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Radi NA, Habba DA, Hallool SI, Almeshari AA, Abd Elsamia HM. Evaluation of Regeneration Potential of Bone Marrow-Derived Mesenchymal Stem Cells on Induced Damaged Submandibular Salivary Gland in Mice. Eur J Dent 2025. [PMID: 40073996 DOI: 10.1055/s-0044-1791940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025] Open
Abstract
OBJECTIVES The ultimate goal of stem cell (SC) transplantation is the regeneration of salivary gland function by transplanted SCs differentiating into salivary gland cells. Therefore, this study aimed to evaluate the regenerative capacity of bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation in irradiated mice using the immunohistochemical markers Ki-67 and CD34. MATERIAL AND METHODS Four groups of male mice were included in the study. Group I (normal control) comprised six mice that were not subjected to gamma radiation. Group II comprised six irradiated mice that were not treated with BM-MSCs. Group III comprised 12 irradiated mice that were treated with intraglandular injection of labeled BM-MSCs into their submandibular salivary glands, 24 hours postradiation. Group IV comprised 12 irradiated mice that were treated with intraglandular injection of labeled BM-MSCs into their submandibular salivary glands, on day 11 postradiation. STATISTICAL ANALYSIS Data were presented as mean and standard deviation. The different groups were compared using a one-way analysis of variance (ANOVA). RESULTS The ANOVA test revealed that the difference between all groups was extremely statistically significant (p < 0.003), and Tukey's post hoc test revealed a statistically significant difference between group II and groups I, III, and IV included in the study regarding microvessel density of CD34 immunoexpression in different groups. CONCLUSION BM-MSCs have a regeneration potential on induced damaged submandibular salivary glands in mice; time is an essential factor in the regeneration capacity of BM-MSCs.
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Affiliation(s)
- Nadia Attia Radi
- Department of Oral and Dental Pathology, Faculty of Dental Medicine for Girls, Al Azhar University, Cairo, Egypt
| | - Doaa Adel Habba
- Department of Oral and Dental Pathology, Faculty of Dental Medicine for Girls, Al Azhar University, Cairo, Egypt
- Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Najran University, Kingdom of Saudi Arabia
| | - Seham Ibrahim Hallool
- Department of Oral and Dental Biology, Faculty of Dental Medicine for Girls, Al Azhar University, Cairo, Egypt
| | - Ahmed Ali Almeshari
- Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Najran University, Kingdom of Saudi Arabia
| | - Hanaa Mohamed Abd Elsamia
- Department of Oral and Maxillofacial Pathology, Faculty of Oral and Dental Surgery and Medicine, Zagazing University, Zagazing, Egypt
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Hazrati A, Mirarefin SMJ, Malekpour K, Rahimi A, Khosrojerdi A, Rasouli A, Akrami S, Soudi S. Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells. Front Immunol 2024; 15:1469696. [PMID: 39582867 PMCID: PMC11581898 DOI: 10.3389/fimmu.2024.1469696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 11/26/2024] Open
Abstract
Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Arezou Rahimi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Ashkan Rasouli
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Akrami
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Tang M, Shen L, Tang M, Liu L, Rao Z, Wang Z, Wang Y, Yin S, Li S, Xu G, Zhang K. Human mesenchymal stromal cells ameliorate cisplatin-induced acute and chronic kidney injury via TSG-6. Stem Cells 2024; 42:848-859. [PMID: 38804841 DOI: 10.1093/stmcls/sxae037] [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: 03/25/2023] [Accepted: 05/15/2024] [Indexed: 05/29/2024]
Abstract
Cisplatin is widely used in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor-α-stimulated gene/protein 6 (rhTSG-6), or PBS through the tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. Human BM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen, tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in the serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, the knockdown of the TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviates cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.
