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Karimi F, Nejati B, Rahimi F, Alivirdiloo V, Alipourfard I, Aghighi A, Raji-Amirhasani A, Eslami M, Babaeizad A, Ghazi F, Firouzi Amandi A, Dadashpour M. A State-of-the-Art Review on the Recent Advances of Mesenchymal Stem Cell Therapeutic Application in Systematic Lupus Erythematosus. Immunol Invest 2024; 53:160-184. [PMID: 38031988 DOI: 10.1080/08820139.2023.2289066] [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] [Indexed: 12/01/2023]
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with an unknown etiology that has widespread clinical and immunological manifestations. Despite the increase in knowledge about the pathogenesis process and the increase in treatment options, however, the treatments fail in half of the cases. Therefore, there is still a need for research on new therapies. Mesenchymal stem cells (MSCs) are powerful regulators of the immune system and can reduce the symptoms of systemic lupus erythematosus. This study aimed to review the mechanisms of immune system modulation by MSCs and the role of these cells in the treatment of SLE. MSCs suppress T lymphocytes through various mechanisms, including the production of transforming growth factor-beta (TGF-B), prostaglandin E2 (PGE2), nitric oxide (NO), and indolamine 2 and 3-oxygenase (IDO). In addition, MSCs inhibit the production of their autoantibodies by inhibiting the differentiation of lymphocytes. The production of autoantibodies against nuclear antigens is an important feature of SLE. On the other hand, MSCs inhibit antigen delivery by antigen-presenting cells (APCs) to T lymphocytes. Studies in animal models have shown the effectiveness of these cells in treating SLE. However, few studies have been performed on the effectiveness of this treatment in humans. It can be expected that new treatment strategies for SLE will be introduced in the future, given the promising results of MSCs application.
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Affiliation(s)
- Farshid Karimi
- Department of Optometry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Babak Nejati
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Rahimi
- Division of Clinical Laboratory, Zahra Mardani Azar Children Training Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Alivirdiloo
- Medical Doctor Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
| | - Iraj Alipourfard
- Institute of Physical Chemistry, Polish Academy of Science, Warsaw, Poland
| | - Ali Aghighi
- Department of Clinical Biochemistry, Zahedan University of Medical Science, Zahedan, Iran
| | - Alireza Raji-Amirhasani
- Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Babaeizad
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Farhood Ghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mehdi Dadashpour
- Department of Medical Biotechnology, Semnan University of Medical Sciences, Semnan, Iran
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Yang H, Cheong S, He Y, Lu F. Mesenchymal stem cell-based therapy for autoimmune-related fibrotic skin diseases-systemic sclerosis and sclerodermatous graft-versus-host disease. Stem Cell Res Ther 2023; 14:372. [PMID: 38111001 PMCID: PMC10729330 DOI: 10.1186/s13287-023-03543-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 10/23/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Systemic sclerosis (SSc) and sclerodermatous graft-versus-host disease (Scl-GVHD)-characterized by similar developmental fibrosis, vascular abnormalities, and innate and adaptive immune response, resulting in severe skin fibrosis at the late stage-are chronic autoimmune diseases of connective tissue. The significant immune system dysfunction, distinguishing autoimmune-related fibrosis from mere skin fibrosis, should be a particular focus of treating autoimmune-related fibrosis. Recent research shows that innovative mesenchymal stem cell (MSC)-based therapy, with the capacities of immune regulation, inflammation suppression, oxidation inhibition, and fibrosis restraint, shows great promise in overcoming the disease. MAIN BODY This review of recent studies aims to summarize the therapeutic effect and theoretical mechanisms of MSC-based therapy in treating autoimmune-related fibrotic skin diseases, SSc and Scl-GVHD, providing novel insights and references for further clinical applications. It is noteworthy that the efficacy of MSCs is not reliant on their migration into the skin. Working on the immune system, MSCs can inhibit the chemotaxis and infiltration of immune cells to the skin by down-regulating the expression of skin chemokines and chemokine receptors and reducing the inflammatory and pro-fibrotic mediators. Furthermore, to reduce levels of oxidative stress, MSCs may improve vascular abnormalities, and enhance the antioxidant defenses through inducible nitric oxide synthase, thioredoxin 1, as well as other mediators. The oxidative stress environment does not weaken MSCs and may even strengthen certain functions. Regarding fibrosis, MSCs primarily target the transforming growth factor-β signaling pathway to inhibit fibroblast activation. Here, miRNAs may play a critical role in ECM remodeling. Clinical studies have demonstrated the safety of these approaches, though outcomes have varied, possibly owing to the heterogeneity of MSCs, the disorders themselves, and other factors. Nevertheless, the research clearly reveals the immense potential of MSCs in treating autoimmune-related fibrotic skin diseases. CONCLUSION The application of MSCs presents a promising approach for treating autoimmune-related fibrotic skin diseases: SSc and Scl-GVHD. Therapies involving MSCs and MSC extracellular vesicles have been found to operate through three primary mechanisms: rebalancing the immune and inflammatory disorders, resisting oxidant stress, and inhibiting overactivated fibrosis (including fibroblast activation and ECM remodeling). However, the effectiveness of these interventions requires further validation through extensive clinical investigations, particularly randomized control trials and phase III/IV clinical trials. Additionally, the hypothetical mechanism underlying these therapies could be elucidated through further research.
