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Ji W, Xu J, Huang C, Liu T, Chen S, Zhao Y, Zhou C, Sun L, Wang M, Wang D, Zhu W. Gastric cancer mesenchymal stem cells upregulate PD-1 expression on the CD8 + T cells by regulating the PI3K/AKT pathway. Mol Immunol 2025; 178:97-106. [PMID: 39870015 DOI: 10.1016/j.molimm.2025.01.005] [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: 11/17/2024] [Revised: 12/27/2024] [Accepted: 01/14/2025] [Indexed: 01/29/2025]
Abstract
Gastric cancer mesenchymal stem cells (GC-MSCs) are a crucial component of the gastric cancer microenvironment, exerting a pivotal influence on the formation of a suppressive immune microenvironment and the progression of gastric cancer. In this study, we utilized GC-MSCs to co-culture peripheral blood mononuclear cells (PBMCs) obtained from both gastric cancer patients and healthy individuals in a proportionate manner by direct cell-to-cell contact. Our findings reveal that co-culture of GC-MSCs with PBMCs led to a notable reduction in CD8+ T cells percentages and an increase in surface PD-1 expression levels on CD8+ T cells. However, flow cytometry analysis demonstrated no significant changes following pretreatment with GC-MSC-conditioned medium (GC-MSC-CM). Moreover, western blotting analysis demonstrated a notable reduction in phosphorylated AKT levels in co-cultured PBMCs. Collectively, our results suggest that GC-MSCs impair the anti-tumor immune response of PBMCs by elevating the PD-1 levels of CD8+ T cells and impairing the killing of CD8+ T cells. These findings provide new evidence that GC-MSCs contribute to immunosuppression within the tumor microenvironment (TME).
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Affiliation(s)
- Weimeng Ji
- Institute of Digestive Diseases, Jiangsu University, Zhenjiang, Jiangsu 212001, China; Department of Oncology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212001, China; School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Juan Xu
- Department of Laboratory Medicine, Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu, China
| | - Chao Huang
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Ting Liu
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Shihan Chen
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Yuanyuan Zhao
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Chenglin Zhou
- Department of Laboratory Medicine, Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu, China
| | - Li Sun
- Department of Clinical Laboratory, Affiliated Kunshan Hospital of jiangsu University, Suzhou, Jiangsu 215399, China
| | - Mei Wang
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Deqiang Wang
- Institute of Digestive Diseases, Jiangsu University, Zhenjiang, Jiangsu 212001, China; Department of Oncology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212001, China.
| | - Wei Zhu
- Institute of Digestive Diseases, Jiangsu University, Zhenjiang, Jiangsu 212001, China; Department of Oncology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212001, China; School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China.
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Ji W, Sun L, Wang D, Zhu W. Mesenchymal stem cells alleviate inflammatory responses through regulation of T-cell subsets. Eur J Pharmacol 2024; 983:176996. [PMID: 39277095 DOI: 10.1016/j.ejphar.2024.176996] [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: 06/22/2024] [Revised: 09/01/2024] [Accepted: 09/11/2024] [Indexed: 09/17/2024]
Abstract
Immune-mediated inflammatory disease (IMID) is a complex disorder characterized by excessive immune responses involving T cells and their subsets, leading to direct tissue damage. T cells can be broadly categorized into CD4+ T cells and CD8+ T cells. CD4+ T cells are composed of several subsets, including T helper (Th)1, Th2, Th9, Th17, Th22, follicular helper T cells (Tfhs), and regulatory T cells (Tregs), while effector CD8+ T cells consist mainly of cytotoxic T cells (CTLs). Current therapies for IMID are ineffective, prompting exploration into mesenchymal stem cells (MSCs) as a promising clinical treatment due to their immunomodulatory effects and self-renewal potential. Recent studies have shown that MSCs can suppress T cells through direct cell-to-cell contact or secretion of soluble cytokines. Nevertheless, the precise effects of MSCs on T cell subsets remain inadequately defined. In this review, we summarize the most recent studies that have examined how MSCs modulate one or more effector T-cell subsets and the mechanisms behind these modifications in vitro and several mouse models of clinical inflammation. This also provides theoretical support and novel insights into the efficacy of clinical treatments involving MSCs. However, the efficacy of MSC therapies in clinical models of inflammation varies, showing effective remission in most cases, but also with exacerbation of T-cell-mediated inflammatory damage in some instances.
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Affiliation(s)
- Weimeng Ji
- Department of Oncology, Affiliated Hospital of Jiangsu University, Institute of Digestive Diseases, Jiangsu University, Zhenjiang, Jiangsu, 212001, China; School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013,China
| | - Li Sun
- Department of Clinical Laboratory, Affiliated Kunshan Hospital Ofjiangsu University, Suzhou, Jiangsu, 215399, China
| | - Deqiang Wang
- Department of Oncology, Affiliated Hospital of Jiangsu University, Institute of Digestive Diseases, Jiangsu University, Zhenjiang, Jiangsu, 212001, China.
| | - Wei Zhu
- Department of Oncology, Affiliated Hospital of Jiangsu University, Institute of Digestive Diseases, Jiangsu University, Zhenjiang, Jiangsu, 212001, China; School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013,China.
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Zhang H, Jin C, Hua J, Chen Z, Gao W, Xu W, Zhou L, Shan L. Roles of Microenvironment on Mesenchymal Stem Cells Therapy for Osteoarthritis. J Inflamm Res 2024; 17:7069-7079. [PMID: 39377043 PMCID: PMC11457791 DOI: 10.2147/jir.s475617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 09/21/2024] [Indexed: 10/09/2024] Open
Abstract
Osteoarthritis (OA) induced microenvironmental alterations are a common and unavoidable phenomenon that greatly exacerbate the pathologic process of OA. Imbalances in the synthesis and degradation of cartilage extracellular matrix (ECM) have been reported to be associated with an adverse microenvironment. Stem cell therapy is a promising treatment for OA, and mesenchymal stem cells (MSCs) are the main cell sources for this therapy. With multispectral differentiation and immunomodulation, MSCs can effectively regulate the microenvironment of articular cartilage, ameliorate inflammation, promote regeneration of damaged cartilage, and ultimately alleviate OA symptoms. However, the efficacy of MSCs in the treatment of OA is greatly influenced by articular cavity microenvironments. This article reviews the five microenvironments of OA articular cavity, including inflammatory microenvironment, senescence microenvironment, hypoxic microenvironment, high glucose microenvironment and high lipid environment, focus on the positive and negative effects of OA microenvironments on the fate of MSCs. In this regard, we emphasize the mechanisms of the current use of MSCs in OA treatment, as well as its limitations and challenges.
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Affiliation(s)
- Haiyan Zhang
- The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chaoying Jin
- School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Jiaqing Hua
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Zuxiang Chen
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Wenxin Gao
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Wenting Xu
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Li Zhou
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Letian Shan
- The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
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Moghaddasi K, Hesaraki S, Arfaee F, Athari SS. Investigating the effect of mesenchymal stem cells on the rate of clinical and pathological improvement of asthmatic lung in mouse model. Regen Ther 2024; 25:157-161. [PMID: 38178929 PMCID: PMC10765480 DOI: 10.1016/j.reth.2023.12.013] [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: 11/22/2023] [Revised: 12/08/2023] [Accepted: 12/17/2023] [Indexed: 01/06/2024] Open
Abstract
Asthma is a pulmonary disease and its pathophysiology includes inflammation, obstruction, edema of the airways, and mucus secretions in the airways. Mesenchymal stem cells (MSCs) are self-renewal that use the therapeutic potential of these cells can be applied as treatments of asthma. In this study, the effect of Mesenchyme stem cells on asthma was investigated. MSCs were administrated for asthmatic mice and then, percentage of eosinophils in blood and bronchoalveolar lavage fluid (BALF), levels of interleukine (IL)-4 and Immunoglubolin (Ig)E were measured. Also histopathological study of lung tissue was done. MSCs administration could control percentage of eosinophils in blood and BALF, levels of IgE and IL-4, eosinophilic inflammation, mucin realizing and goblet cell hyper-plasia. Administration of MSCs as treatment of asthma can be a useful and applicable therapy in control of asthma symptoms.
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Affiliation(s)
- Kambiz Moghaddasi
- Department of Clinical Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Saeed Hesaraki
- Department of Clinical Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Farnoosh Arfaee
- Department of Clinical Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Seyyed Shamsadin Athari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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Wang J, Liu H, Yue G, Deng Y, Cai W, Xu J. Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway. Diabetes Obes Metab 2024; 26:32-45. [PMID: 37722965 DOI: 10.1111/dom.15282] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/23/2023] [Accepted: 08/29/2023] [Indexed: 09/20/2023]
Abstract
AIM To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD). METHODS Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 106 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro. RESULTS The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1β) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance. CONCLUSION We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.
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Affiliation(s)
- Jiao Wang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, China
| | - Honghong Liu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Guanru Yue
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Medical Genetics and Cell Biology, Medical College of Nanchang University, Nanchang, China
| | - Yuanyuan Deng
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wei Cai
- Department of Medical Genetics and Cell Biology, Medical College of Nanchang University, Nanchang, China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, China
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Li H, Yu S, Liu H, Chen L, Liu H, Liu X, Shen C. Immunologic barriers in liver transplantation: a single-cell analysis of the role of mesenchymal stem cells. Front Immunol 2023; 14:1274982. [PMID: 38143768 PMCID: PMC10748593 DOI: 10.3389/fimmu.2023.1274982] [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: 08/09/2023] [Accepted: 11/13/2023] [Indexed: 12/26/2023] Open
Abstract
Background This study aimed to analyze the biomarkers that may reliably indicate rejection or tolerance and the mechanism that underlie the induction and maintenance of liver transplantation (LT) tolerance related to immunosuppressant or mesenchymal stem cells (MSCs). Methods LT models of Lewis-Lewis and F344-Lewis rats were established. Lewis-Lewis rats model served as a control (Syn). F344-Lewis rats were treated with immunosuppressant alone (Allo+IS) or in combination with MSCs (Allo+IS+MSCs). Intrahepatic cell composition particularly immune cells was compared between the groups by single-cell sequencing. Analysis of subclusters, KEGG pathway analysis, and pseudotime trajectory analysis were performed to explore the potential immunoregulatory mechanisms of immunosuppressant alone or combined with MSCs. Results Immunosuppressants alone or combined with MSCs increases the liver tolerance, to a certain extent. Single-cell sequencing identified intrahepatic cell composition signature, including cell subpopulations of B cells, cholangiocytes, endothelial cells, erythrocytes, hepatic stellate cells, hepatocytes, mononuclear phagocytes, neutrophils, T cells, and plasmacytoid dendritic cells. Immunosuppressant particularly its combination with MSCs altered the landscape of intrahepatic cells in transplanted livers, as well as gene expression patterns in immune cells. MSCs may be included in the differentiation of T cells, classical monocytes, and non-classical monocytes. Conclusion These findings provided novel insights for better understanding the heterogeneity and biological functions of intrahepatic immune cells after LT treated by IS alone or in combination with MSCs. The identified markers of immune cells may serve as the immunotherapeutic targets for MSC treatment of liver transplant rejection.