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Affiliation(s)
- Ming Tang
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Linguo Shen
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Maozhi Tang
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Ling Liu
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Zhengsheng Rao
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Zhilin Wang
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Yadi Wang
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Supei Yin
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Shujing Li
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
| | - Guilian Xu
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, People's Republic of China
| | - Keqin Zhang
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, People's Republic of China
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Agamah FE, Ederveen THA, Skelton M, Martin DP, Chimusa ER, ’t Hoen PAC. Network-based integrative multi-omics approach reveals biosignatures specific to COVID-19 disease phases. Front Mol Biosci 2024; 11:1393240. [PMID: 39040605 PMCID: PMC11260748 DOI: 10.3389/fmolb.2024.1393240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/22/2024] [Indexed: 07/24/2024] Open
Abstract
Background COVID-19 disease is characterized by a spectrum of disease phases (mild, moderate, and severe). Each disease phase is marked by changes in omics profiles with corresponding changes in the expression of features (biosignatures). However, integrative analysis of multiple omics data from different experiments across studies to investigate biosignatures at various disease phases is limited. Exploring an integrative multi-omics profile analysis through a network approach could be used to determine biosignatures associated with specific disease phases and enable the examination of the relationships between the biosignatures. Aim To identify and characterize biosignatures underlying various COVID-19 disease phases in an integrative multi-omics data analysis. Method We leveraged a multi-omics network-based approach to integrate transcriptomics, metabolomics, proteomics, and lipidomics data. The World Health Organization Ordinal Scale WHO Ordinal Scale was used as a disease severity reference to harmonize COVID-19 patient metadata across two studies with independent data. A unified COVID-19 knowledge graph was constructed by assembling a disease-specific interactome from the literature and databases. Disease-state specific omics-graphs were constructed by integrating multi-omics data with the unified COVID-19 knowledge graph. We expanded on the network layers of multiXrank, a random walk with restart on multilayer network algorithm, to explore disease state omics-specific graphs and perform enrichment analysis. Results Network analysis revealed the biosignatures involved in inducing chemokines and inflammatory responses as hubs in the severe and moderate disease phases. We observed distinct biosignatures between severe and moderate disease phases as compared to mild-moderate and mild-severe disease phases. Mild COVID-19 cases were characterized by a unique biosignature comprising C-C Motif Chemokine Ligand 4 (CCL4), and Interferon Regulatory Factor 1 (IRF1). Hepatocyte Growth Factor (HGF), Matrix Metallopeptidase 12 (MMP12), Interleukin 10 (IL10), Nuclear Factor Kappa B Subunit 1 (NFKB1), and suberoylcarnitine form hubs in the omics network that characterizes the moderate disease state. The severe cases were marked by biosignatures such as Signal Transducer and Activator of Transcription 1 (STAT1), Superoxide Dismutase 2 (SOD2), HGF, taurine, lysophosphatidylcholine, diacylglycerol, triglycerides, and sphingomyelin that characterize the disease state. Conclusion This study identified both biosignatures of different omics types enriched in disease-related pathways and their associated interactions (such as protein-protein, protein-transcript, protein-metabolite, transcript-metabolite, and lipid-lipid interactions) that are unique to mild, moderate, and severe COVID-19 disease states. These biosignatures include molecular features that underlie the observed clinical heterogeneity of COVID-19 and emphasize the need for disease-phase-specific treatment strategies. The approach implemented here can be used to find associations between transcripts, proteins, lipids, and metabolites in other diseases.
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Affiliation(s)
- Francis E. Agamah
- Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Thomas H. A. Ederveen
- Department of Medical BioSciences, Radboud University Medical Center Nijmegen, Nijmegen, Netherlands
| | - Michelle Skelton
- Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Darren P. Martin
- Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Emile R. Chimusa
- Department of Applied Science, Faculty of Health and Life Sciences, Northumbria University, Newcastle, United Kingdom
| | - Peter A. C. ’t Hoen
- Department of Medical BioSciences, Radboud University Medical Center Nijmegen, Nijmegen, Netherlands
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Lu W, Yan L, Tang X, Wang X, Du J, Zou Z, Li L, Ye J, Zhou L. Efficacy and safety of mesenchymal stem cells therapy in COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials. J Transl Med 2024; 22:550. [PMID: 38851730 PMCID: PMC11162060 DOI: 10.1186/s12967-024-05358-6] [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: 04/14/2024] [Accepted: 05/31/2024] [Indexed: 06/10/2024] Open
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19) has become a serious public health issue. In COVID-19 patients, the elevated levels of inflammatory cytokines lead to the manifestation of COVID-19 symptoms, such as lung tissue edema, lung diffusion dysfunction, acute respiratory distress syndrome (ARDS), secondary infection, and ultimately mortality. Mesenchymal stem cells (MSCs) exhibit anti-inflammatory and immunomodulatory properties, thus providing a potential treatment option for COVID-19. The number of clinical trials of MSCs for COVID-19 has been rising. However, the treatment protocols and therapeutic effects of MSCs for COVID-19 patients are inconsistent. This meta-analysis was performed to systematically determine the safety and efficacy of MSC infusion in COVID-19 patients. METHODS We conducted a comprehensive literature search from PubMed/Medline, Web of Science, EMBASE, and Cochrane Library up to 22 November 2023 to screen for eligible randomized controlled trials. Inclusion and exclusion criteria for searched literature were formulated according to the PICOS principle, followed by the use of literature quality assessment tools to assess the risk of bias. Finally, outcome measurements including therapeutic efficacy, clinical symptoms, and adverse events of each study were extracted for statistical analysis. RESULTS A total of 14 randomized controlled trials were collected. The results of enrolled studies demonstrated that patients with COVID-19 pneumonia who received MSC inoculation showed a decreased mortality compared with counterparts who received conventional treatment (RR: 0.76; 95% CI [0.60, 0.96]; p = 0.02). Reciprocally, MSC inoculation improved the clinical symptoms in patients (RR: 1.28; 95% CI [1.06, 1.55]; p = 0.009). In terms of immune biomarkers, MSC treatment inhibited inflammation responses in COVID-19 patients, as was indicated by the decreased levels of CRP and IL-6. Importantly, our results showed that no significant differences in the incidence of adverse reactions or serious adverse events were monitored in patients after MSC inoculation. CONCLUSION This meta-analysis demonstrated that MSC inoculation is effective and safe in the treatment of patients with COVID-19 pneumonia. Without increasing the incidence of adverse events or serious adverse events, MSC treatment decreased patient mortality and inflammatory levels and improved the clinical symptoms in COVID-19 patients. However, large-cohort randomized controlled trials with expanded numbers of patients are required to further confirm our results.
