs that are resident in the synovial joint and their possible roles in the tissue homeostasis, chronic inflammation as well as in repair. Neural crest is a transient embryonic structure, generating multipotential MSC capable of migrating along peripheral nerves and blood vessels to colonize most tissue types. In adult, these MSC can provide functional stromal support as a stem cell niche for lymphocyte progenitors for instance in the BM and the thymus. Critically, MSC have major immunoregulatory activities to control adverse inflammation and infection. These MSC will remain associated to vessels (perivascular (p) MSC) and their unique expression of markers such as myelin P0 and transcription factors (e.g. Gli1 and FoxD1) has been instrumental to develop transgenic mice to trace the fate of these cells in health and disease conditions. Intriguingly, recent investigations of chronic inflammatory diseases argue for an emerging role of pMSC in several pathological processes. In response to tissue injuries and with the release of host cell debris (e.g. alarmins), pMSC can detach from vessels and proliferate to give rise to either lipofibroblasts, osteoblasts involved in the ossification of arteries and myofibroblasts contributing to fibrosis. This review will discuss currently available data that suggest a role of pMSC in tissue homeostasis and pathogenesis of the synovial tissue and joints. Graphical abstract.
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Affiliation(s)
- Yosra Bedoui
- Unité de recherche EPI (Etudes Pharmacoimmunologiques), Université de la Réunion, 97400, St Denis, La Réunion, France
| | - Grégorie Lebeau
- Unité de recherche EPI (Etudes Pharmacoimmunologiques), Université de la Réunion, 97400, St Denis, La Réunion, France
| | - Xavier Guillot
- Service de Rhumatologie, CHU Bellepierre, Felix Guyon et Unité de recherche EPI, 97400, St Denis, La Réunion, France
| | - Farouk Dargai
- Chirurgie orthopédique et traumatologie, CHU Bellepierre, Felix Guyon, St Denis, La Réunion, France
| | - Pascale Guiraud
- Unité de recherche EPI (Etudes Pharmacoimmunologiques), Université de la Réunion, 97400, St Denis, La Réunion, France
| | - Jim W Neal
- Infection and Immunity, Henry Wellcome Building, Cardiff University, Cardiff, CF14 4XN, UK
| | - Stéphane Ralandison
- Service de Rhumatologie- Médecine Interne, CHU Morafeno, Toamasina, Madagascar
| | - Philippe Gasque
- Unité de recherche EPI (Etudes Pharmacoimmunologiques), Université de la Réunion, 97400, St Denis, La Réunion, France. .,Pôle de Biologie, Laboratoire d'Immunologique Clinique et expérimentale ZOI, LICE-OI, CHU Bellepierre, Felix Guyon, St Denis, La Réunion, France.
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de Oliveira Ramos F, Malard PF, Brunel HDSS, Paludo GR, de Castro MB, da Silva PHS, da Cunha Barreto-Vianna AR. Canine atopic dermatitis attenuated by mesenchymal stem cells. J Adv Vet Anim Res 2020; 7:554-565. [PMID: 33005683 PMCID: PMC7521806 DOI: 10.5455/javar.2020.g453] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 11/23/2022] Open
Abstract
Objective: To evaluate the use of mesenchymal stem cells (MSCs) in the attenuation of canine atopic dermatitis (AD). Materials and methods: Sixteen dogs were selected and divided into three groups, mild, moderate, and severe, according to the Canine Atopic Dermatitis Extent and Severity Index (CADESI-4). They were evaluated for 82 days. The protocol recommended in this experiment was to inject 2 × 106/kg bodyweight of MSC’s in all groups by the intravenous route with intervals of applications of 21 days. The degree of pruritus was evaluated by examining the visual analog scale, the CADESI-4, the histopathology of the skin, hematological and biochemical parameters, the pyogenic effect of MSCs, and the thickness of the epidermis. Results: There was a significant difference in the reduction of epidermal thickness in the moderate and severe groups. Hematological, biochemical, and body temperature parameters remained within normal limits for the species with no side effects Conclusion: MSCs attenuated the clinical signs of AD.
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Affiliation(s)
| | | | | | - Giane Regina Paludo
- Faculty of Agronomy and Veterinary Medicine, University of Brasilia, Brasilia, Brazil
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Wang JH, Liu XL, Sun JM, Yang JH, Xu DH, Yan SS. Role of mesenchymal stem cell derived extracellular vesicles in autoimmunity: A systematic review. World J Stem Cells 2020; 12:879-896. [PMID: 32952864 PMCID: PMC7477661 DOI: 10.4252/wjsc.v12.i8.879] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 07/02/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been reported to possess immune regulatory effects in innate and adaptive immune reactions. MSCs can mediate intercellular communications by releasing extracellular vesicles (EVs), which deliver functional molecules to targeted cells. MSC derived EVs (MSC-EVs) confer altering effects on many immune cells, including T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages. A large number of studies have suggested that MSC-EVs participate in regulating autoimmunity related diseases. This characteristic of MSC-EVs makes them be potential biomarkers for the diagnosis and treatment of autoimmunity related diseases.