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Affiliation(s)
- Haitao Li
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Saihua Yu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Haiyan Liu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Lihong Chen
- Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Hongzhi Liu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Xingwen Liu
- Department of Nursing, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Conglong Shen
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
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Xu W, Yang Y, Li N, Hua J. Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair. Int J Mol Sci 2023; 24:14484. [PMID: 37833933 PMCID: PMC10572976 DOI: 10.3390/ijms241914484] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/13/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms by which immune cells and their cytokines are regulated in bone healing remain unclear. The use of mesenchymal stem cells (MSCs) for cellular therapy of bone injuries is a novel clinical treatment approach. Bone progenitor MSCs not only differentiate into bone, but also interact with the immune system to promote the healing process. We review in vitro and in vivo studies on the role of the immune system and bone marrow MSCs in bone healing and their interactions. A deeper understanding of this paradigm may provide clues to potential therapeutic targets in the healing process, thereby improving the reliability and safety of clinical applications of MSCs to promote bone healing.
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Affiliation(s)
| | | | - Na Li
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
| | - Jinlian Hua
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
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Gholami M, Ghorban K, Sadeghi M, Dadmanesh M, Rouzbahani NH, Dehnavi S. Mesenchymal stem cells and allergic airway inflammation; a therapeutic approach to induce immunoregulatory responses. Int Immunopharmacol 2023; 120:110367. [PMID: 37230032 DOI: 10.1016/j.intimp.2023.110367] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/07/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
Allergic airway inflammations are among the essential disorders worldwide that are already considered a significant concern. Mesenchymal stem cells (MSCs) are stromal cells with regenerative potential and immunomodulatory characteristics and are widely administered for tissue repair as an immunoregulatory agent in different inflammatory diseases. The current review summarized primary studies conducted to evaluate the therapeutic potential of MSCs for allergic airway disorders. In this case, modulation of airway pathologic inflammation and infiltration of inflammatory cells were examined, and modulation of the Th1/Th2 cellular balance and humoral responses. Also, the effects of MSCs on the Th17/Treg ratio and inducing Treg immunoregulatory responses along with macrophage and dendritic cell function were evaluated.
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Affiliation(s)
- Mohammad Gholami
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Medical Microbiology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Khodayar Ghorban
- Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Dadmanesh
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Infectious Diseases, School Of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Negin Hosseini Rouzbahani
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Sajad Dehnavi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Rizzo MG, Best TM, Huard J, Philippon M, Hornicek F, Duan Z, Griswold AJ, Kaplan LD, Hare JM, Kouroupis D. Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents. Cells 2023; 12:1421. [PMID: 37408255 PMCID: PMC10217382 DOI: 10.3390/cells12101421] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/08/2023] [Accepted: 05/13/2023] [Indexed: 07/07/2023] Open
Abstract
Osteoarthritis (OA) is the most common cause of disability worldwide among the elderly. Alarmingly, the incidence of OA in individuals less than 40 years of age is rising, likely due to the increase in obesity and post-traumatic osteoarthritis (PTOA). In recent years, due to a better understanding of the underlying pathophysiology of OA, several potential therapeutic approaches targeting specific molecular pathways have been identified. In particular, the role of inflammation and the immune system has been increasingly recognized as important in a variety of musculoskeletal diseases, including OA. Similarly, higher levels of host cellular senescence, characterized by cessation of cell division and the secretion of a senescence-associated secretory phenotype (SASP) within the local tissue microenvironments, have also been linked to OA and its progression. New advances in the field, including stem cell therapies and senolytics, are emerging with the goal of slowing disease progression. Mesenchymal stem/stromal cells (MSCs) are a subset of multipotent adult stem cells that have demonstrated the potential to modulate unchecked inflammation, reverse fibrosis, attenuate pain, and potentially treat patients with OA. Numerous studies have demonstrated the potential of MSC extracellular vesicles (EVs) as cell-free treatments that comply with FDA regulations. EVs, including exosomes and microvesicles, are released by numerous cell types and are increasingly recognized as playing a critical role in cell-cell communication in age-related diseases, including OA. Treatment strategies for OA are being developed that target senescent cells and the paracrine and autocrine secretions of SASP. This article highlights the encouraging potential for MSC or MSC-derived products alone or in combination with senolytics to control patient symptoms and potentially mitigate the progression of OA. We will also explore the application of genomic principles to the study of OA and the potential for the discovery of OA phenotypes that can motivate more precise patient-driven treatments.
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Affiliation(s)
- Michael G. Rizzo
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Thomas M. Best
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Johnny Huard
- Center for Regenerative and Personalized Medicine (CRPM), Steadman Philippon Research Institute, Vail, CO 81657, USA (M.P.)
| | - Marc Philippon
- Center for Regenerative and Personalized Medicine (CRPM), Steadman Philippon Research Institute, Vail, CO 81657, USA (M.P.)
| | - Francis Hornicek
- Department of Orthopedics, Sarcoma Biology Laboratory, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.H.); (Z.D.)
| | - Zhenfeng Duan
- Department of Orthopedics, Sarcoma Biology Laboratory, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.H.); (Z.D.)
| | - Anthony J. Griswold
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA;
| | - Lee D. Kaplan
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Joshua M. Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Engineering Strategies of Islet Product for Endocrine Regeneration. ENGINEERED REGENERATION 2023. [DOI: 10.1016/j.engreg.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
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Martí‐Chillón G, Muntión S, Preciado S, Osugui L, Navarro‐Bailón A, González‐Robledo J, Sagredo V, Blanco JF, Sánchez‐Guijo F. Therapeutic potential of mesenchymal stromal/stem cells in critical-care patients with systemic inflammatory response syndrome. Clin Transl Med 2023; 13:e1163. [PMID: 36588089 PMCID: PMC9806020 DOI: 10.1002/ctm2.1163] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 12/15/2022] [Accepted: 12/19/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Despite notable advances in the support and treatment of patients admitted to the intensive care unit (ICU), the management of those who develop a systemic inflammatory response syndrome (SIRS) still constitutes an unmet medical need. MAIN BODY Both the initial injury (trauma, pancreatitis, infections) and the derived uncontrolled response promote a hyperinflammatory status that leads to systemic hypotension, tissue hypoperfusion and multiple organ failure. Mesenchymal stromal/stem cells (MSCs) are emerging as a potential therapy for severe ICU patients due to their potent immunomodulatory, anti-inflammatory, regenerative and systemic homeostasis-regulating properties. MSCs have demonstrated clinical benefits in several inflammatory-based diseases, but their role in SIRS needs to be further explored. CONCLUSION In the current review, after briefly overviewing SIRS physiopathology, we explore the potential mechanisms why MSC therapy could aid in the recovery of this condition and the pre-clinical and early clinical evidence generated to date.
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Affiliation(s)
| | - Sandra Muntión
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Silvia Preciado
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Lika Osugui
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Almudena Navarro‐Bailón
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Javier González‐Robledo
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Department of MedicineUniversity of SalamancaSalamancaSpain
| | | | - Juan F. Blanco
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
- Department of SurgeryUniversity of SalamancaSalamancaSpain
| | - Fermín Sánchez‐Guijo
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Department of MedicineUniversity of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
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Zheng L, Zhang L, Guo Y, Xu X, Liu Z, Yan Z, Fu R. The immunological role of mesenchymal stromal cells in patients with myelodysplastic syndrome. Front Immunol 2022; 13:1078421. [PMID: 36569863 PMCID: PMC9767949 DOI: 10.3389/fimmu.2022.1078421] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
Myelodysplastic syndrome (MDS) is a common hematological malignant disease, characterized by malignant hematopoietic stem cell proliferation in the bone marrow (BM); clinically, it mainly manifests clinically mainly by as pathological hematopoiesis, hemocytopenia, and high-risk transformation to acute leukemia. Several studies have shown that the BM microenvironment plays a critical role in the progression of MDS. In this study, we specifically evaluated mesenchymal stromal cells (MSCs) that exert immunomodulatory effects in the BM microenvironment. This immunomodulatory effect occurs through direct cell-cell contact and the secretion of soluble cytokines or micro vesicles. Several researchers have compared MSCs derived from healthy donors to low-risk MDS-associated bone mesenchymal stem cells (BM-MSCs) and have found no significant abnormalities in the MDS-MSC phenotype; however, these cells have been observed to exhibit altered function, including a decline in osteoblastic function. This altered function may promote MDS progression. In patients with MDS, especially high-risk patients, MSCs in the BM microenvironment regulate immune cell function, such as that of T cells, B cells, natural killer cells, dendritic cells, neutrophils, myeloid-derived suppressor cells (MDSCs), macrophages, and Treg cells, thereby enabling MDS-associated malignant cells to evade immune cell surveillance. Alterations in MDS-MSC function include genomic instability, microRNA production, histone modification, DNA methylation, and abnormal signal transduction and cytokine secretion.
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Affiliation(s)
- Likun Zheng
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China,Department of Hematology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Lei Zhang
- Department of Orthopedics, Kailuan General Hospital, Tangshan, Hebei, China
| | - Yixuan Guo
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xintong Xu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhenyu Yan
- Department of Hematology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China,*Correspondence: Rong Fu,
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Mesenchymal stem cell therapy: A review of clinical trials for multiple sclerosis. Regen Ther 2022; 21:201-209. [PMID: 36092509 PMCID: PMC9420954 DOI: 10.1016/j.reth.2022.07.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/02/2022] [Accepted: 07/15/2022] [Indexed: 11/22/2022] Open
Abstract
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that is the result of the body's own immune cells being auto-reactive to the myelin regions of the body as if these regions were foreign antigens. This demyelination process is damaging to the electrical conductivity of neurons. The current medicines are only capable of fighting off the symptoms of the disease, but not the disease itself. Specialized stem cells, known as mesenchymal stem cells (MSCs), seem to be the candidate therapy to get rid of MS. MSCs can be isolated from multiple sources of the person's body, and even from the umbilical cord (UC) and placenta of a donor. These cells have anti-inflammatory effects so they can target the overactivity and self-antigen attacks by T cells and macrophages; this immune system overactivity is characteristic of MS. MSCs show the ability to locate into brain lesions when injected and thus can compensate for the loss of the brain function by differentiating into neuronal precursor cells and glial cells. The author has listed tables of clinical trials that have utilized MSCs from different sources, along with the years and the phase of study completed for each trial. The consensus is that these cells work on inhibiting CD4+ and CD8+ T cell activation, T regulatory cells (Tregs), and macrophage switch into the auto-immune phenotype. The best source of MSCs seems to be the UC due to the easiness of extraction, the noninvasive method of collection, their higher expansion ability and more powerful immune-modulating properties compared to other locations in the body. Studies showed there was a significant decline of mRNA expression of several cytokines after the administration of MSCs derived from the UC (UCMSCs). Other researchers were able to repair the defects of Tregs in MS patients by co-culturing Tregs from these patients with UCMSCs, which decreased the production of the pro-inflammatory cytokine IFN γ, and also suggested a strong link between Tregs lack of functionality in MS patients with the pathogenesis of the disease.