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Affiliation(s)
- Han Yang
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Sousan Cheong
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Yunfan He
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
| | - Feng Lu
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
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Liu YJ, Miao HB, Lin S, Chen Z. Current Progress in Treating Systemic Lupus Erythematosus Using Exosomes/MicroRNAs. Cell Transplant 2023; 32:9636897221148775. [PMID: 36661068 PMCID: PMC9903023 DOI: 10.1177/09636897221148775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease associated with impaired organ functions that can seriously affect the daily life of patients. Recent SLE therapies frequently elicit adverse reactions and side effects in patients, and clinical heterogeneity is considerable. Mesenchymal stromal cells (MSCs) have anti-inflammatory, tissue repair, and immunomodulatory properties. Their ability to treat autoimmune diseases largely depends on secreted extracellular vesicles, especially exosomes. The effects of exosomes and microRNAs (miRNAs) on SLE have recently attracted interest. This review summarizes the applications of MSCs derived from bone marrow, adipocyte tissue, umbilical cord, synovial membrane, and gingival tissue, as well as exosomes to treating SLE and the key roles of miRNAs. The efficacy of MSCs infusion in SLE patients with impaired autologous MSCs are reviewed, and the potential of exosomes and their contents as drug delivery vectors for treating SLE and other autoimmune diseases in the future are briefly described.
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Affiliation(s)
- Yi-jing Liu
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Hai-bing Miao
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China,Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Zhen Chen
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China,Zhen Chen, Department of Rheumatology and Immunology, The Second Affiliated Hospital of Fujian Medical University, 34 Zhongshan Road, Quanzhou 362000, Fujian, P.R. China.
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Cheng HY, Anggelia MR, Lin CH, Wei FC. Toward transplantation tolerance with adipose tissue-derived therapeutics. Front Immunol 2023; 14:1111813. [PMID: 37187733 PMCID: PMC10175575 DOI: 10.3389/fimmu.2023.1111813] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
Solid organ and composite tissue allotransplanation have been widely applied to treat end-stage organ failure and massive tissue defects, respectively. Currently there are a lot of research endeavors focusing on induction of transplantation tolerance, to relieve the burden derived from long-term immunosuppressant uptake. The mesenchymal stromal cells (MSCs) have been demonstrated with potent immunomodulatory capacities and applied as promising cellular therapeutics to promote allograft survival and induce tolerance. As a rich source of adult MSCs, adipose tissue provides additional advantages of easy accessibility and good safety profile. In recent years, the stromal vascular fraction (SVF) isolated from adipose tissues following enzymatic or mechanical processing without in vitro culture and expansion has demonstrated immunomodulatory and proangiogenic properties. Furthermore, the secretome of AD-MSCs has been utilized in transplantation field as a potential "cell-free" therapeutics. This article reviews recent studies that employ these adipose-derived therapeutics, including AD-MSCs, SVF, and secretome, in various aspects of organ and tissue allotransplantation. Most reports validate their efficacies in prolonging allograft survival. Specifically, the SVF and secretome have performed well for graft preservation and pretreatment, potentially through their proangiogenic and antioxidative capacities. In contrast, AD-MSCs were suitable for peri-transplantation immunosuppression. The proper combination of AD-MSCs, lymphodepletion and conventional immunosuppressants could consistently induce donor-specific tolerance to vascularized composite allotransplants (VCA). For each type of transplantation, optimizing the choice of therapeutics, timing, dose, and frequency of administration may be required. Future progress in the application of adipose-derived therapeutics to induce transplantation tolerance will be further benefited by continued research into their mechanisms of action and the development of standardized protocols for isolation methodologies, cell culture, and efficacy evaluation.
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Affiliation(s)
- Hui-Yun Cheng
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- *Correspondence: Hui-Yun Cheng,
| | - Madonna Rica Anggelia
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Cheng-Hung Lin
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Fu-Chan Wei
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
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5
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Shi MY, Liu L, Yang FY. Strategies to improve the effect of mesenchymal stem cell therapy on inflammatory bowel disease. World J Stem Cells 2022; 14:684-699. [PMID: 36188115 PMCID: PMC9516464 DOI: 10.4252/wjsc.v14.i9.684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis and is an idiopathic, chronic inflammatory disease of the colonic mucosa. The occurrence of IBD, causes irreversible damage to the colon and increases the risk of carcinoma. The routine clinical treatment of IBD includes drug treatment, endoscopic treatment and surgery. The vast majority of patients are treated with drugs and biological agents, but the complete cure of IBD is difficult. Mesenchymal stem cells (MSCs) have become a new type of cell therapy for the treatment of IBD due to their immunomodulatory and nutritional functions, which have been confirmed in many clinical trials. This review discusses some potential mechanisms of MSCs in the treatment of IBD, summarizes the experimental results, and provides new insights to enhance the therapeutic effects of MSCs in future applications.