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Affiliation(s)
- Wenming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, 341000, Jiangxi, People's Republic of China
- The First Clinical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Longxiang Yan
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, 341000, Jiangxi, People's Republic of China
- The First Clinical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Xingkun Tang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, 341000, Jiangxi, People's Republic of China
| | - Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, 341000, Jiangxi, People's Republic of China
| | - Jing Du
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, 341000, Jiangxi, People's Republic of China
| | - Zhengwei Zou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Lincai Li
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
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Meng M, Zhang WW, Chen SF, Wang DR, Zhou CH. Therapeutic utility of human umbilical cord-derived mesenchymal stem cells-based approaches in pulmonary diseases: Recent advancements and prospects. World J Stem Cells 2024; 16:70-88. [PMID: 38455096 PMCID: PMC10915951 DOI: 10.4252/wjsc.v16.i2.70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/04/2024] [Accepted: 01/29/2024] [Indexed: 02/26/2024] Open
Abstract
Pulmonary diseases across all ages threaten millions of people and have emerged as one of the major public health issues worldwide. For diverse disease conditions, the currently available approaches are focused on alleviating clinical symptoms and delaying disease progression but have not shown significant therapeutic effects in patients with lung diseases. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) isolated from the human UC have the capacity for self-renewal and multilineage differentiation. Moreover, in recent years, these cells have been demonstrated to have unique advantages in the treatment of lung diseases. We searched the Public Clinical Trial Database and found 55 clinical trials involving UC-MSC therapy for pulmonary diseases, including coronavirus disease 2019, acute respiratory distress syndrome, bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and pulmonary fibrosis. In this review, we summarize the characteristics of these registered clinical trials and relevant published results and explore in depth the challenges and opportunitiesfaced in clinical application. Moreover, the underlying molecular mechanisms involved in UC-MSC-based therapy for pulmonary diseases are also analyzed in depth. In brief, this comprehensive review and detailed analysis of these clinical trials can be expected to provide a scientific reference for future large-scale clinical application.
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Affiliation(s)
- Min Meng
- Department of Central Laboratory, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Wei-Wei Zhang
- Department of Central Laboratory, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Shuang-Feng Chen
- Department of Central Laboratory, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Da-Rui Wang
- Department of Clinical Laboratory, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Chang-Hui Zhou
- Department of Central Laboratory, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China.
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Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: Part 2-Emerging leaders in regenerative medicine. Periodontol 2000 2024; 94:257-414. [PMID: 38591622 DOI: 10.1111/prd.12561] [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: 02/04/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Nathan E Estrin
- Advanced PRF Education, Venice, Florida, USA
- School of Dental Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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Granton J, Novitzky-Basso IN, Binnie A, Mattsson J. Decidual stromal cells for the treatment of severe COVID-19 ARDS. Intensive Care Med 2023; 49:1552-1554. [PMID: 37968285 DOI: 10.1007/s00134-023-07262-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2023] [Indexed: 11/17/2023]
Affiliation(s)
- John Granton
- Department of Medicine, University Health Network, Faculty of Medicine, University of Toronto, Toronto, Canada.