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Intratracheal administration of mesenchymal stem cells modulates lung macrophage polarization and exerts anti-asthmatic effects. Sci Rep 2022; 12:11728. [PMID: 35821386 PMCID: PMC9276742 DOI: 10.1038/s41598-022-14846-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 06/13/2022] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cells (MSCs) possess immunomodulatory properties that have therapeutic potential for the treatment of inflammatory diseases. This study investigates the effects of direct MSC administration on asthmatic airways. Umbilical cord MSCs (ucMSCs) were intratracheally administered to six-week-old female BALB/c mice sensitized and challenged with ovalbumin; airway hyperresponsiveness (AHR), analyses of airway inflammatory cells, lung histology, flow cytometry, and quantitative real-time PCR were performed. Furthermore, ex vivo and in vitro experiments were performed to assess the effects of ucMSC on M2 activation. Intratracheally administered ucMSCs decreased degree of airway resistance and the number of inflammatory cells such as T helper 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), and macrophages in the murine asthma model. Particularly, MHCII and CD86 expression diminished in dendritic cells and alveolar macrophages (AMs) following ucMSC treatment. SiglecF+CD11c+CD11b- AMs show a negative correlation with type II inflammatory cells including Th2 cells, ILC2, and eosinophils in asthmatic mice and were restored following intratracheal ucMSCs treatment. In addition, ucMSCs decreased the macrophage polarization to M2, particularly M2a. The expression levels of markers associated with M2 polarization and Th2 inflammation were also decreased. ucMSC reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla ex vivo. Furthermore, the in vitro study using IL-4 treated macrophages confirmed that both direct and indirect MSC treatment significantly reduced the expression of Il-5 and Il-13. In conclusion, ucMSCs appear to suppress type II inflammation by regulating lung macrophages via soluble mediators.
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15
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Zhang J, Ma X, Cao L, He X, Li S, Yang M, Yang C, Rong P, Yi S, Ghimire K, Kong X, Wang W. Enhancing and stabilization of cord blood regulatory T-cell suppressive function by human mesenchymal stem cell (MSC)-derived exosomes. Clin Exp Immunol 2022; 208:255-267. [PMID: 35439818 PMCID: PMC9226152 DOI: 10.1093/cei/uxac035] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/28/2022] [Accepted: 04/15/2022] [Indexed: 12/26/2022] Open
Abstract
FOXP3+ regulatory T cells (Tregs) are central to maintaining peripheral tolerance and immune homeostasis. They have the potential to be developed as a cellular therapy to treat various clinical ailments such as autoimmune disorders, inflammatory diseases and to improve transplantation outcomes. However, a major question remains whether Tregs can persist and exert their function effectively in a disease state, where a broad spectrum of inflammatory mediators could inactivate Tregs. In this study, we investigated the potential of mesenchymal stem cell (MSC)-derived exosomes to promote and sustain Tregs function. MSC-conditioned media (MSC-CM) cultured Tregs were more suppressive in both polyclonal and allogeneic responses and were resistant to inflammatory stimulation in vitro compared with the controls. A similar enhancement of Treg function was also observed by culturing Tregs with MSC-derived exosomes alone. The enhanced suppressive activity and stability of Treg cultured in MSC-CM was reduced when exosomes were depleted from MSC-CM. We identified that MSC-derived exosomes could upregulate the expression of LC3(II/I), phosphorylate Jak3 and Stat5 to promote Treg survival, and regulate FOXP3 expression in Tregs. Overall, our study demonstrates that MSC-derived exosomes are capable of enhancing Hucb-Tregs function and stability by activating autophagy and Stat5 signalling pathways. Our findings provide a strong rationale for utilizing MSC-derived exosomes as an effective strategy to enhance Treg function, and improve the overall Tregs-based cell therapy landscape.
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Affiliation(s)
- Juan Zhang
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Xiaoqian Ma
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Lu Cao
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Xing He
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Sang Li
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Min Yang
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Cejun Yang
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Pengfei Rong
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Shounan Yi
- Centre for Transplant and Renal Research (CTRR), Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Kedar Ghimire
- Centre for Transplant and Renal Research (CTRR), Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Xiangfeng Kong
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, People’s Republic of China
| | - Wei Wang
- Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
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16
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Yuan M, Hu X, Yao L, Jiang Y, Li L. Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease. Stem Cell Res Ther 2022; 13:179. [PMID: 35505419 PMCID: PMC9066724 DOI: 10.1186/s13287-022-02858-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation, as an alternative strategy to orthotopic liver transplantation, has been evaluated for treating end-stage liver disease. Although the therapeutic mechanism of MSC transplantation remains unclear, accumulating evidence has demonstrated that MSCs can regenerate tissues and self-renew to repair the liver through differentiation into hepatocyte-like cells, immune regulation, and anti-fibrotic mechanisms. Multiple clinical trials have confirmed that MSC transplantation restores liver function and alleviates liver damage. A sufficient number of MSCs must be home to the target tissues after administration for successful application. However, inefficient homing of MSCs after systemic administration is a major limitation in MSC therapy. Here, we review the mechanisms and clinical application status of MSCs in the treatment of liver disease and comprehensively summarize the molecular mechanisms of MSC homing, and various strategies for promoting MSC homing to improve the treatment of liver disease.
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Affiliation(s)
- Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Lanjuan Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China. .,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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17
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Wang X, Zhang J, Hu B, Qian F. High Expression of CSF-1R Predicts Poor Prognosis and CSF-1R high Tumor-Associated Macrophages Inhibit Anti-Tumor Immunity in Colon Adenocarcinoma. Front Oncol 2022; 12:850767. [PMID: 35444953 PMCID: PMC9014714 DOI: 10.3389/fonc.2022.850767] [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: 01/08/2022] [Accepted: 03/10/2022] [Indexed: 11/20/2022] Open
Abstract
Background Colony stimulating factor 1 receptor (CSF-1R) is a single channel III transmembrane receptor tyrosine kinase (RTK) and plays an important role in immune regulation and the development of various cancer types. The expression of CSF-1R in colon adenocarcinoma (COAD) and its prognostic value remain incompletely understood. Therefore, we aim to explore the prognostic value of CSF-1R in COAD and its relationship with tumor immunity. Methods CSF-1R expression in a COAD cohort containing 103 patients was examined using immunohistochemistry (IHC). The relationship between CSF-1R expression and clinicopathological parameters and prognosis was evaluated. Dual immunofluorescence staining was conducted to determine the localization of CSF-1R in COAD tissues. Univariate and multivariate Cox regression analysis were performed to evaluate independent prognostic factors. Transcriptomic profiles of CSF-1Rhigh and CSF-1Rlow tumor-associated macrophages (TAMs) were investigated. Gene enrichment analysis was used to explore the signal pathways related to CSF-1R. In addition, the relationship between CSF-1R in tumor microenvironment (TME) and tumor immunity was also studied. Results IHC analysis showed that CSF-1R was overexpressed in COAD, and higher expression was associated with shorter overall survival (OS). Immunofluorescence staining showed that CSF-1R was co-localized with macrophage marker CD68. Univariate and multivariate Cox regression analysis showed that CSF-1R was an independent prognostic factor for COAD. The results of gene enrichment analysis showed that CSF-1R was involved in tumor immune response and regulation of TME. In addition, CSF-1R was significantly correlated with TME, immune cell infiltration, TMB, MSI, Neoantigen, and immune checkpoint molecules. Conclusion CSF-1R can serve as an independent prognostic factor of COAD and promising immunotherapeutic target of COAD.
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Affiliation(s)
- Xingchao Wang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Jianfeng Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Baoying Hu
- Department of Immunology, Medical College, Nantong University, Nantong, China
| | - Fei Qian
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China
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18
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Corradi G, Bassani B, Simonetti G, Sangaletti S, Vadakekolathu J, Fontana MC, Pazzaglia M, Gulino A, Tripodo C, Cristiano G, Bandini L, Ottaviani E, Ocadlikova D, Piccioli M, Martinelli G, Colombo MP, Rutella S, Cavo M, Ciciarello M, Curti A. Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells. Clin Cancer Res 2022; 28:3141-3155. [PMID: 35349670 DOI: 10.1158/1078-0432.ccr-21-3594] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 02/10/2022] [Accepted: 03/25/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Tregs) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFN-γ released by AML cells in BM Tregs induction and its impact on AML prognosis. EXPERIMENTAL DESIGN BM aspirates from AML patients were subdivided according to IFNG expression. Gene expression profiles in INFGhigh and IFNGlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFN-g release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell co-cultures. In mice, AML cells silenced for IFN-γ expression were injected intrabone. RESULTS IFNGhigh AMLsamples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. By contrast, in AML patients, high IFNG expression associated with poor overall survival. Notably, IFN-g release by AML cells positively correlated with a higher BM suppressive Tregs' frequency. In co-culture experiments, IFNGhigh AML cells modified MSC transcriptome by up-regulating IFN-γ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFN-γ release by AML cells on MSC-derived Treg induction. Invivo, the genetic ablation of IFN-γ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment. CONCLUSIONS IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment.
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Affiliation(s)
- Giulia Corradi
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Universit� di Bologna, Bologna, Italy, Bologna, Italy
| | | | - Giorgia Simonetti
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), Meldola, FC, Italy
| | | | | | | | | | | | | | - Gianluca Cristiano
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Universit� di Bologna, Bologna, Italy
| | - Lorenza Bandini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia, Italy
| | | | | | - Milena Piccioli
- 8Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, Italy
| | - Giovanni Martinelli
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), Meldola (FC), Italy
| | | | - Sergio Rutella
- Nottingham Trent University, Nottingham, NA, United Kingdom
| | - Michele Cavo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia, Bologna, Italy
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19
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Ohori-Morita Y, Niibe K, Limraksasin P, Nattasit P, Miao X, Yamada M, Mabuchi Y, Matsuzaki Y, Egusa H. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:434-449. [PMID: 35267026 PMCID: PMC9052431 DOI: 10.1093/stcltm/szab030] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 12/02/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
- Yumi Ohori-Morita
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Kunimichi Niibe
- Corresponding authors: Kunimichi Niibe, DDS, PhD, Associate Professor, Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai-city, Miyagi 980-8575, Japan. Tel: +81-22-717-8363; Fax: +81-22-717-8367;
| | - Phoonsuk Limraksasin
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Praphawi Nattasit
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Xinchao Miao
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Masahiro Yamada
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Yo Mabuchi
- Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yumi Matsuzaki
- Department of Life Science, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Hiroshi Egusa
- Hiroshi Egusa, DDS, PhD, Director, Center for Advanced Stem Cell and Regenerative Research, Professor and Chair, Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai-city 980-8575, Japan. Tel: +81-22-717-8363; Fax: +81-22-717-8367;
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20
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Huang M, Mehrabi Nasab E, Athari SS. Immunoregulatory effect of mesenchymal stem cell via mitochondria signaling pathways in allergic asthma. Saudi J Biol Sci 2021; 28:6957-6962. [PMID: 34866995 PMCID: PMC8626264 DOI: 10.1016/j.sjbs.2021.07.071] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 06/23/2021] [Accepted: 07/26/2021] [Indexed: 12/05/2022] Open
Abstract
Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied. After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf's eosinophil Counting, The levels of IL-4, −5, −13, −25, –33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done. BALf's eosinophils, the levels of IL-4, −5, −13, −25, –33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4. MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology.