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Affiliation(s)
- Meng-Yue Shi
- School of Medicine, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Fu-Yuan Yang
- Health Science Center, Yangtze University, Jingzhou 434020, Hubei Province, China
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6
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Li A, Guo F, Pan Q, Chen S, Chen J, Liu HF, Pan Q. Mesenchymal Stem Cell Therapy: Hope for Patients With Systemic Lupus Erythematosus. Front Immunol 2021; 12:728190. [PMID: 34659214 PMCID: PMC8516390 DOI: 10.3389/fimmu.2021.728190] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 09/14/2021] [Indexed: 12/26/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Although previous studies have demonstrated that SLE is related to the imbalance of cells in the immune system, including B cells, T cells, and dendritic cells, etc., the mechanisms underlying SLE pathogenesis remain unclear. Therefore, effective and low side-effect therapies for SLE are lacking. Recently, mesenchymal stem cell (MSC) therapy for autoimmune diseases, particularly SLE, has gained increasing attention. This therapy can improve the signs and symptoms of refractory SLE by promoting the proliferation of Th2 and Treg cells and inhibiting the activity of Th1, Th17, and B cells, etc. However, MSC therapy is also reported ineffective in some patients with SLE, which may be related to MSC- or patient-derived factors. Therefore, the therapeutic effects of MSCs should be further confirmed. This review summarizes the status of MSC therapy in refractory SLE treatment and potential reasons for the ineffectiveness of MSC therapy from three perspectives. We propose various MSC modification methods that may be beneficial in enhancing the immunosuppression of MSCs in SLE. However, their safety and protective effects in patients with SLE still need to be confirmed by further experimental and clinical evidence.
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Affiliation(s)
- Aifen Li
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fengbiao Guo
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Quanren Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shuxian Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiaxuan Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hua-Feng Liu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Qingjun Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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7
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Yang C, Sun J, Tian Y, Li H, Zhang L, Yang J, Wang J, Zhang J, Yan S, Xu D. Immunomodulatory Effect of MSCs and MSCs-Derived Extracellular Vesicles in Systemic Lupus Erythematosus. Front Immunol 2021; 12:714832. [PMID: 34603289 PMCID: PMC8481702 DOI: 10.3389/fimmu.2021.714832] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/23/2021] [Indexed: 12/29/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a common autoimmune connective tissue disease with unclear etiology and pathogenesis. Mesenchymal stem cell (MSC) and MSC derived extracellular vesicles (EVs) play important roles in regulating innate and adaptive immunity, which are involved in many physiological and pathological processes and contribute to the immune homeostasis in SLE. The effects of MSCs and EVs on SLE have been drawing more and more attention during the past few years. This article reviews the immunomodulatory effects and underlying mechanisms of MSC/MSC-EVs in SLE, which provides novel insight into understanding SLE pathogenesis and guiding the biological therapy.
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Affiliation(s)
- Chunjuan Yang
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, China.,Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Jianmei Sun
- Department of Chemistry, School of Applied Chemistry, Food and Drug, Weifang Engineering Vocational College, Qingzhou, China
| | - Yipeng Tian
- Material Procurement Office of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Haibo Li
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Lili Zhang
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Jinghan Yang
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, China.,Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Jinghua Wang
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, China.,Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Jiaojiao Zhang
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Shushan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Donghua Xu
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, China.,Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
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8
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Preconditioned Mesenchymal Stromal Cells to Improve Allotransplantation Outcome. Cells 2021; 10:cells10092325. [PMID: 34571974 PMCID: PMC8469056 DOI: 10.3390/cells10092325] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are tissue-derived progenitor cells with immunomodulatory as well as multilineage differentiation capacities, and have been widely applied as cellular therapeutics in different disease systems in both preclinical models and clinical studies. Although many studies have applied MSCs in different types of allotransplantation, the efficacy varies. It has been demonstrated that preconditioning MSCs prior to in vivo administration may enhance their efficacy. In the field of organ/tissue allotransplantation, many recent studies have shown that preconditioning of MSCs with (1) pretreatment with bioactive factors or reagents such as cytokines, or (2) specific gene transfection, could prolong allotransplant survival and improve allotransplant function. Herein, we review these preconditioning strategies and discuss potential directions for further improvement.