AIM To verify the potential of MSC-EVs for molecular targeted therapy of autoimmunity related diseases.
METHODS Literature search was conducted in PubMed to retrieve the articles published between 2010 and 2020 in the English language. The keywords, such as “MSCs,” “EVs,” “exosome,” “autoimmunity,” “tumor immunity,” and “transplantation immunity,” and Boolean operator “AND” and “NOT” coalesced admirably to be used for searching studies on the specific molecular mechanisms of MSC-EVs in many immune cell types and many autoimmunity related diseases. Studies that did not investigate the molecular mechanisms of MSC-EVs in the occurrence and development of autoimmune diseases were excluded.
RESULTS A total of 96 articles were chosen for final reference lists. After analyzing those publications, we found that it had been well documented that MSC-EVs have the ability to induce multiple immune cells, like T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages, to regulate immune responses in innate immunity and adaptive immunity. Many validated EVs-delivered molecules have been identified as key biomarkers, such as proteins, lipids, and nucleotides. Some EVs-encapsulated functional molecules can serve as promising therapeutic targets particularly for autoimmune disease.
CONCLUSION MSC-EVs play an equally important part in the differentiation, activation, and proliferation of immune cells, and they may become potential biomarkers for diagnosis and treatment of autoimmunity related diseases.
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Affiliation(s)
- Jing-Hua Wang
- Clinical Medicine College, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Xiao-Ling Liu
- Department of Emergency Medicine, Yantai Shan Hospital, Yantai 264001, Shandong Province, China
| | - Jian-Mei Sun
- Department of Chemistry, School of Applied Chemistry, Food and Drug, Weifang Engineering Vocational College, Qingzhou 262500, Shandong Province, China
| | - Jing-Han Yang
- Clinical Medicine College, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Dong-Hua Xu
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Central Laboratory of the First Affiliated Hospital, Weifang 261000, Shandong Province, China
| | - Shu-Shan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
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Park HH, Lee S, Yu Y, Yoo SM, Baek SY, Jung N, Seo KW, Kang KS. TGF-β secreted by human umbilical cord blood-derived mesenchymal stem cells ameliorates atopic dermatitis by inhibiting secretion of TNF-α and IgE. Stem Cells 2020; 38:904-916. [PMID: 32277785 DOI: 10.1002/stem.3183] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 03/03/2020] [Accepted: 03/17/2020] [Indexed: 12/20/2022]
Abstract
Human mesenchymal stem cells (MSCs) are promising therapeutics for autoimmune diseases due to their immunomodulatory effects. In particular, human umbilical cord blood-derived MSCs (hUCB-MSCs) have a prominent therapeutic effect on atopic dermatitis (AD). However, the underlying mechanism is unclear. This study investigated the role of transforming growth factor-beta (TGF-β) in the therapeutic effect of hUCB-MSCs on AD. Small interfering RNA (siRNA)-mediated depletion of TGF-β disrupted the therapeutic effect of hUCB-MSCs in a mouse model of AD by attenuating the beneficial changes in histopathology, mast cell infiltration, tumor necrosis factor-alpha (TNF-α) expression, and the serum IgE level. To confirm that hUCB-MSCs regulate secretion of TNF-α, we investigated whether they inhibit TNF-α secretion by activated LAD2 cells. Coculture with hUCB-MSCs significantly inhibited secretion of TNF-α by LAD2 cells. However, this effect was abolished by siRNA-mediated depletion of TGF-β in hUCB-MSCs. TNF-α expression in activated LAD2 cells was regulated by the extracellular signal-related kinase signaling pathway and was suppressed by TGF-β secreted from hUCB-MSCs. In addition, TGF-β secreted by hUCB-MSCs inhibited maturation of B cells. Taken together, our findings suggest that TGF-β plays a key role in the therapeutic effect of hUCB-MSCs on AD by regulating TNF-α in mast cells and maturation of B cells.