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Key Words
- AHR, Airway hyperresponsiveness
- ATP, Adenosine triphosphate
- Allergy
- BALF, Bronchoalveolar lavage fluid
- BM, Bone marrow
- CCL, Chemokine (C-C motif) ligand
- CD, Cluster of differentiation
- COX, Cyclooxygenase
- Cys-LT, Cysteinyl Leukotriene
- Cytb, Cytochrome b
- Drp1, Mitochondrial fission depends on the cytosolic GTPase dynamin-related protein 1
- ELISA, Enzyme-linked immunosorbent assay
- FIS1, Mitochondrial fission 1 protein
- H&E, Haemotoxylin and eosin
- HGF, Hepatocyte growth factor
- HLA, Human leukocyte antigen
- HO, Heme oxygenase
- IDO, Indoleamine 2,3-dioxygenase
- IFN, Interferon
- IL, Interleukin
- IP, Intraperitoneal injection
- IT, Intratrachea administration
- Ig, Immunoglobulin
- Immune system
- Inflammation
- LT, Leukotriene
- MFN, Mitofusin
- MIP, macrophage inflammatory protein
- MMP, Matrix metalloproteinase
- MSC
- MSC, mesenchymal stem cell
- MSC/BI, mesenchymal stem cell bronchial administration
- MSC/IV, mesenchymal stem cell intravenous injection
- ND1, NADH-ubiquinone oxidoreductase chain 1
- NO, Nitric oxide
- Nrf, Nuclear erythroid 2 p45-related factor
- OPA1, Mitochondrial dynamin like GTPase
- OVA, Ovalbumin
- PAS, Periodic-acid-Schiff
- PBS, Phosphate-buffered saline
- PGC1a, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
- PGE2, Prostaglandin E2
- ROS, Reactive oxygen species
- TFAM, Transcription factor A mitochondrial
- TGF, Transforming growth factor
- TNF, Tumor necrosis factor
- Th, T helper
- iPSC, induced pluripotent stem cells
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Affiliation(s)
- Minmin Huang
- Department of ICU, People's Hospital of Haimen District, Nantong City, Jiangsu Province, Haimen District, Nantong City, Jiangsu Province 226100, China
| | - Entezar Mehrabi Nasab
- Department of Cardiology, School of Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed Shamsadin Athari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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Gu G, Lv X, Liu G, Zeng R, Li S, Chen L, Liang Z, Wang H, Lu F, Zhan L, Lv X. Tnfaip6 Secreted by Bone Marrow-Derived Mesenchymal Stem Cells Attenuates TNBS-Induced Colitis by Modulating Follicular Helper T Cells and Follicular Regulatory T Cells Balance in Mice. Front Pharmacol 2021; 12:734040. [PMID: 34707499 PMCID: PMC8542666 DOI: 10.3389/fphar.2021.734040] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/31/2021] [Indexed: 12/16/2022] Open
Abstract
Objective: To investigate the immunological mechanism of bone marrow-derived mesenchymal stem cells (BM-MSCs) in inflammatory bowel disease (IBD). Methods: Mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were intraperitoneally injected with phosphate-buffered saline, BM-MSCs, BM-MSCs with tumor necrosis factor-induced protein 6 (Tnfaip6) knockdown mediated by RNA interference recombinant adenovirus, and BM-MSCs-infected with control adenovirus or recombinant mouse Tnfaip6. The disease activity index, weight loss, and histological scores were recorded. Serum levels of Tnfaip6 and pro- and anti-inflammatory cytokines, including interleukin (IL)-21, tumor necrosis factor-alpha (TNF-α), IL-10 were measured by enzyme-linked immunosorbent assay. The relative expression levels of these cytokines, B-cell lymphoma 6 (BCL-6) and fork-like transcription factor p3 (Foxp3) in the colon were determined by real-time quantitative PCR (RT-qPCR). BCL-6 and Foxp3 are the master regulators of follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr), respectively. The infiltration of Tfh and Tfr in mesenteric lymph nodes (MLNs) and spleens was analyzed by flow cytometry. Results: Compared to the normal control group, the expression levels of BCL-6 and IL-21 in the colon, Tfh infiltration, and ratios of Tfh/Tfr in the MLNs and spleen, and the serum concentrations of IL-21 and TNF-α increased significantly in the colitis model group (p < 0.05). Intraperitoneal injection of BM-MSCs or Tnfaip6 ameliorated weight loss and clinical and histological severity of colitis, downregulated the expression of BCL-6, IL-21, and TNF-α, upregulated the expression of Foxp3, IL-10, and Tnfaip6 (p < 0.05), increased Tfr and reduced the infiltration of Tfh in the MLNs and spleen, and downregulated the Tfh/Tfr ratio (p < 0.05). On the other hand, BM-MSCs lost the therapeutic effect and immune regulatory functions on Tfh and Tfr after Tnfaip6 knockdown. Conclusion: Tfh increase in the inflamed colon, Tfh decrease and Tfr increase during the colitis remission phase, and the imbalance of the Tfh/Tfr ratio is closely related to the progression of IBD. Tnfaip6 secreted by BM-MSCs alleviates IBD by inhibiting Tfh differentiation, promoting Tfr differentiation, and improving the imbalance of Tfh/Tfr in mice.
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Affiliation(s)
- Guangli Gu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaodan Lv
- Department of Clinical Experimental Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Gengfeng Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ruizhi Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shiquan Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhaoliang Liang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Huiqin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fei Lu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lingling Zhan
- Department of Clinical Experimental Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaoping Lv
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance? Cancers (Basel) 2021; 13:cancers13215319. [PMID: 34771483 PMCID: PMC8582363 DOI: 10.3390/cancers13215319] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Despite high rates of remission obtained with conventional chemotherapy, the persistence of leukemic cells after treatments, eventually exiting in disease relapse, remains the main challenge in acute myeloid leukemia (AML). Increasing evidence indicates that, besides AML cell mutations, stromal and immune cells, as leukemic microenvironment components, may protect AML cells from therapies. Here, we will recapitulate emerging bone marrow (BM) microenvironment-dependent mechanisms of therapy resistance. The understanding of these processes will help find new drug combinations and conceive novel and more effective treatments. Abstract Acute myeloid leukemia (AML) has been considered for a long time exclusively driven by critical mutations in hematopoietic stem cells. Recently, the contribution of further players, such as stromal and immune bone marrow (BM) microenvironment components, to AML onset and progression has been pointed out. In particular, mesenchymal stromal cells (MSCs) steadily remodel the leukemic niche, not only favoring leukemic cell growth and development but also tuning their responsiveness to treatments. The list of mechanisms driven by MSCs to promote a leukemia drug-resistant phenotype has progressively expanded. Moreover, the relative proportion and the activation status of immune cells in the BM leukemic microenvironment may vary by influencing their reactivity against leukemic cells. In that, the capacity of the stroma to re-program immune cells, thus promoting and/or hampering therapeutic efficacy, is emerging as a crucial aspect in AML biology, adding an extra layer of complexity. Current treatments for AML have mainly focused on eradicating leukemia cells, with little consideration for the leukemia-damaged BM niche. Increasing evidence on the contribution of stromal and immune cells in response to therapy underscores the need to hold the mutual interplay, which takes place in the BM. A careful dissection of these interactions will help provide novel applications for drugs already under experimentation and open a wide array of opportunities for new drug discovery.
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Wu S, Wang L, Fang Y, Huang H, You X, Wu J. Advances in Encapsulation and Delivery Strategies for Islet Transplantation. Adv Healthc Mater 2021; 10:e2100965. [PMID: 34480420 DOI: 10.1002/adhm.202100965] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/23/2021] [Indexed: 12/13/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic β-cells in response to autoimmune reactions. Shapiro et al. conducted novel islet transplantation with a glucocorticoid-free immunosuppressive agent in 2000 and achieved great success; since then, islet transplantation has been increasingly regarded as a promising strategy for the curative treatment of T1DM. However, many unavoidable challenges, such as a lack of donors, poor revascularization, blood-mediated inflammatory reactions, hypoxia, and side effects caused by immunosuppression have severely hindered the widespread application of islet transplantation in clinics. Biomaterial-based encapsulation and delivery strategies are proposed for overcoming these obstacles, and have demonstrated remarkable improvements in islet transplantation outcomes. Herein, the major problems faced by islet transplantation are summarized and updated biomaterial-based strategies for islet transplantation, including islet encapsulation across different scales, delivery of stem cell-derived beta cells, co-delivery of islets with accessory cells and immunomodulatory molecules are highlighted.
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Affiliation(s)
- Siying Wu
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province School of Biomedical Engineering Sun Yat‐sen University Guangzhou 510006 P. R. China
| | - Liying Wang
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province School of Biomedical Engineering Sun Yat‐sen University Guangzhou 510006 P. R. China
| | - Yifen Fang
- The Affiliated TCM Hospital of Guangzhou Medical University Guangzhou 511436 P. R. China
| | - Hai Huang
- Department of Urology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 P. R. China
| | - Xinru You
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province School of Biomedical Engineering Sun Yat‐sen University Guangzhou 510006 P. R. China
| | - Jun Wu
- Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province School of Biomedical Engineering Sun Yat‐sen University Guangzhou 510006 P. R. China
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TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell-Cell Contact and Extracellular Vesicles. Int J Mol Sci 2021; 22:ijms22179531. [PMID: 34502453 PMCID: PMC8431422 DOI: 10.3390/ijms22179531] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/10/2021] [Accepted: 08/26/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of MSC immunoregulatory mechanisms. In addition, the importance of cell–cell contact for MSCs to efficiently modulate the immune response has recently been highlighted. Because these interactions would be difficult to achieve in the physiological context, the release of extracellular vesicles (EVs) and their participation as intermediaries of communication between MSCs and immune cells becomes relevant. Therefore, this article focuses on analyzing immunoregulatory mechanisms mediated by cell contact, highlighting the importance of intercellular adhesion molecule-1 (ICAM-1) and the participation of EVs. Moreover, the effects of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), the main cytokines involved in MSC activation, are examined. These cytokines, when used at the appropriate concentrations and times, would promote increases in the expression of immunoregulatory molecules in the cell and allow the acquisition of EVs enriched with these molecules. The establishment of certain in vitro activation guidelines will facilitate the design of conditioning protocols to obtain functional MSCs or EVs in different pathophysiological conditions.
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25
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Abstract
PURPOSE OF REVIEW Allergic asthma reflects the interplay between inflammatory mediators and immune, airway epithelial, and other cells. This review summarizes key insights in these areas over the past year. RECENT FINDINGS Key findings over the past year demonstrate that epithelial cells mediate tight junction breakdown to facilitate the development of asthma-like disease in mice. Innate lymph lymphoid cells (ILC), while previously shown to promote allergic airway disease, have now been shown to inhibit the development of severe allergic disease in mice. Fibrinogen cleavage products (previously shown to mediate allergic airway disease and macrophage fungistatic immunity by signaling through Toll-like receptor 4) have now been shown to first bind to the integrin Mac-1 (CD11c/CD18). Therapeutically, recent discoveries include the development of the antiasthma drug PM-43I that inhibits the allergy-related transcription factors STAT5 and STAT6 in mice, and confirmatory evidence of the efficacy of the antifungal agent voriconazole in human asthma. SUMMARY Studies over the past year provide critical new insight into the mechanisms by which epithelial cells, ILC, and coagulation factors contribute to the expression of asthma-like disease and further support the development antiasthma drugs that block STAT factors and inhibit fungal growth in the airways.