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9
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Sertoli Cells Possess Immunomodulatory Properties and the Ability of Mitochondrial Transfer Similar to Mesenchymal Stromal Cells. Stem Cell Rev Rep 2021; 17:1905-1916. [PMID: 34115315 DOI: 10.1007/s12015-021-10197-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2021] [Indexed: 12/15/2022]
Abstract
It is becoming increasingly evident that selecting an optimal source of mesenchymal stromal cells (MSCs) is crucial for the successful outcome of MSC-based therapies. During the search for cells with potent regenerative properties, Sertoli cells (SCs) have been proven to modulate immune response in both in vitro and in vivo models. Based on morphological properties and expression of surface markers, it has been suggested that SCs could be a kind of MSCs, however, this hypothesis has not been fully confirmed. Therefore, we compared several parameters of MSCs and SCs, with the aim to evaluate the therapeutic potential of SCs in regenerative medicine. We showed that SCs successfully underwent osteogenic, chondrogenic and adipogenic differentiation and determined the expression profile of canonical MSC markers on the SC surface. Besides, SCs rescued T helper (Th) cells from undergoing apoptosis, promoted the anti-inflammatory phenotype of these cells, but did not regulate Th cell proliferation. MSCs impaired the Th17-mediated response; on the other hand, SCs suppressed the inflammatory polarisation in general. SCs induced M2 macrophage polarisation more effectively than MSCs. For the first time, we demonstrated here the ability of SCs to transfer mitochondria to immune cells. Our results indicate that SCs are a type of MSCs and modulate the reactivity of the immune system. Therefore, we suggest that SCs are promising candidates for application in regenerative medicine due to their anti-inflammatory and protective effects, especially in the therapies for diseases associated with testicular tissue inflammation.
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El-Jawhari JJ, El-Sherbiny Y, McGonagle D, Jones E. Multipotent Mesenchymal Stromal Cells in Rheumatoid Arthritis and Systemic Lupus Erythematosus; From a Leading Role in Pathogenesis to Potential Therapeutic Saviors? Front Immunol 2021; 12:643170. [PMID: 33732263 PMCID: PMC7959804 DOI: 10.3389/fimmu.2021.643170] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/29/2021] [Indexed: 12/15/2022] Open
Abstract
The pathogenesis of the autoimmune rheumatological diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is complex with the involvement of several immune cell populations spanning both innate and adaptive immunity including different T-lymphocyte subsets and monocyte/macrophage lineage cells. Despite therapeutic advances in RA and SLE, some patients have persistent and stubbornly refractory disease. Herein, we discuss stromal cells' dual role, including multipotent mesenchymal stromal cells (MSCs) also used to be known as mesenchymal stem cells as potential protagonists in RA and SLE pathology and as potential therapeutic vehicles. Joint MSCs from different niches may exhibit prominent pro-inflammatory effects in experimental RA models directly contributing to cartilage damage. These stromal cells may also be key regulators of the immune system in SLE. Despite these pro-inflammatory roles, MSCs may be immunomodulatory and have potential therapeutic value to modulate immune responses favorably in these autoimmune conditions. In this review, the complex role and interactions between MSCs and the haematopoietically derived immune cells in RA and SLE are discussed. The harnessing of MSC immunomodulatory effects by contact-dependent and independent mechanisms, including MSC secretome and extracellular vesicles, is discussed in relation to RA and SLE considering the stromal immune microenvironment in the diseased joints. Data from translational studies employing MSC infusion therapy against inflammation in other settings are contextualized relative to the rheumatological setting. Although safety and proof of concept studies exist in RA and SLE supporting experimental and laboratory data, robust phase 3 clinical trial data in therapy-resistant RA and SLE is still lacking.
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Affiliation(s)
- Jehan J El-Jawhari
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Yasser El-Sherbiny
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Dennis McGonagle
- Faculty of Medicine and Health, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.,The National Institute for Health Research Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, United Kingdom
| | - Elena Jones
- Faculty of Medicine and Health, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.,The National Institute for Health Research Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, United Kingdom
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11
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Janikashvili N, Gérard C, Thébault M, Brazdova A, Boibessot C, Cladière C, Ciudad M, Greigert H, Ouandji S, Ghesquière T, Samson M, Audia S, Saas P, Bonnotte B. Efficiency of human monocyte-derived suppressor cell-based treatment in graft-versus-host disease prevention while preserving graft-versus-leukemia effect. Oncoimmunology 2021; 10:1880046. [PMID: 33659098 PMCID: PMC7899641 DOI: 10.1080/2162402x.2021.1880046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background Immunosuppressive cell-based therapy is a recent strategy for controlling Graft-versus-Host Disease (GvHD). Such cells ought to maintain their suppressive function in inflammatory conditions and in the presence of immunosuppressive agents currently used in allogeneic hematopoietic cell transplantation (allo-HCT). Moreover, these therapies should not diminish the benefits of allo-HCT, the Graft-versus-Leukemia (GvL) effect. We have previously reported on a novel subset of human monocyte-derived suppressor cells (HuMoSC) as a prospective approach for controlling GvHD.Objective The objective of this study was to explore the therapeutic relevance of the HuMoSC in clinical conditions. Methods Immune regulatory functions of HuMoSC were assessed in inflammatory conditions and in the presence of immunosuppressants. The therapeutic efficiency of the association of HuMoSC with immunosuppressants was evaluated in an experimental model of GvHD induced by human PBMC in NOD/SCID/IL2-Rγc−/− (NSG) mice. Interestingly, the inhibitory functions of HuMoSC against T lymphocytes and their ability to polarize Treg are preserved, in vitro, in inflammatory environments and are not affected by immunosuppressive agents. In vivo, the association of HuMoSC-based treatment with an immunosuppressive drug showed a synergistic effect for controlling GvHD. Furthermore, HuMoSC control GvHD while preserving GvL effect in a xeno-GvHD conditioned mouse model with cell neoplasm (CAL-1). HuMoSC are generated according to good manufacturing practices (GMP) and we demonstrated that these cells tolerate long-term preservation with unaltered phenotype and function.Conclusion HuMoSC-based therapy represents a promising approach for controlling GvHD and could be quickly implemented in clinical practice.