- Toronto General Hospital, Toronto, Canada.
| | - Igor N Novitzky-Basso
- Department of Medicine, University Health Network, Faculty of Medicine, University of Toronto, Toronto, Canada
- Hans Messner Blood and Marrow Allogeneic Stem Cell Transplant Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | | | - Jonas Mattsson
- Department of Medicine, University Health Network, Faculty of Medicine, University of Toronto, Toronto, Canada
- Hans Messner Blood and Marrow Allogeneic Stem Cell Transplant Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Gloria and Seymour Epstein Chair in Cellular, Therapy University of Toronto, Toronto, Canada
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Pochon C, Laroye C, Kimmoun A, Reppel L, Dhuyser A, Rousseau H, Gauthier M, Petitpain N, Chabot JF, Valentin S, de Carvalho Bittencourt M, Peres M, Aarnink A, Decot V, Bensoussan D, Gibot S. Efficacy of Wharton Jelly Mesenchymal Stromal Cells infusions in moderate to severe SARS-Cov-2 related acute respiratory distress syndrome: a phase 2a double-blind randomized controlled trial. Front Med (Lausanne) 2023; 10:1224865. [PMID: 37706025 PMCID: PMC10495568 DOI: 10.3389/fmed.2023.1224865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/03/2023] [Indexed: 09/15/2023] Open
Abstract
Background The COVID-19 pandemic caused a wave of acute respiratory distress syndrome (ARDS) with a high in-hospital mortality, especially in patients requiring invasive mechanical ventilation. Wharton Jelly-derived Mesenchymal Stromal Cells (WJ-MSCs) may counteract the pulmonary damage induced by the SARS-CoV-2 infection through pro-angiogenic effects, lung epithelial cell protection, and immunomodulation. Methods In this randomized, double-blind, placebo-controlled phase 2a trial, adult patients receiving invasive mechanical ventilation for SARS-CoV-2 induced moderate or severe ARDS were assigned to receive 1 intravenous infusion of 1 × 106 WJ-MSCs/kg or placebo within 48 h of invasive ventilation followed by 2 infusions of 0.5 × 106 WJ-MSCs/kg or placebo over 5 days. The primary endpoint was the percentage of patients with a PaO2/FiO2 > 200 on day 10. Results Thirty patients were included from November 2020 to May 2021, 15 in the WJ-MSC group and 15 in the placebo group. We did not find any significant difference in the PaO2/FiO2 ratio at day 10, with 18 and 15% of WJ-MSCs and placebo-treated patients reaching a ratio >200, respectively. Survival did not differ in the 2 groups with a 20% mortality rate at day 90. While we observed a higher number of ventilation-free days at 28 days in the WJ-MSC arm, this difference was not statistically significant (median of 11 (0-22) vs. 0 (0-18), p = 0.2). The infusions were well tolerated, with a low incidence of anti-HLA alloimmunization after 90 days. Conclusion While treatment with WJ-MSCs appeared safe and feasible in patients with SARS-CoV2 moderate or severe ARDS in this phase 2a trial, the treatment was not associated with an increased percentage of patients with P/F > 200 at 10d, nor did 90 day mortality improve in the treated group. Clinical trial registration https://beta.clinicaltrials.gov/study/NCT04625738, identifier NCT04625738.
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Affiliation(s)
- Cécile Pochon
- CHRU-Nancy, Pediatric Onco-Hematology Department, Nancy, France
- Team 6 IMoPA, UMR 7365 CNRS-UL, Université de Lorraine, Nancy, France
| | - Caroline Laroye
- Team 6 IMoPA, UMR 7365 CNRS-UL, Université de Lorraine, Nancy, France
- CHRU-Nancy, Unité de Thérapie Cellulaire et banque de tissus, Nancy, France
| | - Antoine Kimmoun
- CHRU-Nancy, Service de Médecine Intensive et Réanimation, Hôpitaux de Brabois, Nancy, France
- Université de Lorraine, Nancy, France
| | - Loic Reppel
- Team 6 IMoPA, UMR 7365 CNRS-UL, Université de Lorraine, Nancy, France
- CHRU-Nancy, Unité de Thérapie Cellulaire et banque de tissus, Nancy, France
| | - Adéle Dhuyser
- CHRU-Nancy, HLA and Histocompatibility Laboratory, Nancy, France
| | - Hélène Rousseau
- CHRU-Nancy, Département Méthodologie, Promotion, Investigation, Hôpitaux de Brabois, Nancy, France
| | - Mélanie Gauthier
- Team 6 IMoPA, UMR 7365 CNRS-UL, Université de Lorraine, Nancy, France
- CHRU-Nancy, Unité de Thérapie Cellulaire et banque de tissus, Nancy, France
| | - Nadine Petitpain
- CHRU-Nancy, Département de Pharmacovigilance, Hôpitaux de Brabois, Nancy, France
| | - Jean-François Chabot
- CHRU-Nancy, Pôle des Spécialités Médicales/Département de Pneumologie, Hôpitaux de Brabois, Nancy, France
| | - Simon Valentin
- CHRU-Nancy, Pôle des Spécialités Médicales/Département de Pneumologie, Hôpitaux de Brabois, Nancy, France
| | | | - Michael Peres
- CHRU-Nancy, HLA and Histocompatibility Laboratory, Nancy, France
| | - Alice Aarnink
- Team 6 IMoPA, UMR 7365 CNRS-UL, Université de Lorraine, Nancy, France
- CHRU-Nancy, HLA and Histocompatibility Laboratory, Nancy, France
| | - Véronique Decot
- Team 6 IMoPA, UMR 7365 CNRS-UL, Université de Lorraine, Nancy, France
- CHRU-Nancy, Unité de Thérapie Cellulaire et banque de tissus, Nancy, France
| | - Danièle Bensoussan
- Team 6 IMoPA, UMR 7365 CNRS-UL, Université de Lorraine, Nancy, France
- CHRU-Nancy, Unité de Thérapie Cellulaire et banque de tissus, Nancy, France
| | - Sébastien Gibot
- CHRU-Nancy, Service de Médecine Intensive et Réanimation, Hôpital Central, Nancy, France
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10
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Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, Nguyen GH, Le PTT, Hoang VT, Forsyth NR, Heke M, Nguyen LT. Stem cell-based therapy for human diseases. Signal Transduct Target Ther 2022; 7:272. [PMID: 35933430 PMCID: PMC9357075 DOI: 10.1038/s41392-022-01134-4] [Citation(s) in RCA: 435] [Impact Index Per Article: 145.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/07/2023] Open
Abstract
Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.