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26
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Demir S, Erturk A, Gunal YD, Ozmen I, Zengin M, Yildiz D, Karaoz E, Karahan S, Senel E. Contribution of Bone Marrow-Derived Mesenchymal Stem Cells to Healing of Pulmonary Contusion-Created Rats. J Surg Res 2021; 261:205-214. [PMID: 33450629 DOI: 10.1016/j.jss.2020.12.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 11/28/2020] [Accepted: 12/04/2020] [Indexed: 01/29/2023]
Abstract
BACKGROUND The most common thoracic injury in children, resulting in trauma, is pulmonary contusion (PC). Bone marrow-derived mesenchymal stem cells (BM-MSCs) are used in wound healing and many other diseases. This study aims to examine the effects of BM-MSCs on PC healing in rats. MATERIALS AND METHODS A total of 45 male Wistar albino rats were used. Four groups were formed. BM-MSCs were labeled with the green fluorescent protein. PC was observed in the control group. In group II, PC occured and left to spontaneous healing. In group III, PC formed and BM-MSCs were given. In group IV, BM-MSCs were given without PC formation. Subjects were sacrificed 1 week later. Whether there was any difference in terms of BM-MSC involvement and lung injury score was investigated. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS), version 17.0, software (SPSS Inc., Chicago, IL), and p value of <0.05 was considered statistically significant. RESULTS BM-MSCs were collected much more in the lungs in group III than in group IV. Group III had a lower lung injury score value than group II. CONCLUSION The greater involvement of the BM-MSCs in the injury site, and further reductions in lung injury score suggest that BM-MSCs are contributing to the healing of the injury. The use of BM-MSCs in risky patients with diffuse PC may be an alternative treatment to conventional methods.
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Affiliation(s)
- Sabri Demir
- Department of Pediatric Surgery, Ankara Bilkent City Hospital, Children Hospital, Ankara, Turkey; Department of Pediatric Surgery, School of Medicine, Kirikkale University, Kirikkale, Turkey.
| | - Ahmet Erturk
- Department of Pediatric Surgery, Ankara Bilkent City Hospital, Children Hospital, Ankara, Turkey; Department of Pediatric Surgery, School of Medicine, Kirikkale University, Kirikkale, Turkey
| | - Yasemin Dere Gunal
- Department of Pediatric Surgery, School of Medicine, Kirikkale University, Kirikkale, Turkey
| | - Ismail Ozmen
- Department of Pediatric Surgery, School of Medicine, Kirikkale University, Kirikkale, Turkey
| | - Mehmet Zengin
- Department of Pathology, School of Medicine, Kirikkale University, Kirikkale, Turkey
| | - Dincer Yildiz
- Faculty of Veterinary, Department of Anatomy, Kirikkale University, Kirikkale, Turkey
| | - Erdal Karaoz
- Department of Histology and Embryology, School of Medicine, Istinye University, İstanbul, Turkey
| | - Siyami Karahan
- Faculty of Veterinary, Department of Histology, Kirikkale University, Kirikkale, Turkey
| | - Emrah Senel
- Department of Pediatric Surgery, School of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
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Cañas JA, Rodrigo-Muñoz JM, Gil-Martínez M, Sastre B, del Pozo V. Exosomes: A Key Piece in Asthmatic Inflammation. Int J Mol Sci 2021; 22:963. [PMID: 33478047 PMCID: PMC7835850 DOI: 10.3390/ijms22020963] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
Asthma is a chronic disease of the airways that has an important inflammatory component. Multiple cells are implicated in asthma pathogenesis (lymphocytes, eosinophils, mast cells, basophils, neutrophils), releasing a wide variety of cytokines. These cells can exert their inflammatory functions throughout extracellular vesicles (EVs), which are small vesicles released by donor cells into the extracellular microenvironment that can be taken up by recipient cells. Depending on their size, EVs can be classified as microvesicles, exosomes, or apoptotic bodies. EVs are heterogeneous spherical structures secreted by almost all cell types. One of their main functions is to act as transporters of a wide range of molecules, such as proteins, lipids, and microRNAs (miRNAs), which are single-stranded RNAs of approximately 22 nucleotides in length. Therefore, exosomes could influence several physiological and pathological processes, including those involved in asthma. They can be detected in multiple cell types and biofluids, providing a wealth of information about the processes that take account in a pathological scenario. This review thus summarizes the most recent insights concerning the role of exosomes from different sources (several cell populations and biofluids) in one of the most prevalent respiratory diseases, asthma.
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Affiliation(s)
- José A. Cañas
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 2, 28040 Madrid, Spain; (J.A.C.); (J.M.R.-M.); (M.G.-M.)
- CIBER de Enfermedades Respiratorias (CIBERES), Av. de Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - José M. Rodrigo-Muñoz
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 2, 28040 Madrid, Spain; (J.A.C.); (J.M.R.-M.); (M.G.-M.)
- CIBER de Enfermedades Respiratorias (CIBERES), Av. de Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Marta Gil-Martínez
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 2, 28040 Madrid, Spain; (J.A.C.); (J.M.R.-M.); (M.G.-M.)
| | - Beatriz Sastre
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 2, 28040 Madrid, Spain; (J.A.C.); (J.M.R.-M.); (M.G.-M.)
- CIBER de Enfermedades Respiratorias (CIBERES), Av. de Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Victoria del Pozo
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 2, 28040 Madrid, Spain; (J.A.C.); (J.M.R.-M.); (M.G.-M.)
- CIBER de Enfermedades Respiratorias (CIBERES), Av. de Monforte de Lemos, 3-5, 28029 Madrid, Spain
- Faculty of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain
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28
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Özgül Özdemir RB, Özdemir AT, Kırmaz C, Ovalı E, Ölmez E, Kerem H, Evrenos MK, Deniz G. Mesenchymal Stem Cells: a Potential Treatment Approach for Refractory Chronic Spontaneous Urticaria. Stem Cell Rev Rep 2020; 17:911-922. [PMID: 33089453 DOI: 10.1007/s12015-020-10059-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2020] [Indexed: 11/25/2022]
Abstract
The etiopathogenesis of chronic spontaneous urticaria (CSU) is not fully elucidated, and almost 30-40% of patients are resistant to treatments; therefore, there is still a need for the development of new and effective treatments. This study aimed to develop experimental cellular therapy for CSU patients resistant to current treatment options. Autologous adipose tissue mesenchymal stem cells (MSC) were administered to 10 refractory CSU patients who were then followed up for six months. The efficacy of treatment was evaluated according to the weekly urticaria activity scores (UAS7) and drug use scores (DUS7). To observe the effect of treatment on immune cells, CD4+ T cell subsets were analyzed by flow cytometry, and the serum IFN-γ, TNF-α, IL2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17a, IL-21, IL-22, TGF-β1, PGE2, IDO and anti-FcεRI levels were measured using the Luminex and ELISA methods. The values obtained were compared with 10 control refractory CSU patients and five healthy controls. We found that the T cell subsets and inflammatory molecules were not affected by MSC treatment during the follow-up period. In control patients, a significant decrease was detected only at the Th2 subset, TGF-β1, PGE2, IDO and anti-FcεRI levels on the 14th day of treatment. The UAS7 and DUS7 values of the MSC-treated patients significantly decreased during the follow-up period, but in control patients, a significant but temporary decrease was seen. According to our findings, unlike conventional treatment, MSC therapy resulted in longer and more effective recovery. Our data indicate that MSCs may be an alternative and effective approach for treatment-resistant CSU patients. Graphical Abstract.
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Affiliation(s)
| | - Alper Tunga Özdemir
- Department of Medical Biochemistry, Merkezefendi State Hospital, Manisa, Turkey.
- Institute of Health Sciences, Department of Stem Cell, Ege University, İzmir, Turkey.
| | - Cengiz Kırmaz
- Medical School, Department of Allergy and Clinical Immunology, Manisa Celal Bayar University, Manisa, Turkey
| | - Ercüment Ovalı
- Medical School, Department of Internal Medicine, Division of Hematology, Acıbadem University, Istanbul, Turkey
| | - Ercüment Ölmez
- Medical School, Department of Pharmacology, Manisa Celal Bayar University, Manisa, Turkey
| | - Hakan Kerem
- Medical School, Department of Plastic Surgery, Manisa Celal Bayar University, Manisa, Turkey
| | - Mustafa Kürşat Evrenos
- Medical School, Department of Plastic Surgery, Manisa Celal Bayar University, Manisa, Turkey
| | - Günnur Deniz
- Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul University, Istanbul, Turkey
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29
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Liu S, Liu F, Zhou Y, Jin B, Sun Q, Guo S. Immunosuppressive Property of MSCs Mediated by Cell Surface Receptors. Front Immunol 2020; 11:1076. [PMID: 32849489 PMCID: PMC7399134 DOI: 10.3389/fimmu.2020.01076] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/04/2020] [Indexed: 12/16/2022] Open
Abstract
In the past decade, mesenchymal stem cells (MSCs) tend to exhibit inherent tropism for refractory inflammatory diseases and engineered MSCs have appeared on the market as therapeutic agents. Recently, engineered MSCs target to cell surface molecules on immune cells has been a new strategy to improve MSC applications. In this review, we discuss the roles of multiple receptors (ICAM-1, Gal-9, PD-L1, TIGIT, CD200, and CXCR4) in the process of MSCs' immunosuppressive properties. Furthermore, we discuss the principles and strategies for developing receptor-regulated MSCs and their mechanisms of action and the challenges of using MSCs as immunosuppressive therapies.
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Affiliation(s)
- Siyu Liu
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Fei Liu
- Department of Breast Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - You Zhou
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Baeku Jin
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Qiang Sun
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
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30
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Zavvar M, Assadiasl S, Zargaran S, Akhtari M, Poopak B, Dinarvand R, Fatahi Y, Tayebi L, Soleimanifar N, Nicknam MH. Adoptive Treg cell-based immunotherapy: Frontier therapeutic aspects in rheumatoid arthritis. Immunotherapy 2020; 12:933-946. [PMID: 32635779 DOI: 10.2217/imt-2020-0071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The major current focus on treating rheumatoid arthritis is to put an end to long-term treatments and instead, specifically block widespread immunosuppression by developing antigen-specific tolerance, while also permitting an intact immune response toward other antigens to occur. There have been promising preclinical findings regarding adoptive Treg cells immunotherapy with a critically responsible function in the prevention of autoimmunity, tissue repair and regeneration, which make them an attractive candidate to develop effective therapeutic approaches to achieve this interesting concept in many human immune-mediated diseases, such as rheumatoid arthritis. Ex vivo or invivo manipulation protocols are not only utilized to correct Treg cells defect, but also to benefit from their specific immunosuppressive properties by identifying specific antigens that are expressed in the inflamedjoint. The methods able to address these deficiencies can be considered as a target for immunity interventions to restore appropriate immune function.