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Affiliation(s)
- Nona Janikashvili
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France.,Department of Immunology, Faculty of Medicine, Tbilisi State Medical University (TSMU), Tbilisi, Georgia
| | - Claire Gérard
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France.,Department of Internal Medicine, University Hospital, Dijon, France
| | - Marine Thébault
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France
| | - Andrea Brazdova
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France.,Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Clovis Boibessot
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France
| | - Claudie Cladière
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France
| | - Marion Ciudad
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France
| | - Hélène Greigert
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France
| | - Séthi Ouandji
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France
| | - Thibault Ghesquière
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France.,Department of Internal Medicine, University Hospital, Dijon, France
| | - Maxime Samson
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France.,Department of Internal Medicine, University Hospital, Dijon, France
| | - Sylvain Audia
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France.,Department of Internal Medicine, University Hospital, Dijon, France
| | - Philippe Saas
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Besançon, France
| | - Bernard Bonnotte
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire Et Génique, Dijon, France.,Department of Internal Medicine, University Hospital, Dijon, France
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12
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Yao P, Zhou L, Zhu L, Zhou B, Yu Q. Mesenchymal Stem Cells: A Potential Therapeutic Strategy for Neurodegenerative Diseases. Eur Neurol 2020; 83:235-241. [PMID: 32690856 DOI: 10.1159/000509268] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/07/2020] [Indexed: 11/19/2022]
Abstract
Neurodegenerative disease is a kind of chronic, progressive nervous system disease characterized by neuron degeneration or apoptosis. Current treatments cannot prevent the development of the disease. Possible alternative treatments include cell therapy, especially with the use of mesenchymal stem cells (MSCs). MSCs are pluripotent stem cells with capacities for self-renewal and multidirectional differentiation. MSCs may serve as a reliable source of neural cells for potential cell replacement therapy or regenerative medicine treatment. Here, we summarized the therapeutic mechanisms of MSCs and how they can contribute to the development of treatments for neurodegenerative diseases.
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Affiliation(s)
- Panpan Yao
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Liping Zhou
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lujie Zhu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Binjie Zhou
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qin Yu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China,
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13
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Cyclosporine A promotes the therapeutic effect of mesenchymal stem cells on transplantation reaction. Clin Sci (Lond) 2020; 133:2143-2157. [PMID: 31654074 DOI: 10.1042/cs20190294] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 10/15/2019] [Accepted: 10/17/2019] [Indexed: 12/15/2022]
Abstract
The successful application of mesenchymal stem cells (MSCs) remains a major challenge in stem cell therapy. Currently, several in vitro studies have indicated potentially beneficial interactions of MSCs with immunosuppressive drugs. These interactions can be even more complex in vivo, and it is in this setting that we investigate the effect of MSCs in combination with Cyclosporine A (CsA) on transplantation reaction and allogeneic cell survival. Using an in vivo mouse model, we found that CsA significantly promoted the survival of MSCs in various organs and tissues of the recipients. In addition, compared to treatment with CsA or MSCs alone, the survival of transplanted allogeneic cells was significantly improved after the combined application of MSCs with CsA. We further observed that the combinatory treatment suppressed immune response to the alloantigen challenge and modulated the immune balance by harnessing proinflammatory CD4+T-bet+ and CD4+RORγt+ cell subsets. These changes were accompanied by a significant decrease in IL-17 production along with an elevated level of IL-10. Co-cultivation of purified naive CD4+ cells with peritoneal macrophages isolated from mice treated with MSCs and CsA revealed that MSC-educated macrophages play an important role in the immunomodulatory effect observed on distinct T-cell subpopulations. Taken together, our findings suggest that CsA promotes MSC survival in vivo and that the therapeutic efficacy of the combination of MSCs with CsA is superior to each monotherapy. This combinatory treatment thus represents a promising approach to reducing immunosuppressant dosage while maintaining or even improving the outcome of therapy.