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Affiliation(s)
- Duc M Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam.
| | - Phuong T Pham
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trung Q Bach
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh T L Ngo
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Quyen T Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trang T K Phan
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Giang H Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Phuong T T Le
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Nicholas R Forsyth
- Institute for Science & Technology in Medicine, Keele University, Keele, UK
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Liem Thanh Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
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11
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Wiercinska E, Bönig H. Zelltherapie in den Zeiten von SARS-CoV-2. TRANSFUSIONSMEDIZIN 2022. [DOI: 10.1055/a-1720-7975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
ZusammenfassungEin breites Spektrum von Disruptionen, aber auch blitzschnelle Innovationen, hat
die SARS-CoV-2 Pandemie gebracht. Dieser Übersichtsartikel betrachtet
die Pandemie aus der Warte der Zelltherapie; konkret werden vier Aspekte
untersucht: Wie unterscheiden sich die Risiken von Zelltherapie-Patienten mit
SARS-CoV-2 Infektion und COVID von denen der Allgemeinbevölkerung? Sind
Empfänger von Zelltherapien, hier speziell autologe und allogene
Stammzelltransplantationsempfänger sowie Empfänger von
CAR-T-Zell-Präparaten, klinisch relevant durch SARS-CoV-2 Vakzine
immunisierbar? Welche Auswirkungen hat die Pandemie mit Spenderausfallrisiko und
Zusammenbruch von Supply Chains auf die Versorgung mit Zelltherapeutika? Gibt es
Zelltherapeutika, die bei schwerem COVID therapeutisch nutzbringend eingesetzt
werden können? In aller Kürze, das erwartete massiv
erhöhte Risiko von Zelltherapie-Patienten, im Infektionsfall einen
schweren Verlauf zu erleiden oder zu sterben, wurde bestätigt. Die
Vakzine induziert jedoch bei vielen dieser Patienten humorale und
zelluläre Immunität, wenn auch weniger zuverlässig als
bei Gesunden. Dank kreativer Lösungen gelang es, die Versorgung mit
Zelltherapeutika im Wesentlichen uneingeschränkt aufrecht zu erhalten.
SARS-CoV-2-spezifische T-Zell-Präparate für den adoptiven
Immuntransfer wurden entwickelt, eine therapeutische Konstellation diese
anzuwenden ergab sich jedoch nicht. Therapiestudien mit mesenchymalen
Stromazellen beim schweren COVID laufen weltweit; die Frage der Wirksamkeit
bleibt zurzeit offen, bei jedoch substanziellem Optimismus in der Szene. Einige
der Erkenntnisse und Innovationen aus der SARS-CoV-2-Pandemie können
möglicherweise verallgemeinert werden und so auf die Zeit nach ihrem
Ende langfristig nachwirken.