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Affiliation(s)
- Mahdi Zavvar
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Assadiasl
- Molecular Immunology Research Centre, Tehran University of Medical Sciences, Tehran, Iran
| | - Sina Zargaran
- Faculty of Paramedical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Akhtari
- Department of Cell & Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Behzad Poopak
- Department of Hematology, Faculty of Paramedical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Rassoul Dinarvand
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Yousef Fatahi
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI 53233, USA
| | - Narjes Soleimanifar
- Molecular Immunology Research Centre, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Nicknam
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Molecular Immunology Research Centre, Tehran University of Medical Sciences, Tehran, Iran
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31
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Azevedo RI, Minskaia E, Fernandes-Platzgummer A, Vieira AIS, da Silva CL, Cabral JMS, Lacerda JF. Mesenchymal stromal cells induce regulatory T cells via epigenetic conversion of human conventional CD4 T cells in vitro. Stem Cells 2020; 38:1007-1019. [PMID: 32352186 PMCID: PMC7497276 DOI: 10.1002/stem.3185] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 02/21/2020] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Treg) play a critical role in immune tolerance. The scarcity of Treg therapy clinical trials in humans has been largely due to the difficulty in obtaining sufficient Treg numbers. We performed a preclinical investigation on the potential of mesenchymal stromal cells (MSCs) to expand Treg in vitro to support future clinical trials. Human peripheral blood mononuclear cells from healthy donors were cocultured with allogeneic bone marrow‐derived MSCs expanded under xenogeneic‐free conditions. Our data show an increase in the counts and frequency of CD4+ CD25high Foxp3+ CD127low Treg cells (4‐ and 6‐fold, respectively) after a 14‐day coculture. However, natural Treg do not proliferate in coculture with MSCs. When purified conventional CD4 T cells (Tcon) are cocultured with MSCs, only cells that acquire a Treg‐like phenotype proliferate. These MSC‐induced Treg‐like cells also resemble Treg functionally, since they suppress autologous Tcon proliferation. Importantly, the DNA methylation profile of MSC‐induced Treg‐like cells more closely resembles that of natural Treg than of Tcon, indicating that this population is stable. The expression of PD‐1 is higher in Treg‐like cells than in Tcon, whereas the frequency of PDL‐1 increases in MSCs after coculture. TGF‐β levels are also significantly increased MSC cocultures. Overall, our data suggest that Treg enrichment by MSCs results from Tcon conversion into Treg‐like cells, rather than to expansion of natural Treg, possibly through mechanisms involving TGF‐β and/or PD‐1/PDL‐1 expression. This MSC‐induced Treg population closely resembles natural Treg in terms of phenotype, suppressive ability, and methylation profile.
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Affiliation(s)
- Rita I Azevedo
- Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Ekaterina Minskaia
- Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Ana Fernandes-Platzgummer
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Ana I S Vieira
- Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Cláudia L da Silva
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Joaquim M S Cabral
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - João F Lacerda
- Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
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32
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Wagner MJ, Khan M, Mohsin S. Healing the Broken Heart; The Immunomodulatory Effects of Stem Cell Therapy. Front Immunol 2020; 11:639. [PMID: 32328072 PMCID: PMC7160320 DOI: 10.3389/fimmu.2020.00639] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/20/2020] [Indexed: 12/14/2022] Open
Abstract
Cardiovascular Disease (CVD) is a leading cause of mortality within the United States. Current treatments being administered to patients who suffered a myocardial infarction (MI) have increased patient survival, but do not facilitate the replacement of damaged myocardium. Recent studies demonstrate that stem cell-based therapies promote myocardial repair; however, the poor engraftment of the transferred stem cell populations within the infarcted myocardium is a major limitation, regardless of the cell type. One explanation for poor cell retention is attributed to the harsh inflammatory response mounted following MI. The inflammatory response coupled to cardiac repair processes is divided into two distinct phases. The first phase is initiated during ischemic injury when necrosed myocardium releases Danger Associated Molecular Patterns (DAMPs) and chemokines/cytokines to induce the activation and recruitment of neutrophils and pro-inflammatory M1 macrophages (MΦs); in turn, facilitating necrotic tissue clearance. During the second phase, a shift from the M1 inflammatory functional phenotype to the M2 anti-inflammatory and pro-reparative functional phenotype, permits the resolution of inflammation and the establishment of tissue repair. T-regulatory cells (Tregs) are also influential in mediating the establishment of the pro-reparative phase by directly regulating M1 to M2 MΦ differentiation. Current studies suggest CD4+ T-lymphocyte populations become activated when presented with autoantigens released from the injured myocardium. The identity of the cardiac autoantigens or paracrine signaling molecules released from the ischemic tissue that directly mediate the phenotypic plasticity of T-lymphocyte populations in the post-MI heart are just beginning to be elucidated. Stem cells are enriched centers that contain a diverse paracrine secretome that can directly regulate responses within neighboring cell populations. Previous studies identify that stem cell mediated paracrine signaling can influence the phenotype and function of immune cell populations in vitro, but how stem cells directly mediate the inflammatory microenvironment of the ischemic heart is poorly characterized and is a topic of extensive investigation. In this review, we summarize the complex literature that details the inflammatory microenvironment of the ischemic heart and provide novel insights regarding how paracrine mediated signaling produced by stem cell-based therapies can regulate immune cell subsets to facilitate pro-reparative myocardial wound healing.
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Affiliation(s)
- Marcus J Wagner
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Mohsin Khan
- Center for Metabolic Disease, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Sadia Mohsin
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
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Zhou X, Jin N, Wang F, Chen B. Mesenchymal stem cells: a promising way in therapies of graft-versus-host disease. Cancer Cell Int 2020; 20:114. [PMID: 32280306 PMCID: PMC7137413 DOI: 10.1186/s12935-020-01193-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 03/27/2020] [Indexed: 12/11/2022] Open
Abstract
It is well acknowledged that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for numerous malignant blood diseases, which has also been applied to autoimmune diseases for more than a decade. Whereas graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a common serious complication, seriously affecting the efficacy of transplantation. Mesenchymal stem cells (MSCs) derived from a wealth of sources can easily isolate and expand with low immunogenicity. MSCs also have paracrine and immune regulatory functions, leading to a broad application prospect in treatment and tissue engineering. This review focuses on immunoregulatory function of MSCs, factors affecting mesenchymal stem cells to exert immunosuppressive effects, clinical application of MSCs in GVHD and researches on MSC-derived extracellular vesicles (EVs). The latest research progress on MSC in related fields is reviewed as well. The relevant literature from PubMed databases is reviewed in this article.
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Affiliation(s)
- Xinyi Zhou
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing, 210009 Jiangsu People's Republic of China
| | - Nan Jin
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing, 210009 Jiangsu People's Republic of China
| | - Fei Wang
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing, 210009 Jiangsu People's Republic of China
| | - Baoan Chen
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing, 210009 Jiangsu People's Republic of China
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Rostami Z, Khorashadizadeh M, Naseri M. Immunoregulatory properties of mesenchymal stem cells: Micro-RNAs. Immunol Lett 2020; 219:34-45. [PMID: 31917251 DOI: 10.1016/j.imlet.2019.12.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/16/2019] [Accepted: 12/30/2019] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells that are excellent candidates for different cellular therapies due to their physiological properties such as immunoregulatory function. whetheare currently utilized for regenerative medication and treatment of a number of inflammatory illnesses given their ability to considerably impact tissue microenvironments via extracellular vesicles or toll-like receptor pathway modulation. MicroRNAs (miRNAs) are small noncoding RNAs that target the messenger RNA and play a critical role in different biological procedures, such as the development and reaction of the immune system. Moreover, miRNAs have recently been revealed to have serious functions in MSCs to regulate immunomodulatory properties. In this review, we study how the miRNAs pathway can modulate the immunoregulatory activity of MSCs by counting their interactions with immune cells and also discuss the possibility of using miRNA-based implications for MSC-based therapies.
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Affiliation(s)
- Zeinab Rostami
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran; Department of Immunology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohsen Khorashadizadeh
- Medical Biotechnology (PhD), Department of Medical Biotechnology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohsen Naseri
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran; Department of Immunology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran.
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Sangaphunchai P, Todd I, Fairclough LC. Extracellular vesicles and asthma: A review of the literature. Clin Exp Allergy 2020; 50:291-307. [PMID: 31925972 DOI: 10.1111/cea.13562] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 12/22/2019] [Accepted: 12/28/2019] [Indexed: 12/12/2022]
Abstract
Asthma is a chronic, recurrent and incurable allergy-related respiratory disease characterized by inflammation, bronchial hyperresponsiveness and narrowing of the airways. Extracellular vesicles (EVs) are a universal feature of cellular function and can be detected in different bodily fluids. Recent evidence has shown the possibility of using EVs in understanding the pathogenesis of asthma, including their potential as diagnostic and therapeutic tools. Studies have reported that EVs released from key cells involved in asthma can induce priming and activation of other asthma-associated cells. A literature review was conducted on all current research regarding the role and function of EVs in the pathogenesis of asthma via the PRISMA statement method. An electronic search was performed using EMBASE and PubMed through to November 2018. The EMBASE search returned 76 papers, while the PubMed search returned 211 papers. Following duplicate removal, titles and abstracts were screened for eligibility with a total of 34 studies included in the final qualitative analysis. The review found evidence of association between the presence of EVs and physiological changes characteristic of asthma, suggesting that EVs are involved in the pathogenesis, with the weight of evidence presently favouring deleterious effects of EVs in asthma. Numerous studies highlighted differences in exosomal contents between EVs of healthy and asthmatic individuals, which could be employed as potential diagnostic markers. In some circumstances, EVs were also found to be suppressive to disease, but more often promote inflammation and airway remodelling. In conclusion, EVs hold immense potential in understanding the pathophysiology of asthma, and as diagnostic and therapeutic markers. While more research is needed for definitive conclusions and their application in medical practice, the literature presented in this review should encourage further research and discovery within the field of EVs and asthma.
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Affiliation(s)
| | - Ian Todd
- School of Life Sciences, The University of Nottingham, Nottingham, UK
| | - Lucy C Fairclough
- School of Life Sciences, The University of Nottingham, Nottingham, UK
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Medhat D, Rodríguez CI, Infante A. Immunomodulatory Effects of MSCs in Bone Healing. Int J Mol Sci 2019; 20:ijms20215467. [PMID: 31684035 PMCID: PMC6862454 DOI: 10.3390/ijms20215467] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are capable of differentiating into multilineage cells, thus making them a significant prospect as a cell source for regenerative therapy; however, the differentiation capacity of MSCs into osteoblasts seems to not be the main mechanism responsible for the benefits associated with human mesenchymal stem cells hMSCs when used in cell therapy approaches. The process of bone fracture restoration starts with an instant inflammatory reaction, as the innate immune system responds with cytokines that enhance and activate many cell types, including MSCs, at the site of the injury. In this review, we address the influence of MSCs on the immune system in fracture repair and osteogenesis. This paradigm offers a means of distinguishing target bone diseases to be treated with MSC therapy to enhance bone repair by targeting the crosstalk between MSCs and the immune system.