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14
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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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15
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Wang K, Shi YJ, Song ZL, Wu B, Zhou CL, Liu W, Gao W. Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in vitro. Mol Med Rep 2020; 21:2123-2130. [PMID: 32186771 PMCID: PMC7115201 DOI: 10.3892/mmr.2020.11019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 02/20/2020] [Indexed: 12/29/2022] Open
Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) regulate the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells. However, the role of different factors on BM-MSCs-mediated regulation of the Treg/Th17 balance is unknown. BM-MSCs and CD4+ T lymphocytes were co-cultured with various treatments. The ratio of Treg/Th17 cells was calculated and the expression of different cytokines was measured. BM-MSCs were found to have a proliferative effect on Th17 cells at a basal concentration and at a 2-fold increase in the number of BM-MSCs. However, when the number of BM-MSCs used was increased 4-fold, they had an inhibitory effect on the Th17 cells. The effect of BM-MSCs on Tregs was inhibited by the addition of tacrolimus but not rapamycin. The effect of BM-MSCs on Th17 cells was inhibited by rapamycin. Additionally, the effect of BM-MSCs on Tregs were inhibited by the addition of a transforming growth factor-β (TGF-β) blocker, whereas these TGF-β-blockers had no effect on Th17 cells. Addition of an interleukin (IL)-2 blocker reduced the proportion of Th17 cells when co-cultured with a high number of MSCs compared with the low concentration group and the proportion of Treg cells was significantly decreased when cells were treated with an IL-2 blocker compared with the control group. Together, these results showed the varying effects of MSCs on the ratio of Treg/Th17, its dependence on the number of MSCs and the effects of cytokines in inducing these changes in the balance.
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Affiliation(s)
- Kai Wang
- Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Yan-Jun Shi
- Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA
| | - Zhuo-Lun Song
- Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Bin Wu
- Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Chun-Lei Zhou
- Clinical Laboratory, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Wei Liu
- Blood Transfusion Department, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Wei Gao
- Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
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16
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Xu J, Chen J, Li W, Lian W, Huang J, Lai B, Li L, Huang Z. Additive Therapeutic Effects of Mesenchymal Stem Cells and IL-37 for Systemic Lupus Erythematosus. J Am Soc Nephrol 2020; 31:54-65. [PMID: 31604808 PMCID: PMC6935004 DOI: 10.1681/asn.2019050545] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 09/11/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Although mesenchymal stem cells (MSCs) might offer a promising strategy for treating SLE, their immunoregulatory plasticity makes their therapeutic effects unpredictable. Whether overexpressing IL-37, an IL-1 family member with immunosuppressive activity, might enhance the therapeutic effects of these cells for SLE is unknown. METHODS We genetically modified MSCs to overexpress IL-37 and assessed their effects on immune suppression in vitro. We also evaluated the effects of such cells versus effects of various controls after transplanting them into MRL/lpr mice (model of SLE). RESULTS Stem cell characteristics did not appear altered in MSCs overexpressing IL-37. These cells had enhanced immunosuppression in vitro in terms of inhibiting splenocyte proliferation, reducing proinflammatory factors (IL-1β, TNF-α, IL-17, and IL-6), and suppressing autoantibodies (anti-dsDNA and anti-ANA). Compared with animals receiving control MSCs or IL-37 treatment alone, MRL/lpr mice transplanted with IL-37-overexpressing cells displayed improved survival and reduced signs of SLE (indicated by urine protein levels, spleen weight, and renal pathologic scores); they also had significantly lower expression of proinflammatory factors, lower total antibody levels in serum and urine, lower autoantibody production, and showed reduced T cell numbers in the serum and kidney. Expression of IL-37 by MSCs can maintain higher serum levels of IL-37, and MSCs had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment. CONCLUSIONS Mutually reinforcing interaction between MSCs and IL-37 appears to underlie their additive therapeutic effects. Genetic modification to overexpress IL-37 might offer a way to enhance the stability and effectiveness of MSCs in treating SLE.