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Affiliation(s)
- Eliza Wiercinska
- DRK-Blutspendedienst Baden-Württemberg-Hessen, Institut
Frankfurt, Frankfurt a.M
| | - Halvard Bönig
- DRK-Blutspendedienst Baden-Württemberg-Hessen, Institut
Frankfurt, Frankfurt a.M
- Goethe Universität, Institut für Transfusionsmedizin
und Immunhämatologie, Frankfurt a.M
- University of Washington, Seattle, WA
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12
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Kirkham AM, Bailey AJM, Monaghan M, Shorr R, Lalu MM, Fergusson DA, Allan DS. Updated Living Systematic Review and Meta-analysis of Controlled Trials of Mesenchymal Stromal Cells to Treat COVID-19: A Framework for Accelerated Synthesis of Trial Evidence for Rapid Approval-FASTER Approval. Stem Cells Transl Med 2022; 11:675-687. [PMID: 35758400 PMCID: PMC9299509 DOI: 10.1093/stcltm/szac038] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/18/2022] [Indexed: 12/11/2022] Open
Abstract
Background Mesenchymal stromal cells (MSCs) may reduce mortality in patients with COVID-19; however, early evidence is based on few studies with marked interstudy heterogeneity. The second iteration of our living systematic review and meta-analysis evaluates a framework needed for synthesizing evidence from high-quality studies to accelerate consideration for approval. Methods A systematic search of the literature was conducted on November 15, 2021, to identify all English-language, full-text, and controlled clinical studies examining MSCs to treat COVID-19 (PROSPERO: CRD42021225431). Findings Eleven studies were identified (403 patients with severe and/or critical COVID-19, including 207 given MSCs and 196 controls). All 11 studies reported mortality and were pooled through random-effects meta-analysis. MSCs decreased relative risk of death at study endpoint (RR: 0.50 [95% CI, 0.34-0.75]) and RR of death at 28 days after treatment (0.19 [95% CI], 0.05-0.78) compared to controls. MSCs also decreased length of hospital stay (mean difference (MD: −3.97 days [95% CI, −6.09 to −1.85], n = 5 studies) and increased oxygenation levels at study endpoint compared to controls (MD: 105.62 mmHg O2 [95% CI, 73.9-137.3,], n = 3 studies). Only 2 of 11 studies reported on all International Society for Cellular Therapy (ISCT) criteria for MSC characterization. Included randomized controlled trials were found to have some concerns (n = 2) to low (n = 4) risk of bias (RoB), while all non-randomized studies were found to have moderate (n = 5) RoB. Interpretation Our updated living systematic review concludes that MSCs can likely reduce mortality in patients with severe or critical COVID-19. A master protocol based on our Faster Approval framework appears necessary to facilitate the more accelerated accumulation of high-quality evidence that would reduce RoB, improve consistency in product characterization, and standardize outcome reporting.
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Affiliation(s)
- Aidan M Kirkham
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Adrian J M Bailey
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Madeline Monaghan
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Risa Shorr
- Medical Information and Learning Services, The Ottawa Hospital, Ottawa, ON, Canada
| | - Manoj M Lalu
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.,Department of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, ON, Canada.,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Anesthesia, The Ottawa Hospital, Ottawa, ON, Canada
| | - Dean A Fergusson
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Medicine, University of Ottawa, Ottawa, ON, Canada.,Department of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.,Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - David S Allan
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Medicine, University of Ottawa, Ottawa, ON, Canada.,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
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13
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Aslan A, Aslan C, Zolbanin NM, Jafari R. Acute respiratory distress syndrome in COVID-19: possible mechanisms and therapeutic management. Pneumonia (Nathan) 2021; 13:14. [PMID: 34872623 PMCID: PMC8647516 DOI: 10.1186/s41479-021-00092-9] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 11/20/2021] [Indexed: 02/07/2023] Open
Abstract
COVID-19 pandemic is a serious concern in the new era. Acute respiratory distress syndrome (ARDS), and lung failure are the main lung diseases in COVID-19 patients. Even though COVID-19 vaccinations are available now, there is still an urgent need to find potential treatments to ease the effects of COVID-19 on already sick patients. Multiple experimental drugs have been approved by the FDA with unknown efficacy and possible adverse effects. Probably the increasing number of studies worldwide examining the potential COVID-19 related therapies will help to identification of effective ARDS treatment. In this review article, we first provide a summary on immunopathology of ARDS next we will give an overview of management of patients with COVID-19 requiring intensive care unit (ICU), while focusing on the current treatment strategies being evaluated in the clinical trials in COVID-19-induced ARDS patients.
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Affiliation(s)
- Anolin Aslan
- Department of Critical Care Nursing, School of Nursing and Midwifery, Tehran University of Medical Science, Tehran, Iran
| | - Cynthia Aslan
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Naime Majidi Zolbanin
- Experimental and Applied Pharmaceutical Research Center, Urmia University of Medical Sciences, Urmia, Iran.,Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Reza Jafari
- Nephrology and Kidney Transplant Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Shafa St., Ershad Blvd., P.O. Box: 1138, Urmia, 57147, Iran. .,Hematology, Immune Cell Therapy, and Stem Cell Transplantation Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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14
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Dunlap NE, van Berkel V, Cai L. COVID-19 and low-dose radiation therapy. RADIATION MEDICINE AND PROTECTION 2021; 2:139-145. [PMID: 34522905 PMCID: PMC8429076 DOI: 10.1016/j.radmp.2021.09.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19), has caused more than 179 million infections and 3.8 million deaths worldwide. Global health authorities working on the COVID-19 outbreak continue to explore methods to reduce the rate of its transmission to healthy individuals. Treatment protocols thus far have focused on social distancing and masking, treatment with antivirals early in infection, and steroids to reduce the inflammatory response. An alternative approach is therapy with low dose radiation (LDR), which has several advantages compared to the current drugs and medicines. To date more than 10 case reports and pilot clinical trial preliminary outcome are available from different countries. These reports cover a wide range of patient conditions and LDR treatment strategies. Although one report showed the failure to observe the improvement of COVID-19 patients after LDR therapy, the majority showed some clinical improvement, and demonstrated the safety of LDR for COVID-19 patients, particularly with 0.5 Gy. This review aims to summarize the potential rationales and mechanisms of LDR therapy for COVID-19 patients, and its current clinical status and potential use.