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Affiliation(s)
- Dalia Medhat
- Medical Biochemistry Department, National Research Centre, Dokki, Giza 12622, Egypt.
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Bizkaia, Spain.
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Bizkaia, Spain.
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Ciciarello M, Corradi G, Loscocco F, Visani G, Monaco F, Cavo M, Curti A, Isidori A. The Yin and Yang of the Bone Marrow Microenvironment: Pros and Cons of Mesenchymal Stromal Cells in Acute Myeloid Leukemia. Front Oncol 2019; 9:1135. [PMID: 31709192 PMCID: PMC6823864 DOI: 10.3389/fonc.2019.01135] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/10/2019] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have, for a long time, been recognized as pivotal contributors in the set up and maintenance of the hematopoietic stem cell (HSC) niche, as well as in the development and differentiation of the lympho-hematopoietic system. MSCs also have a unique immunomodulatory capacity, which makes them able to affect, both in vitro and in vivo, the function of immune cells. These features, namely the facilitation of stem cell engraftment and the inhibition of lymphocyte responses, have both proven essential for successful allogeneic stem cell transplantation (allo-SCT), which remains the only curative option for several hematologic malignancies. For example, in steroid-refractory acute graft-vs. host disease developing after allo-SCT, MSCs have produced significant results and are now considered a treatment option. However, more recently, the other side of the MSC coin has been unveiled, because of their emerging role in creating a protective and immune-tolerant microenvironment able to support the survival of leukemic cells and affect the response to therapies. In this light, it has been proposed that the failure of current treatments to efficiently override the stroma-mediated protection of leukemic cells accounts for the high rate of relapse in acute myeloid leukemia, at least in part. In this review, we will focus on emerging microenvironment-driven mechanisms conferring a survival advantage to leukemic cells overt physiological HSCs. This body of evidence increasingly highlights the opportunity to consider tumor-microenvironment interactions when designing new therapeutic strategies.
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Affiliation(s)
- Marilena Ciciarello
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Giulia Corradi
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Federica Loscocco
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
| | - Giuseppe Visani
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
| | - Federica Monaco
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
| | - Michele Cavo
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.,Department of Hematology and Oncology, Institute of Hematology "L. and A. Seràgnoli", University Hospital S.Orsola-Malpighi, Bologna, Italy
| | - Antonio Curti
- Department of Hematology and Oncology, Institute of Hematology "L. and A. Seràgnoli", University Hospital S.Orsola-Malpighi, Bologna, Italy
| | - Alessandro Isidori
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
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Fakhimi M, Talei AR, Ghaderi A, Habibagahi M, Razmkhah M. Helios, CD73 and CD39 Induction in Regulatory T Cells Exposed to Adipose Derived Mesenchymal Stem Cells. CELL JOURNAL 2019; 22:236-244. [PMID: 31721539 PMCID: PMC6874788 DOI: 10.22074/cellj.2020.6313] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 02/25/2019] [Indexed: 12/22/2022]
Abstract
Objective Mesenchymal stem cells (MSCs) have prominent immunomodulatory roles in the tumor microenvironment.
The current study intended to elucidate Treg subsets and their cytokines after exposing naïve T lymphocytes to adipose-
derived MSCs (ASCs).
Materials and Methods In this experimental study, to obtain ASCs, breast adipose tissues of a breast cancer patient
and a normal individual were used. Magnetic cell sorting (MACS) was employed for purifying naïve CD4+T cells
from peripheral blood of five healthy donors. Naïve CD4+T cells were then co-cultured with ASCs for five days. The
phenotype of regulatory T cells (Tregs) and production of interleukine-10 (IL-10), transforming growth factor beta
(TGF-β) and IL-17 were assessed using flow cytometry and ELISPOT assays, respectively.
Results CD4+CD25-FOXP3+CD45RA+Tregs were expanded in the presence of cancer ASCs but
CD4+CD25+Foxp3+CD45RA+regulatory T cells were up-regulated in the presence of both cancer- and normal-ASCs.
This up-regulation was statistically significant in breast cancer-ASCs compared to the cells cultured without ASCs
(P=0.002). CD4+CD25+ FOXP3+Helios+, CD4+CD25-FOXP3+Helios+and CD25+FOXP3+CD73+CD39+Tregs were
expanded after co-culturing of T cells with both cancer-ASCs and normal-ASCs, while they were statistically significant
only in the presence of cancer-ASCs (P<0.05). Production of IL-10, IL-17 and TGF-β by T cells was increased in the
presence of either normal- or cancer-ASCs; however, significant effect was only observed in the IL-10 and TGF-β of
cancer-ASCs (P<0.05).
Conclusion The results further confirm the immunosuppressive impacts of ASCs on T lymphocytes and direct them
to specific regulatory phenotypes which may support immune evasion and tumor growth.
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Affiliation(s)
- Maryam Fakhimi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdol Rasoul Talei
- Breast Diseases Research Center (BDRC), Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mojtaba Habibagahi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Immune responses towards bioengineered tissues and strategies to control them. Curr Opin Organ Transplant 2019; 24:582-589. [PMID: 31385889 DOI: 10.1097/mot.0000000000000688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Research into development of artificial tissues and bioengineered organs to replace physiological functions of injured counterparts has highlighted a previously underestimated challenge for its clinical translatability: the immune response against biomaterials. Herein, we will provide an update and review current knowledge regarding this important barrier to regenerative medicine. RECENT FINDINGS Although a clear understanding of the immune reactivity against biomaterials remains elusive, accumulating evidence indicates that innate immune cells, primarily neutrophils and macrophages, play a key role in the initial phases of the immune response. More recently, data have shown that in later phases, T and B cells are also involved. The use of physicochemical modifications of biomaterials and cell-based strategies to modulate the host inflammatory response is being actively investigated for effective biomaterial integration. SUMMARY The immune response towards biomaterials and bioengineered organs plays a crucial role in determining their utility as transplantable grafts. Expanding our understanding of these responses is necessary for developing protolerogenic strategies and delivering on the ultimate promise of regenerative medicine.
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Cao T, Shao S, Fang H, Li B, Wang G. Role of Regulatory Immune Cells and Molecules in Autoimmune Bullous Dermatoses. Front Immunol 2019; 10:1746. [PMID: 31428090 PMCID: PMC6688483 DOI: 10.3389/fimmu.2019.01746] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Accepted: 07/10/2019] [Indexed: 12/12/2022] Open
Abstract
Autoimmune bullous dermatoses (AIBD) include a series of typical organ-specific autoimmune diseases characterized by extensive mucocutaneous blisters. It is generally accepted to be caused by pathological autoantibodies that directly target specific adhesion components of the skin or the adjacent mucous membranes. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Recent studies have indicated that the dysfunction of regulatory T cells, regulatory B cells, and complement regulatory proteins that play essential roles in maintaining a healthy immune environment is also closely related to immune disorders in AIBD. It is important to summarize these studies, elucidate the changes in these regulatory immune cells and molecules for the pathogenesis of AIBD, and reveal the mechanisms by which they lose their ability to regulate immune disorders. In this review, we highlight the role of regulatory immune cells and molecules in the pathogenesis of pemphigus vulgaris and bullous pemphigoid, the two most representative forms of AIBD, and indicate issues that should be addressed in future investigations.
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Affiliation(s)
- Tianyu Cao
- Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Shuai Shao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Hui Fang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Bing Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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41
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Mesenchymal stem cells immunomodulation: The road to IFN-γ licensing and the path ahead. Cytokine Growth Factor Rev 2019; 47:32-42. [DOI: 10.1016/j.cytogfr.2019.05.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 05/14/2019] [Accepted: 05/15/2019] [Indexed: 12/11/2022]
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Herrmann M, Stanić B, Hildebrand M, Alini M, Verrier S. In vitro simulation of the early proinflammatory phase in fracture healing reveals strong immunomodulatory effects of CD146-positive mesenchymal stromal cells. J Tissue Eng Regen Med 2019; 13:1466-1481. [PMID: 31132812 DOI: 10.1002/term.2902] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 03/27/2019] [Accepted: 04/29/2019] [Indexed: 01/06/2023]
Abstract
The impact of microenvironmental cues and changes due to injury on the phenotype and fate of mesenchymal stromal cells (MSCs) is poorly understood. Here, we aimed to simulate the microenvironment associated with the early stage of bone healing in vitro and to study the regenerative response of MSCs. We enriched CD146+ MSCs from the human bone marrow. Different physiological and pathological microenvironments were simulated by using conditioned medium (CM) from human endothelial cells and osteoblasts (healthy bone), femoral head-derived bone fragments (injured bone), and activated platelets (platelet-rich plasma [PRP], injury). Cells were incubated in CM and analyzed with respect to proliferation, gene expression, migration, osteogenic differentiation, and their effect on polyclonally induced proliferation of peripheral blood mononuclear cells. CD146+ MSCs showed a specific response to different microenvironments. Cell proliferation was observed in all media with the highest values in PRP-CM and injured bone-CM. Gene expression analysis revealed the upregulation of chemokines, proinflammatory, proangiogenic, and genes involved in immunomodulation in cells stimulated with PRP- and injured bone-CM, suggesting strong paracrine activity. PRP-CM led to pronounced inhibition of lymphocyte proliferation by CD146+MSCs. Our results indicate that a microenvironment simulating bone injury elicits strong immunomodulatory and proangiogenic activity of CD146+ MSCs. This suggests that in the early stage of bone healing, the prime function of MSCs and their CD146+ subpopulation is in regulating the immune response and inducing neovascularization. Future studies will investigate the key components in CM driving this function, which might be potential targets to therapeutically stimulate the regenerative potential of MSCs.
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Affiliation(s)
- Marietta Herrmann
- AO Research Institute Davos, Davos Platz, Switzerland.,IZKF Research Group Tissue Regeneration in Musculoskeletal Diseases, University Clinics Würzburg and Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany
| | | | | | - Mauro Alini
- AO Research Institute Davos, Davos Platz, Switzerland
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Geiger S, Ozay EI, Geumann U, Hereth MK, Magnusson T, Shanthalingam S, Hirsch D, Kälin S, Günther C, Osborne BA, Tew GN, Hermann FG, Minter LM. Alpha-1 Antitrypsin-Expressing Mesenchymal Stromal Cells Confer a Long-Term Survival Benefit in a Mouse Model of Lethal GvHD. Mol Ther 2019; 27:1436-1451. [PMID: 31138510 DOI: 10.1016/j.ymthe.2019.05.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/02/2019] [Accepted: 05/04/2019] [Indexed: 12/29/2022] Open
Abstract
Acute graft-versus-host disease is a frequent complication associated with allogeneic hematopoietic stem cell transplantation. Patients that become refractory to initial steroid treatment have a poor prognosis. apceth-201 consists of human allogeneic mesenchymal stromal cells, engineered by lentiviral transduction to express the protease inhibitor alpha-1 antitrypsin, to augment the anti-inflammatory potential of the mesenchymal stromal cells. We show that apceth-201 mesenchymal stromal cells efficiently suppress T cell proliferation and polarize macrophages to an anti-inflammatory M2 type, in vitro. To assess the in vivo efficacy of apceth-201, it was tested in two different mouse models of acute graft-versus-host disease. Control animals in a humanized model succumbed quickly to disease, whereas median survival was doubled in apceth-201-treated animals. The product was also tested in a graft-versus-host disease model system that closely mimics haploidentical hematopoietic stem cell transplantation, an approach that is now being evaluated for use in the clinic. Control animals succumbed quickly to disease, whereas treatment with apceth-201 resulted in long-term survival of 57% of the animals. Within 25 days after the second injection, clinical scores returned to baseline in responding animals, indicating complete resolution of graft-versus-host disease. These promising data have led to planning of a phase I study using apceth-201.