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Affiliation(s)
- Hwan Hee Park
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Yeonsil Yu
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Sae Mi Yoo
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Song Yi Baek
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Namhee Jung
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Kwang-Won Seo
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Kyung-Sun Kang
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
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Abstract
Mesenchymal stromal or stem cells (MSC) possess strong immunomodulatory properties. Due to their impressive potential to differentiate into various cell types they are capable of inducing mechanisms of tissue repair. Experimental data have demonstrated impaired MSC function in several rheumatic diseases in vitro; however, the relevance of these phenomena for the pathogenesis of rheumatic disorders has not been convincingly demonstrated. Nevertheless, allogeneic MSC transplantation (MSCT), and possibly autologous MSCT as well, could prove to be an interesting instrument for the treatment of autoimmune rheumatic diseases. The first clinical trials have demonstrated positive effects in systemic lupus erythematosus, systemic sclerosis and Sjogren's syndrome; however, questions regarding the long-term benefits and safety as well as the best source, the optimal cultivation technique and the most effective way of application of MSC are still unanswered.
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The Role of Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles (MSC-EVs) in Normal and Abnormal Hematopoiesis and Their Therapeutic Potential. J Clin Med 2020; 9:jcm9030856. [PMID: 32245055 PMCID: PMC7141498 DOI: 10.3390/jcm9030856] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/12/2020] [Accepted: 03/17/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) represent a heterogeneous cellular population responsible for the support, maintenance, and regulation of normal hematopoietic stem cells (HSCs). In many hematological malignancies, however, MSCs are deregulated and may create an inhibitory microenvironment able to induce the disease initiation and/or progression. MSCs secrete soluble factors including extracellular vesicles (EVs), which may influence the bone marrow (BM) microenvironment via paracrine mechanisms. MSC-derived EVs (MSC-EVs) may even mimic the effects of MSCs from which they originate. Therefore, MSC-EVs contribute to the BM homeostasis but may also display multiple roles in the induction and maintenance of abnormal hematopoiesis. Compared to MSCs, MSC-EVs have been considered a more promising tool for therapeutic purposes including the prevention and treatment of Graft Versus Host Disease (GVHD) following allogenic HSC transplantation (HSCT). There are, however, still unanswered questions such as the molecular and cellular mechanisms associated with the supportive effect of MSC-EVs, the impact of the isolation, purification, large-scale production, storage conditions, MSC source, and donor characteristics on MSC-EV biological effects as well as the optimal dose and safety for clinical usage. This review summarizes the role of MSC-EVs in normal and malignant hematopoiesis and their potential contribution in treating GVHD.
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Therapeutic Mesenchymal Stromal Cells for Immunotherapy and for Gene and Drug Delivery. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 16:204-224. [PMID: 32071924 PMCID: PMC7012781 DOI: 10.1016/j.omtm.2020.01.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess several fairly unique properties that, when combined, make them ideally suited for cellular-based immunotherapy and as vehicles for gene and drug delivery for a wide range of diseases and disorders. Key among these are: (1) their relative ease of isolation from a variety of tissues; (2) the ability to be expanded in culture without a loss of functionality, a property that varies to some degree with tissue source; (3) they are relatively immune-inert, perhaps obviating the need for precise donor/recipient matching; (4) they possess potent immunomodulatory functions that can be tailored by so-called licensing in vitro and in vivo; (5) the efficiency with which they can be modified with viral-based vectors; and (6) their almost uncanny ability to selectively home to damaged tissues, tumors, and metastases following systemic administration. In this review, we summarize the latest research in the immunological properties of MSCs, their use as immunomodulatory/anti-inflammatory agents, methods for licensing MSCs to customize their immunological profile, and their use as vehicles for transferring both therapeutic genes in genetic disease and drugs and genes designed to destroy tumor cells.
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35
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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: 383] [Impact Index Per Article: 76.6] [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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36
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Hu C, Li L. The immunoregulation of mesenchymal stem cells plays a critical role in improving the prognosis of liver transplantation. J Transl Med 2019; 17:412. [PMID: 31823784 PMCID: PMC6905033 DOI: 10.1186/s12967-019-02167-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 12/04/2019] [Indexed: 12/14/2022] Open
Abstract
The liver is supplied by a dual blood supply, including the portal venous system and the hepatic arterial system; thus, the liver organ is exposed to multiple gut microbial products, metabolic products, and toxins; is sensitive to extraneous pathogens; and can develop liver failure, liver cirrhosis and hepatocellular carcinoma (HCC) after short-term or long-term injury. Although liver transplantation (LT) serves as the only effective treatment for patients with end-stage liver diseases, it is not very popular because of the complications and low survival rates. Although the liver is generally termed an immune and tolerogenic organ with adaptive systems consisting of humoral immunity and cell-mediated immunity, a high rejection rate is still the main complication in patients with LT. Growing evidence has shown that mesenchymal stromal cell (MSC) transplantation could serve as an effective immunomodulatory strategy to induce tolerance in various immune-related disorders. MSCs are reported to inhibit the immune response from innate immune cells, including macrophages, dendritic cells (DCs), natural killer cells (NK cells), and natural killer T (NKT) cells, and that from adaptive immune cells, including T cells, B cells and other liver-specific immune cells, for the generation of a tolerogenic microenvironment. In this review, we summarized the relationship between LT and immunoregulation, and we focused on how to improve the effects of MSC transplantation to improve the prognosis of LT. Only after exhaustive clarification of the potential immunoregulatory mechanisms of MSCs in vitro and in vivo can we implement MSC protocols in routine clinical practice to improve LT outcome.