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Affiliation(s)
- Neal E Dunlap
- Department of Radiation Oncology, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Victor van Berkel
- Department of Cardiovascular and Thoracic Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Lu Cai
- Department of Radiation Oncology, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Pediatric Research Institute, Departments of Pediatrics, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40202, USA
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15
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The Potential of Mesenchymal Stem Cells for the Treatment of Cytokine Storm due to COVID-19. BIOMED RESEARCH INTERNATIONAL 2021; 2021:3178796. [PMID: 34840969 PMCID: PMC8626179 DOI: 10.1155/2021/3178796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 10/24/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022]
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seriously affected public health and social stability. The main route of the transmission is droplet transmission, where the oral cavity is the most important entry point to the body. Due to both the direct harmful effects of SARS-CoV-2 and disordered immune responses, some COVID-19 patients may progress to acute respiratory distress syndrome or even multiple organ failure. Genetic variants of SARS-CoV-2 have been emerging and circulating around the world. Currently, there is no internationally approved precise treatment for COVID-19. Mesenchymal stem cells (MSCs) can traffic and migrate towards the affected tissue, regulate both the innate and acquired immune systems, and participate in the process of healing. Here, we will discuss and investigate the mechanisms of immune disorder in COVID-19 and the therapeutic activity of MSCs, in particular human gingiva mesenchymal stem cells.
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16
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Li C, Zhao H, Cheng L, Wang B. Allogeneic vs. autologous mesenchymal stem/stromal cells in their medication practice. Cell Biosci 2021; 11:187. [PMID: 34727974 PMCID: PMC8561357 DOI: 10.1186/s13578-021-00698-y] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 10/12/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapeutics is already available for treatment of a range of diseases or medical conditions. Autologous or allogeneic MSCs obtained from self or donors have their own advantages and disadvantages in their medical practice. Therapeutic benefits of using autologous vs. allogeneic MSCs are inconclusive. Transplanted MSCs within the body interact with their physical microenvironment or niche, physiologically or pathologically, and such cells in a newly established tissue microenvironment may be impacted by the pathological harmful environmental factors to alter their unique biological behaviors. Meanwhile, a temporary microenvironment/niche may be also altered by the resident or niche-surrounding MSCs. Therefore, the functional plasticity and heterogeneity of MSCs caused by different donors and subpopulations of MSCs may result in potential uncertainty in their safe and efficacious medical practice. Acknowledging a connection between MSCs' biology and their existing microenvironment, donor-controlled clinical practice for the long-term therapeutic benefit is suggested to further consider minimizing MSCs potential harm for MSC-based individual therapies. In this review, we summarize the advantages and disadvantages of autologous vs. allogeneic MSCs in their therapeutic applications. Among other issues, we highlight the importance of better understanding of the various microenvironments that may affect the properties of niche-surrounding MSCs and discuss the clinical applications of MSCs within different contexts for treatment of different diseases including cardiomyopathy, lupus and lupus nephritis, diabetes and diabetic complications, bone and cartilage repair, cancer and tissue fibrosis.
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Affiliation(s)
- Chenghai Li
- Stem Cell Program of Clinical Research Center, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China.
| | - Hua Zhao
- Institute of Reproductive Medicine, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China
| | - Linna Cheng
- Institute of Hematology, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China
| | - Bin Wang
- Department of Neurosurgery, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China.