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Affiliation(s)
- Jianyong Xu
- Guangdong Provincial Key Laboratory of Regional Immunity and Disease and
- Department of Immunology, Health Science Center, Shenzhen University, Shenzhen, P.R. China
| | - Jieting Chen
- Department of Obstetrics, People's Hospital of Baoan, Shenzhen, P.R. China; and
| | - Wenlei Li
- Department of Obstetrics, Women and Children Health Institute of Futian, Shenzhen, P.R. China
| | - Wei Lian
- Department of Immunology, Health Science Center, Shenzhen University, Shenzhen, P.R. China
| | - Jieyong Huang
- Department of Immunology, Health Science Center, Shenzhen University, Shenzhen, P.R. China
| | - Baoyu Lai
- Department of Immunology, Health Science Center, Shenzhen University, Shenzhen, P.R. China
| | - Lingyun Li
- Department of Immunology, Health Science Center, Shenzhen University, Shenzhen, P.R. China
| | - Zhong Huang
- Guangdong Provincial Key Laboratory of Regional Immunity and Disease and
- Department of Immunology, Health Science Center, Shenzhen University, Shenzhen, P.R. China
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17
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Cheng RJ, Xiong AJ, Li YH, Pan SY, Zhang QP, Zhao Y, Liu Y, Marion TN. Mesenchymal Stem Cells: Allogeneic MSC May Be Immunosuppressive but Autologous MSC Are Dysfunctional in Lupus Patients. Front Cell Dev Biol 2019; 7:285. [PMID: 31799252 PMCID: PMC6874144 DOI: 10.3389/fcell.2019.00285] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have a potently immunosuppressive capacity in both innate and adaptive immune responses. Consequently, MSCs transplantation has emerged as a potential beneficial therapy for autoimmune diseases even though the mechanisms underlying the immunomodulatory activity of MSCs is incompletely understood. Transplanted MSCs from healthy individuals with no known history of autoimmune disease are immunosuppressive in systemic lupus erythematosus (SLE) patients and can ameliorate SLE disease symptoms in those same patients. In contrast, autologous MSCs from SLE patients are not immunosuppressive and do not ameliorate disease symptoms. Recent studies have shown that MSCs from SLE patients are dysfunctional in both proliferation and immunoregulation and phenotypically senescent. The senescent phenotype has been attributed to multiple genes and signaling pathways. In this review, we focus on the possible mechanisms for the defective phenotype and function of MSCs from SLE patients and summarize recent research on MSCs in autoimmune diseases.
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Affiliation(s)
- Rui-Juan Cheng
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - An-Ji Xiong
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Yan-Hong Li
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Shu-Yue Pan
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiu-Ping Zhang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Tony N Marion
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China.,Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States
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18
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Caplan H, Olson SD, Kumar A, George M, Prabhakara KS, Wenzel P, Bedi S, Toledano-Furman NE, Triolo F, Kamhieh-Milz J, Moll G, Cox CS. Mesenchymal Stromal Cell Therapeutic Delivery: Translational Challenges to Clinical Application. Front Immunol 2019; 10:1645. [PMID: 31417542 PMCID: PMC6685059 DOI: 10.3389/fimmu.2019.01645] [Citation(s) in RCA: 209] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 07/02/2019] [Indexed: 12/12/2022] Open
Abstract
For several decades, multipotent mesenchymal stromal cells (MSCs) have been extensively studied for their therapeutic potential across a wide range of diseases. In the preclinical setting, MSCs demonstrate consistent ability to promote tissue healing, down-regulate excessive inflammation and improve outcomes in animal models. Several proposed mechanisms of action have been posited and demonstrated across an array of in vitro models. However, translation into clinical practice has proven considerably more difficult. A number of prominent well-funded late-phase clinical trials have failed, thus calling out for new efforts to optimize product delivery in the clinical setting. In this review, we discuss novel topics critical to the successful translation of MSCs from pre-clinical to clinical applications. In particular, we focus on the major routes of cell delivery, aspects related to hemocompatibility, and potential safety concerns associated with MSC therapy in the different settings.
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Affiliation(s)
- Henry Caplan
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Scott D. Olson
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Akshita Kumar
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Mitchell George
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Karthik S. Prabhakara
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Pamela Wenzel
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Supinder Bedi
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Naama E. Toledano-Furman
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Fabio Triolo
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Julian Kamhieh-Milz
- Department of Transfusion Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Guido Moll
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Charles S. Cox
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
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19
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Abstract
Nerve injury-induced neuropathic pain is difficult to treat. In this study, we used exosomes derived from human umbilical cord mesenchymal stem cell (UCMSC) as a cell-free therapy for nerve injury-induced pain in rats. Isolated UCMSC exosomes range in size from 30 to 160 nm and contain CD63, HSP60, and CD81 exosome markers. After L5/6 spinal nerve ligation surgery, single intrathecal injection of exosomes reversed nerve ligation-induced mechanical and thermal hypersensitivities of right hindpaw of rats at initial and well-developed pain stages. Moreover, continuous intrathecal infusion of exosomes achieved excellent preventive and reversal effects for nerve ligation-induced pain. In immunofluorescent study, lots of Exo-green-labelled exosomes could be found majorly in the ipsilateral L5 spinal dorsal horn, dorsal root ganglion, and peripheral axons, suggesting the homing ability of UCMSC exosomes. They also appeared in the central terminals or cell bodies of IB4, CGRP, and NF200 sensory neurons. In addition, exosome treatment suppressed nerve ligation-induced upregulation of c-Fos, CNPase, GFAP, and Iba1. All these data suggest that the analgesic effects of exosomes may involve their actions on neuron and glial cells. Exosomes also inhibited the level of TNF-α and IL-1β, while enhanced the level of IL-10, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in the ipsilateral L5/6 dorsal root ganglion of nerve-ligated rats, indicating anti-inflammatory and proneurotrophic abilities. Protein analysis revealed the content of vascular endothelial growth factor C, angiopoietin-2, and fibroblast growth factor-2 in the exosomes. In summary, intrathecal infusion of exosomes from UCMSCs may be considered as a novel therapeutic approach for nerve injury-induced pain.