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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, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of 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, People's Republic of China. .,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
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37
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Ishida N, Ishiyama K, Saeki Y, Tanaka Y, Ohdan H. Cotransplantation of preactivated mesenchymal stem cells improves intraportal engraftment of islets by inhibiting liver natural killer cells in mice. Am J Transplant 2019; 19:2732-2745. [PMID: 30859713 DOI: 10.1111/ajt.15347] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 02/10/2019] [Accepted: 03/03/2019] [Indexed: 01/25/2023]
Abstract
The activation of natural killer (NK) cells in the liver inhibits engraftment of intraportally transplanted islets. We attempted to modulate the activity of NK cells by cotransplanting mesenchymal stem cells (MSCs) with islets in mice. We first investigated the ability of MSCs to secrete prostaglandin E2 , a predominant inhibitor of NK cell function, in various combinations of inflammatory cytokines. Notably, we found that prostaglandin E2 production was partially delayed in MSCs activated by inflammatory cytokines in vitro, whereas liver NK cells were activated early after islet transplant in vivo. Accordingly, preactivated MSCs, but not naive MSCs, substantially suppressed the expression of activation markers in liver NK cells after cotransplant with islets. Similarly, cotransplant with preactivated MSCs, but not naive MSCs, markedly improved the survival of islet grafts. These results highlight MSC cotransplant as an effective and clinically feasible method for enhancing engraftment efficiency.
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Affiliation(s)
- Nobuki Ishida
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kohei Ishiyama
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | - Yoshihiro Saeki
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
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38
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Regmi S, Pathak S, Kim JO, Yong CS, Jeong JH. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur J Cell Biol 2019; 98:151041. [PMID: 31023504 DOI: 10.1016/j.ejcb.2019.04.002] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/01/2019] [Accepted: 04/09/2019] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are promising alternative agents for the treatment of inflammatory disorders due to their immunomodulatory functions, and several clinical trials on MSC-based products are currently being conducted. In this review, we discuss recent progress made on the use of MSCs as immunomodulatory agents, developmental challenges posed by MSC-based therapy, and the strategies being used to overcome these challenges. In this context, current understanding of the mechanisms responsible for MSC interactions with the immune system and the molecular responses of MSCs to inflammatory signals are discussed. The immunosuppressive activities of MSCs are initiated by cell-to-cell contact and the release of immuno-regulatory molecules. By doing so, MSCs can inhibit the proliferation and function of T cells, natural killer cells, B cells, and dendritic cells, and can also increase the proliferation of regulatory T cells. However, various problems, such as low transplanted cell viability, poor homing and engraftment into injured tissues, MSC heterogeneity, and lack of adequate information on optimum MSC doses impede clinical applications. On the other hand, it has been shown that the immunomodulatory activities and viabilities of MSCs might be enhanced by 3D-cultured systems, genetic modifications, preconditioning, and targeted-delivery.
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Affiliation(s)
- Shobha Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Shiva Pathak
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
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39
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Stem Cell-Derived Extracellular Vesicles as Immunomodulatory Therapeutics. Stem Cells Int 2019; 2019:5126156. [PMID: 30936922 PMCID: PMC6413386 DOI: 10.1155/2019/5126156] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 02/05/2019] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been reported to possess regulatory functions on immune cells which make them alternative therapeutics for the treatment of inflammatory and autoimmune diseases. The interaction between MSCs and immune cells through paracrine factors might be crucial for these immunomodulatory effects of MSCs. Extracellular vesicles (EVs) are defined as bilayer membrane structures including exosomes and microvesicles which contain bioactive paracrine molecules affecting the characteristics of target cells. Recently, several studies have revealed that EVs derived from MSCs (MSC-EVs) can reproduce similar therapeutic impacts of parent MSCs; MSC-EVs could regulate proliferation, maturation, polarization, and migration of various immune effector cells and modulate the immune microenvironment depending on the context by delivering inflammatory cytokines, transcription factors, and microRNAs. Therefore, MSC-EVs can be applied as novel and promising tools for the treatment of immune-related disorders to overcome the limitations of conventional cell therapy regarding efficacy and toxicity issues. In this review, we will discuss current insights regarding the major outcomes in the evaluation of MSC-EV function against inflammatory disease models, as well as immune cells.