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Affiliation(s)
| | - Emrah I Ozay
- Program in Molecular & Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Ulf Geumann
- apceth Biopharma GmbH, 81377 Munich, Germany
| | | | | | - Sudarvili Shanthalingam
- Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | | | | | | | - Barbara A Osborne
- Program in Molecular & Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Gregory N Tew
- Department of Polymer Science and Engineering, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | | | - Lisa M Minter
- Program in Molecular & Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA.
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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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Immunomodulatory Functions of Mesenchymal Stem Cells in Tissue Engineering. Stem Cells Int 2019; 2019:9671206. [PMID: 30766609 PMCID: PMC6350611 DOI: 10.1155/2019/9671206] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 10/26/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023] Open
Abstract
The inflammatory response to chronic injury affects tissue regeneration and has become an important factor influencing the prognosis of patients. In previous stem cell treatments, it was revealed that stem cells not only have the ability for direct differentiation or regeneration in chronic tissue damage but also have a regulatory effect on the immune microenvironment. Stem cells can regulate the immune microenvironment during tissue repair and provide a good "soil" for tissue regeneration. In the current study, the regulation of immune cells by mesenchymal stem cells (MSCs) in the local tissue microenvironment and the tissue damage repair mechanisms are revealed. The application of the concepts of "seed" and "soil" has opened up new research avenues for regenerative medicine. Tissue engineering (TE) technology has been used in multiple tissues and organs using its biomimetic and cellular cell abilities, and scaffolds are now seen as an important part of building seed cell microenvironments. The effect of tissue engineering techniques on stem cell immune regulation is related to the shape and structure of the scaffold, the preinflammatory microenvironment constructed by the implanted scaffold, and the material selection of the scaffold. In the application of scaffold, stem cell technology has important applications in cartilage, bone, heart, and liver and other research fields. In this review, we separately explore the mechanism of MSCs in different tissue and organs through immunoregulation for tissue regeneration and MSC combined with 3D scaffolds to promote MSC immunoregulation to repair damaged tissues.
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Ren K. Exosomes in perspective: a potential surrogate for stem cell therapy. Odontology 2018; 107:271-284. [PMID: 30324571 DOI: 10.1007/s10266-018-0395-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 10/05/2018] [Indexed: 12/12/2022]
Abstract
Exosomes as a unique subtype of small extracellular vesicles (sEVs) have attracted increasing interest in recent years in the fields of mesenchymal stromal cell (MSC) research. Studies have confirmed that exosomes derived from MSCs preserve immunosuppressive phenotype and can mimic therapeutic benefits of their parent cells. This review briefly summarizes most recent findings on the potential of exosomes as an alternative of therapeutic MSCs, focusing on the role of MSCs and their secreted exosomes in regulation of immune cells, preclinical and clinical evidence of therapeutic outcomes of MSC exosomes, and the biodistribution and pharmacokinetic profile of systemically administered exosomes. It is appreciated that exosomes from MSCs of different sources have variable contents including inflammatory mediators, tropic factors, signaling molecules, and nucleic acids (DNA, mRNA, microRNA and long non-coding RNA). Diverse functions of exosomes derived from different sources are expected. More importantly, exosomes isolated in vitro may not mirror that from in vivo, where donor MSCs are exposed to specific disease or injury-related conditions. Simulating in vivo microenvironment by pretreatment of MSCs with relevant chemical mediators may lead to their secretion of therapeutically more efficient exosomes/sEVs. However, we know very little about the key molecules involved and the differences between exosomes released under different conditions. These issues would be of tremendous interest to preclinical research that pursues exosome biology-underlain therapeutic mechanisms of MSCs. Further studies are expected to demonstrate the superiority of MSC-derived exsomes/sEVs as a pharmaceutical entity with regard to efficacy, safety, and practicability.
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Affiliation(s)
- Ke Ren
- Department of Neural and Pain Sciences, School of Dentistry, & Program in Neuroscience, University of Maryland, 650 W. Baltimore St, Dental-8 South, Baltimore, MD, 21201, USA.
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Yang C, Chen Y, Li F, You M, Zhong L, Li W, Zhang B, Chen Q. The biological changes of umbilical cord mesenchymal stem cells in inflammatory environment induced by different cytokines. Mol Cell Biochem 2018; 446:171-184. [PMID: 29356988 DOI: 10.1007/s11010-018-3284-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 01/18/2018] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are used as therapeutic tool for the treatment of immune diseases. The inflammatory environment also influences the characteristics of MSCs after transplantation. The aim of the study was to investigate the effects of pro-inflammatory cytokines on the characteristics of umbilical cord mesenchymal stem cells (UCMSCs). UCMSCs were exposed to pro-inflammatory cytokines in vitro for 3 and 7 days, and the biological properties were analyzed. The results showed that the proliferation ability was suppressed by interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). The adipogenic capacity was inhibited in all conditioned medium, while the chondrogenic and osteogenic capacity was enhanced by TNF-α and IL-1β in vitro. Prostaglandin E2 (PGE2) was increased by IL-1β on the third day, and angiopoietin-1 (Ang-1) was inhibited appreciably by TNF-α on the seventh day. Interleukin-6 (IL-6) was increased by TNF-α and IL-1β, and hepatocyte growth factor (HGF) was inhibited by all inflammatory cytokines. IFN-γ secretion level from human peripheral mononuclear cells (hPBMCs) was lowered by UCMSCs which had been stimulated by TNF-α or IL-1β for 3 days. Moreover, IFN-γ and TNF-α secretion level was only inhibited by UCMSCs which had been by stimulated IFN-γ for 3 days but not 7 days. Our data demonstrated that different inflammatory cytokines and the duration of treatment had different effects on the properties of UCMSCs, which might be instructive for clinical pretreatment in cellular therapeutics.
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Affiliation(s)
- Chao Yang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Yu Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Fan Li
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Min You
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Liwu Zhong
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Wenxian Li
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Bo Zhang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Qiang Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China.
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Abstract
Regenerative medicine seeks to harness the potential of cell biology for tissue replacement therapies, which will restore lost tissue functionality. Controlling and enhancing tissue healing is not just a matter of cells, but also of molecules and mechanical forces. We first describe the main biological technologies to boost musculoskeletal healing, including bone marrow and subcutaneous fat-derived regenerative products, as well as platelet-rich plasma and conditioned media. We provide some information describing possible mechanisms of action. We performed a literature search up to January 2016 searching for clinical outcomes following the use of cell therapies for sports conditions, tendons, and joints. The safety and efficacy of cell therapies for tendon conditions was examined in nine studies involving undifferentiated and differentiated (skin fibroblasts, tenocytes) cells. A total of 54 studies investigated the effects of mesenchymal stem-cell (MSC) products for joint conditions including anterior cruciate ligament, meniscus, and chondral lesions as well as osteoarthritis. In 22 studies, cellular products were injected intra-articularly, whereas in 32 studies MSC products were implanted during surgical/arthroscopic procedures. The heterogeneity of clinical conditions, cellular products, and approaches for delivery/implantation make comparability difficult. MSC products appear safe in the short- and mid-term, but studies with a long follow-up are scarce. Although the current number of randomized clinical studies is low, stem-cell products may have therapeutic potential. However, these regenerative technologies still need to be optimized.
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Affiliation(s)
- Isabel Andia
- Regenerative Medicine Laboratory, BioCruces Health Research Institute, Cruces University Hospital, Pza Cruces 12, 48903, Barakaldo, Spain.
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, University of Salerno School of Medicine and Dentistry, Salerno, Italy.,Queen Mary University of London, Barts and the London School of Medicine and Dentistry Centre for Sports and Exercise Medicine, Mile End Hospital, 275 Bancroft Road, London, E1 4DG, England
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Brandão JS, Alvarenga ML, Pfeifer JPH, Dos Santos VH, Fonseca-Alves CE, Rodrigues M, Laufer-Amorim R, Castillo JAL, Alves ALG. Allogeneic mesenchymal stem cell transplantation in healthy equine superficial digital flexor tendon: A study of the local inflammatory response. Res Vet Sci 2018; 118:423-430. [PMID: 29715649 DOI: 10.1016/j.rvsc.2018.03.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 03/13/2018] [Accepted: 03/18/2018] [Indexed: 01/01/2023]
Abstract
The superficial digital flexor tendon (SDFT) is a structure frequently affected by injuries in high-performance athletic horses, and there are limited therapeutic options. Regenerative medicine has evolved significantly in treating different illnesses. However, understanding the cellular behaviour during mesenchymal stem cell (MSC) transplantation in healthy tissues is not fully known yet. To address the inflammatory response induced by allogeneic MSC transplantation, this study evaluated the local inflammatory response after the application of allogeneic adipose tissue-derived mesenchymal stem cells (AT-MSCs) in the equine tendon compared to an autologous transplant and the control group. Eighteen thoracic limbs (TL) in nine animals were divided into three groups and subjected to the application of AT-MSCs in the healthy tendon. In the allogeneic group (Gallog), the animals received an allogeneic AT-MSC application in the TL. The autologous group (Gauto) received an application of autologous cells in the TL, and in the control group (Gcont), phosphate-buffered saline (PBS) was applied. There were no significant differences among the evaluated groups in the physical, morphological, thermography, and ultrasonography analyses. A higher number of CD3-positive lymphocytes was observed in the Gauto group compared to the control (P < 0.05). Additionally, we did not observe different expressions of CD172 and microvascular density among the groups. The allogeneic transplantation of AT-MSCs did not result in an adverse or inflammatory reaction that compromised the use of these cells in this experiment. Their behaviour was similar to that of autologous transplantation.
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Affiliation(s)
- Jaqueline Souza Brandão
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil
| | - Marina Landim Alvarenga
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil
| | - João Pedro Hubbe Pfeifer
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil
| | - Vitor Hugo Dos Santos
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil
| | - Carlos Eduardo Fonseca-Alves
- Department de Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil
| | - Mirian Rodrigues
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil
| | - Renée Laufer-Amorim
- Department de Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil
| | - José Antonio Lucas Castillo
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil
| | - Ana Liz Garcia Alves
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Distrito de Rubião Júnior s/n, Botucatu, SP 18618-9070, Brazil.
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Chulpanova DS, Kitaeva KV, Tazetdinova LG, James V, Rizvanov AA, Solovyeva VV. Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment. Front Pharmacol 2018; 9:259. [PMID: 29615915 PMCID: PMC5869248 DOI: 10.3389/fphar.2018.00259] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 03/08/2018] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs), which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.
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Affiliation(s)
- Daria S Chulpanova
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Kristina V Kitaeva
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Leysan G Tazetdinova
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Victoria James
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
| | - Albert A Rizvanov
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Valeriya V Solovyeva
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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