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17
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Infante A, Rodríguez CI. Cell and Cell-Free Therapies to Counteract Human Premature and Physiological Aging: MSCs Come to Light. J Pers Med 2021; 11:1043. [PMID: 34683184 PMCID: PMC8541473 DOI: 10.3390/jpm11101043] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022] Open
Abstract
The progressive loss of the regenerative potential of tissues is one of the most obvious consequences of aging, driven by altered intercellular communication, cell senescence and niche-specific stem cell exhaustion, among other drivers. Mesenchymal tissues, such as bone, cartilage and fat, which originate from mesenchymal stem cell (MSC) differentiation, are especially affected by aging. Senescent MSCs show limited proliferative capacity and impairment in key defining features: their multipotent differentiation and secretory abilities, leading to diminished function and deleterious consequences for tissue homeostasis. In the past few years, several interventions to improve human healthspan by counteracting the cellular and molecular consequences of aging have moved closer to the clinic. Taking into account the MSC exhaustion occurring in aging, advanced therapies based on the potential use of young allogeneic MSCs and derivatives, such as extracellular vesicles (EVs), are gaining attention. Based on encouraging pre-clinical and clinical data, this review assesses the strong potential of MSC-based (cell and cell-free) therapies to counteract age-related consequences in both physiological and premature aging scenarios. We also discuss the mechanisms of action of these therapies and the possibility of enhancing their clinical potential by exposing MSCs to niche-relevant signals.
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Affiliation(s)
- Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Spain
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18
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Matrix biophysical cues direct mesenchymal stromal cell functions in immunity. Acta Biomater 2021; 133:126-138. [PMID: 34365041 DOI: 10.1016/j.actbio.2021.07.075] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/14/2021] [Accepted: 07/30/2021] [Indexed: 12/25/2022]
Abstract
Hydrogels have been used to design synthetic matrices that capture salient features of matrix microenvironments to study and control cellular functions. Recent advances in understanding of both extracellular matrix biology and biomaterial design have shown that biophysical cues are powerful mediators of cell biology, especially that of mesenchymal stromal cells (MSCs). MSCs have been tested in many clinical trials because of their ability to modulate immune cells in different pathological conditions. While roles of biophysical cues in MSC biology have been studied in the context of multilineage differentiation, their significance in regulating immunomodulatory functions of MSCs is just beginning to be elucidated. This review first describes design principles behind how biophysical cues in native microenvironments influence the ability of MSCs to regulate immune cell production and functions. We will then discuss how biophysical cues can be leveraged to optimize cell isolation, priming, and delivery, which can help improve the success of MSC therapy for immunomodulation. Finally, a perspective is presented on how implementing biophysical cues in MSC potency assay can be important in predicting clinical outcomes. STATEMENT OF SIGNIFICANCE: Stromal cells of mesenchymal origin are known to direct immune cell functions in vivo by secreting paracrine mediators. This property has been leveraged in developing mesenchymal stromal cell (MSC)-based therapeutics by adoptive transfer to treat immunological rejection and tissue injuries, which have been tested in over one thousand clinical trials to date, but with mixed success. Advances in biomaterial design have enabled precise control of biophysical cues based on how stromal cells interact with the extracellular matrix in microenvironments in situ. Investigators have begun to use this approach to understand how different matrix biophysical parameters, such as fiber orientation, porosity, dimensionality, and viscoelasticity impact stromal cell-mediated immunomodulation. The insights gained from this effort can potentially be used to precisely define the microenvironmental cues for isolation, priming, and delivery of MSCs, which can be tailored based on different disease indications for optimal therapeutic outcomes.
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19
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Rasouli M, Vakilian F, Ranjbari J. Therapeutic and protective potential of mesenchymal stem cells, pharmaceutical agents and current vaccines against covid-19. Curr Stem Cell Res Ther 2021; 17:166-185. [PMID: 33349221 DOI: 10.2174/1574888x16666201221151853] [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: 03/19/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 11/22/2022]
Abstract
It has been almost 18 months since the first outbreak of COVID-19 disease was reported in Wuhan, China. This unexpected devastating phenomenon, raised a great deal of concerns and anxiety among people around the world and imposed a huge economic burden on the nations' health care systems. Accordingly, clinical scientists, pharmacologists and physicians worldwide felt an urgent demand for a safe, effective therapeutic agent, treatment strategy or vaccine in order to prevent or cure the recently-emerged disease. Initially, due to lack of specific pharmacological agents and approved vaccines to combat the COVID-19, the disease control in the confirmed cases was limited to supportive care. Accordingly, repositioning or repurposing current drugs and examining their possible therapeutic efficacy received a great deal of attention. Despite revealing promising results in some clinical trials, the overall results are conflicting. For this reason, there is an urgent to seek and investigate other potential therapeutics. Mesenchymal stem cells (MSC) representing immunomodulatory and regenerative capacity to treat both curable and intractable diseases, have been investigated in COVID-19 clinical trials carried out in different parts of the world. Nevertheless, up to now, none of MSC-based approaches has been approved in controlling COVID-19 infection. Thanks to the fact that the final solution for defeating the pandemic is developing a safe, effective vaccine, enormous efforts and clinical research have been carried out. In this review, we will concisely discuss the safety and efficacy of the most relevant pharmacological agents, MSC-based approaches and candidate vaccines for treating and preventing COVID-19 infection.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | | | - Javad Ranjbari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
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