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40
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Marrazzo P, Crupi AN, Alviano F, Teodori L, Bonsi L. Exploring the roles of MSCs in infections: focus on bacterial diseases. J Mol Med (Berl) 2019; 97:437-450. [PMID: 30729280 DOI: 10.1007/s00109-019-01752-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 02/08/2023]
Abstract
Despite human healthcare advances, some microorganisms continuously react evolving new survival strategies, choosing between a commensal fitness and a pathogenic attitude. Many opportunistic microbes are becoming an increasing cause of clinically evident infections while several renowned infectious diseases sustain a considerable number of deaths. Besides the primary and extensively investigated role of immune cells, other cell types are involved in the microbe-host interaction during infection. Interestingly, mesenchymal stem cells (MSCs), the current leading players in cell therapy approaches, have been suggested to contribute to tackling pathogens and modulating the host immune response. In this context, this review critically explores MSCs' role in E. coli, S. aureus, and polymicrobial infections. Summarizing from various studies, in vitro and in vivo results support the mechanistic involvement of MSCs and their derivatives in fighting infection and in contributing to microbial spreading. Our work outlines the double face of MSCs during infection, disease, and sepsis, highlighting potential pitfalls in MSC-based therapy due to the MSCs' susceptibility to pathogens' weapons. We also identify potential targets to improve infection treatments, and propose the potential applications of MSCs for vaccine research.
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Affiliation(s)
- Pasquale Marrazzo
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy
| | | | - Francesco Alviano
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy.
| | - Laura Teodori
- Diagnostics and Metrology, FSN-TECFIS-DIM, Enea Frascati, Rome, Italy
| | - Laura Bonsi
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy
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41
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Bertheuil N, Chaput B, Ménard C, Varin A, Laloze J, Watier E, Tarte K. Adipose mesenchymal stromal cells: Definition, immunomodulatory properties, mechanical isolation and interest for plastic surgery. ANN CHIR PLAST ESTH 2019; 64:1-10. [DOI: 10.1016/j.anplas.2018.07.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 07/13/2018] [Indexed: 12/14/2022]
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42
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Clinical Application of Stem/Stromal Cells in COPD. STEM CELL-BASED THERAPY FOR LUNG DISEASE 2019. [PMCID: PMC7121219 DOI: 10.1007/978-3-030-29403-8_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive life-threatening disease that is significantly increasing in prevalence and is predicted to become the third leading cause of death worldwide by 2030. At present, there are no true curative treatments that can stop the progression of the disease, and new therapeutic strategies are desperately needed. Advances in cell-based therapies provide a platform for the development of new therapeutic approaches in severe lung diseases such as COPD. At present, a lot of focus is on mesenchymal stem (stromal) cell (MSC)-based therapies, mainly due to their immunomodulatory properties. Despite increasing number of preclinical studies demonstrating that systemic MSC administration can prevent or treat experimental COPD and emphysema, clinical studies have not been able to reproduce the preclinical results and to date no efficacy or significantly improved lung function or quality of life has been observed in COPD patients. Importantly, the completed appropriately conducted clinical trials uniformly demonstrate that MSC treatment in COPD patients is well tolerated and no toxicities have been observed. All clinical trials performed so far, have been phase I/II studies, underpowered for the detection of potential efficacy. There are several challenges ahead for this field such as standardized isolation and culture procedures to obtain a cell product with high quality and reproducibility, administration strategies, improvement of methods to measure outcomes, and development of potency assays. Moreover, COPD is a complex pathology with a diverse spectrum of clinical phenotypes, and therefore it is essential to develop methods to select the subpopulation of patients that is most likely to potentially respond to MSC administration. In this chapter, we will discuss the current state of the art of MSC-based cell therapy for COPD and the hurdles that need to be overcome.
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43
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Mehler VJ, Burns C, Moore ML. Concise Review: Exploring Immunomodulatory Features of Mesenchymal Stromal Cells in Humanized Mouse Models. Stem Cells 2018; 37:298-305. [PMID: 30395373 PMCID: PMC6446739 DOI: 10.1002/stem.2948] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/26/2018] [Accepted: 10/25/2018] [Indexed: 12/15/2022]
Abstract
With their immunosuppressive features, human mesenchymal stromal cells (MSCs), sometimes also termed as mesenchymal stem cells, hold great potential as a cell-based therapy for various immune-mediated diseases. Indeed, MSCs have already been approved as a treatment for graft versus host disease. However, contradictory data from clinical trials and lack of conclusive proof of efficacy hinder the progress toward wider clinical use of MSCs and highlight the need for more relevant disease models. Humanized mice are increasingly used as models to study immune-mediated disease, as they simulate human immunobiology more closely than conventional murine models. With further advances in their resemblance to human immunobiology, it is very likely that humanized mice will be used more commonly as models to investigate MSCs with regard to their therapeutic safety and their immunomodulatory effect and its underlying mechanisms. Recent studies that explore the immunosuppressive features of MSCs in humanized mouse models will be discussed in this review. Stem Cells 2019;37:298-305.
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Affiliation(s)
- Vera J Mehler
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, United Kingdom.,Division of Infection and Immunity, University College London, London, United Kingdom
| | - Chris Burns
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, United Kingdom
| | - Melanie L Moore
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, United Kingdom
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44
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Kim M, Lee SH, Kim Y, Kwon Y, Park Y, Lee HK, Jung HS, Jeoung D. Human Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Atopic Dermatitis by Regulating the Expression of MIP-2, miR-122a-SOCS1 Axis, and Th1/Th2 Responses. Front Pharmacol 2018; 9:1175. [PMID: 30459600 PMCID: PMC6232252 DOI: 10.3389/fphar.2018.01175] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 09/28/2018] [Indexed: 01/26/2023] Open
Abstract
The objective of this study was to investigate the effect of human adipose tissue-derived mesenchymal stem cells (AdMSCs) on atopic dermatitis (AD) in the BALB/c mouse model. The AdMSCs attenuated clinical symptoms associated with AD, decreased numbers of degranulated mast cells (MCs), IgE level, amount of histamine released, and prostaglandin E2 level. Atopic dermatitis increased the expression levels of cytokines/chemokines, such as interleukin-5 (IL-5), macrophage inflammatory protein-1ß (MIP-1ß), MIP-2, chemokine (C-C motif) ligand 5 (CCL5), and IL-17, in BALB/c mouse. The AdMSCs showed decreased expression levels of these cytokines in the mouse model of AD. In vivo downregulation of MIP-2 attenuated the clinical symptoms associated with AD. Atopic dermatitis increased the expression levels of hallmarks of allergic inflammation, induced interactions of Fc𝜀RIβ with histone deacetylase 3 (HDAC3) and Lyn, increased ß-hexosaminidase activity, increased serum IgE level, and increased the amount of histamine released in an MIP-2-dependent manner. Downregulation of MIP-2 increased the levels of several miRNAs, including miR-122a-5p. Mouse miR-122a-5p mimic inhibited AD, while suppressor of cytokine signaling 1 (SOCS1), a predicted downstream target of miR-122a-5p, was required for AD. The downregulation of SOCS1 decreased the expression levels of MIP-2 and chemokine (C-X-C motif) ligand 13 (CXCL13) in the mouse model of AD. The downregulation of CXCL13 attenuated AD and allergic inflammation such as passive cutaneous anaphylaxis. The role of T cell transcription factors in AD was also investigated. Atopic dermatitis increased the expression levels of T-bet and GATA-3 [transcription factors of T-helper 1 (Th1) and T-helper 2 (Th2) cells, respectively] but decreased the expression of Foxp3, a transcription factor of regulatory T (Treg) cells, in an SOCS1-dependent manner. In addition to this, miR-122a-5p mimic also prevented AD from regulating the expression of T-bet, GATA-3, and Foxp3. Atopic dermatitis increased the expression of cluster of differentiation 163 (CD163), a marker of M2 macrophages, but decreased the expression of inducible nitric oxide synthase (iNOS), a marker of M1 macrophages. Additionally, SOCS1 and miR-122a-5p mimic regulated the expression of CD163 and iNOS in the mouse model of AD. Experiments employing conditioned medium showed interactions between MCs and macrophages in AD. The conditioned medium of AdMSCs, but not the conditioned medium of human dermal fibroblasts, negatively inhibited the features of allergic inflammation. In summary, we investigated the anti-atopic effects of AdMSCs, identified targets of AdMSCs, and determined the underlying mechanism for the anti-atopic effects of AdMSCs.
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Affiliation(s)
- Misun Kim
- Department of Biochemistry, Kangwon National University, Chunchon, South Korea
| | - Sung-Hoon Lee
- Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang, South Korea
| | - Youngmi Kim
- Department of Biochemistry, Kangwon National University, Chunchon, South Korea
| | - Yoojung Kwon
- Department of Biochemistry, Kangwon National University, Chunchon, South Korea
| | - Yeongseo Park
- Department of Biochemistry, Kangwon National University, Chunchon, South Korea
| | - Hong-Ki Lee
- Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang, South Korea
| | - Hyun Suk Jung
- Department of Biochemistry, Kangwon National University, Chunchon, South Korea
| | - Dooil Jeoung
- Department of Biochemistry, Kangwon National University, Chunchon, South Korea
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45
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Allogeneic mesenchymal stromal cells for refractory luminal Crohn's disease: A phase I-II study. Dig Liver Dis 2018; 50:1251-1255. [PMID: 30195816 DOI: 10.1016/j.dld.2018.08.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/06/2018] [Accepted: 08/07/2018] [Indexed: 12/11/2022]
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46
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Shadmanfar S, Labibzadeh N, Emadedin M, Jaroughi N, Azimian V, Mardpour S, Kakroodi FA, Bolurieh T, Hosseini SE, Chehrazi M, Niknejadi M, Baharvand H, Gharibdoost F, Aghdami N. Intra-articular knee implantation of autologous bone marrow–derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: Results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy 2018; 20:499-506. [DOI: 10.1016/j.jcyt.2017.12.009] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Revised: 12/15/2017] [Accepted: 12/27/2017] [Indexed: 12/11/2022]
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47
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Shin TH, Lee BC, Choi SW, Shin JH, Kang I, Lee JY, Kim JJ, Lee HK, Jung JE, Choi YW, Lee SH, Yoon JS, Choi JS, Lee CS, Seo Y, Kim HS, Kang KS. Human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis via regulation of B lymphocyte maturation. Oncotarget 2018; 8:512-522. [PMID: 27888809 PMCID: PMC5352174 DOI: 10.18632/oncotarget.13473] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 11/12/2016] [Indexed: 01/01/2023] Open
Abstract
Mesenchymal stem cell (MSC) has been applied for the therapy of allergic disorders due to its beneficial immunomodulatory abilities. However, the underlying mechanisms for therapeutic efficacy are reported to be diverse according to the source of cell isolation or the route of administration. We sought to investigate the safety and the efficacy of human adipose tissue-derived MSCs (hAT-MSCs) in mouse atopic dermatitis (AD) model and to determine the distribution of cells after intravenous administration. Murine AD model was established by multiple treatment of Dermatophagoides farinae. AD mice were intravenously infused with hAT-MSCs and monitored for clinical symptoms. The administration of hAT-MSCs reduced the gross and histological signatures of AD, as well as serum IgE level. hAT-MSCs were mostly detected in lung and heart of mice within 3 days after administration and were hardly detectable at 2 weeks. All of mice administered with hAT-MSCs survived until sacrifice and did not demonstrate any adverse events. Co-culture experiments revealed that hAT-MSCs significantly inhibited the proliferation and the maturation of B lymphocytes via cyclooxygenase (COX)-2 signaling. Moreover, mast cell (MC) degranulation was suppressed by hAT-MSC. In conclusion, the intravenous infusion of hAT-MSCs can alleviate AD through the regulation of B cell function.
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Affiliation(s)
- Tae-Hoon Shin
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea
| | - Byung-Chul Lee
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea
| | - Soon Won Choi
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea
| | - Ji-Hee Shin
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea
| | - Insung Kang
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea
| | - Jin Young Lee
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea
| | - Jae-Jun Kim
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea
| | - Hong-Ki Lee
- Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang 16006, South Korea
| | - Jae-Eon Jung
- Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang 16006, South Korea
| | - Yong-Woon Choi
- Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang 16006, South Korea
| | - Sung-Hoon Lee
- Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang 16006, South Korea
| | - Jin-Sang Yoon
- Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang 16006, South Korea
| | - Jin-Sub Choi
- Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang 16006, South Korea
| | - Chi-Seung Lee
- School of Medicine, Pusan National University, Busan 49241, South Korea.,Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Yoojin Seo
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,School of Medicine, Pusan National University, Busan 49241, South Korea.,Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Hyung-Sik Kim
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,School of Medicine, Pusan National University, Busan 49241, South Korea.,Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Kyung-Sun Kang
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.,Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea
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48
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Krajewska-Włodarczyk M, Owczarczyk-Saczonek A, Placek W, Osowski A, Engelgardt P, Wojtkiewicz J. Role of Stem Cells in Pathophysiology and Therapy of Spondyloarthropathies-New Therapeutic Possibilities? Int J Mol Sci 2017; 19:ijms19010080. [PMID: 29283375 PMCID: PMC5796030 DOI: 10.3390/ijms19010080] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 12/23/2017] [Accepted: 12/25/2017] [Indexed: 12/14/2022] Open
Abstract
Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-α, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Although they adequately control inflammatory symptoms, they do not affect the abnormal bone formation processes associated with SpA. However, the traditional therapeutic approach does not cover the regenerative treatment of damaged tissues. In this regards, stem cells may offer a promising, safe and effective therapeutic option. The aim of this paper is to present the role of mesenchymal stromal cells (MSC) in pathogenesis of SpA and to highlight the opportunities for using stem cells in regenerative processes and in the treatment of inflammatory changes in articular structures.
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Affiliation(s)
- Magdalena Krajewska-Włodarczyk
- Department of Rheumatology, Municipal Hospital in Olsztyn, 10-900 Olsztyn, Poland.
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Agnieszka Owczarczyk-Saczonek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Waldemar Placek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Adam Osowski
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Piotr Engelgardt
- Department of Forensic Medicine, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Joanna Wojtkiewicz
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
- Laboratory for Regenerative Medicine, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
- Foundation for Nerve Cell Regeneration, University of Warmia and Mazury in Olsztyn, 10-900 Olsztyn, Poland.
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49
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Volarevic V, Gazdic M, Simovic Markovic B, Jovicic N, Djonov V, Arsenijevic N. Mesenchymal stem cell-derived factors: Immuno-modulatory effects and therapeutic potential. Biofactors 2017; 43:633-644. [PMID: 28718997 DOI: 10.1002/biof.1374] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 06/07/2017] [Accepted: 06/16/2017] [Indexed: 12/17/2022]
Abstract
Stem cell-based therapy is considered to be a new hope in transplantation medicine. Among stem cells, mesenchymal stem cells (MSCs) are, due to their differentiation and immuno-modulatory characteristics, the most commonly used as therapeutic agents in the treatment of immune-mediated diseases. MSCs migrate to the site of inflammation and modulate immune response. The capacity of MSC to alter phenotype and function of immune cells are largely due to the production of soluble factors which expression varies depending on the pathologic condition to which MSCs are exposed. Under inflammatory conditions, MSCs-derived factors suppress both innate and adaptive immunity by attenuating maturation and capacity for antigen presentation of dendritic cells, by inducing polarization of macrophages towards alternative phenotype, by inhibiting activation and proliferation of T and B lymphocytes and by reducing cytotoxicity of NK and NKT cells. In this review, we emphasized current findings regarding immuno-modulatory effects of MSC-derived factors and emphasize their potential in the therapy of immune-mediated diseases. © 2017 BioFactors, 43(5):633-644, 2017.
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Affiliation(s)
- Vladislav Volarevic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Marina Gazdic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Bojana Simovic Markovic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nemanja Jovicic
- Department of Histology and embryology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Valentin Djonov
- Department of Topographic and Clinical Anatomy, Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Nebojsa Arsenijevic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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50
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Andreeva E, Bobyleva P, Gornostaeva A, Buravkova L. Interaction of multipotent mesenchymal stromal and immune cells: Bidirectional effects. Cytotherapy 2017; 19:1152-1166. [PMID: 28823421 DOI: 10.1016/j.jcyt.2017.07.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 05/24/2017] [Accepted: 07/02/2017] [Indexed: 12/11/2022]
Abstract
Adult multipotent mesenchymal stromal cells (MSCs) are considered one of the key players in physiological remodeling and tissue reparation. Elucidation of MSC functions is one of the most intriguing issues in modern cell physiology. In the present review, the interaction of MSCs and immune cells is discussed in terms of reciprocal effects, which modifies the properties of "partner" cells with special focus on the contribution of direct cell-to-cell contacts, soluble mediators and local microenvironmental factors, the most important of which is oxygen tension. The immunosuppressive phenomenon of MSCs is considered as the integral part of the response-to-injury mechanism.
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Affiliation(s)
- Elena Andreeva
- Institute of Biomedical Problems, the Russian Academy of Sciences, Moscow, Russia
| | - Polina Bobyleva
- Institute of Biomedical Problems, the Russian Academy of Sciences, Moscow, Russia
| | | | - Ludmila Buravkova
- Institute of Biomedical Problems, the Russian Academy of Sciences, Moscow, Russia
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