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20
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Fucà G, Galli G, Poggi M, Lo Russo G, Proto C, Imbimbo M, Ferrara R, Zilembo N, Ganzinelli M, Sica A, Torri V, Colombo MP, Vernieri C, Balsari A, de Braud F, Garassino MC, Signorelli D. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open 2019; 4:e000457. [PMID: 30964126 PMCID: PMC6435242 DOI: 10.1136/esmoopen-2018-000457] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 11/09/2018] [Accepted: 12/26/2018] [Indexed: 12/26/2022] Open
Abstract
Background Steroids are frequently used in patients with metastatic non-small cell lung cancer (mNSCLC), but they could be detrimental for patients treated with immune checkpoint inhibitors (ICIs). Here, we assessed the association between early use of steroids, clinical outcomes and peripheral immune blood cells modulation in patients with mNSCLC treated with ICIs. Methods We reviewed patients with mNSCLC treated at our institution between April 2013 and December 2017. Early use of steroids was defined as the use of a daily prednisone-equivalent dose ≥10 mg for at least 1 day within 28 days after ICI initiation. Peripheral immune blood cell counts were retrieved at baseline and at 4 and 6 weeks after ICI initiation. Results Out of 151 patients included, 35 (23%) made early use of steroids that was associated with poor disease control (OR 0.32, p=0.006), progression-free survival (HR 1.80, p=0.003) and overall survival (HR 2.60, p<0.001). Early use of steroids significantly correlated with higher median absolute neutrophil count, neutrophil to lymphocyte ratio (NLR) and derived NLR, and lower median absolute and relative eosinophil count, both at 4 and 6 weeks after ICI initiation. Conclusions In patients with mNSCLC treated with ICIs, early use of steroids was associated with worse clinical outcomes and remarkable modulation of peripheral blood immune cells, which could contribute to restraining the activation of antitumour immunity. If confirmed in prospective studies, these findings would highlight the importance of carefully evaluating and, whenever possible, avoiding steroids during early phases of ICI treatment.
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Affiliation(s)
- Giovanni Fucà
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Giulia Galli
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Marta Poggi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Giuseppe Lo Russo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Claudia Proto
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Martina Imbimbo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Roberto Ferrara
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Nicoletta Zilembo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Monica Ganzinelli
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Antonio Sica
- Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale 'Amedeo Avogadro', Novara, Italy.,Department of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Valter Torri
- Laboratory of Methodology for Biomedical Research, IRCCS Mario Negri Institute for Pharmacological Research, Milan, Italy
| | - Mario Paolo Colombo
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Claudio Vernieri
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.,Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy
| | - Andrea Balsari
- Dipartimento di Scienze Biomediche per la Salute, University of Milan, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.,Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
| | - Marina Chiara Garassino
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Diego Signorelli
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
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21
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Yi J, Chen Z, Xu F, Wang Z, Zhang A, Liu T, Zhao N, Xiong Y, Jiang G, Ma J, Luan X. IL-27 Promotes Human Placenta-Derived Mesenchymal Stromal Cell Ability To Induce the Generation of CD4 +IL-10 +IFN-γ + T Cells via the JAK/STAT Pathway in the Treatment of Experimental Graft-versus-Host Disease. THE JOURNAL OF IMMUNOLOGY 2019; 202:1124-1136. [PMID: 30651340 DOI: 10.4049/jimmunol.1800963] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022]
Abstract
Human mesenchymal stromal cells (MSCs) harbor immunomodulatory properties to induce the generation of suppressive T cells. MSCs have been successfully used in treating graft-versus-host disease (GVHD) accompanied by abundant inflammatory cytokines such as IL-27. This study investigated the effects of IL-27 on the human placenta-derived MSCs (hPMSCs) to induce generation of CD4+IL-10+IFN-γ+ T cells in vitro and in the humanized xenogenic GVHD NOD/SCID model. The results showed that the percentages of CD4+IL-10+IFN-γ+ T cells were significantly increased in activated human PBMC from both healthy donors and GVHD patients with hPMSCs and in the liver and spleen of hPMSC-treated GVHD mice, and the level of CD4+IL-10+IFN-γ+ T cells in the liver was greater than that in the spleen in hPMSC-treated GVHD mice. The serum level of IL-27 decreased and the symptoms abated in hPMSC-treated GVHD. Further, in vitro results showed that IL-27 promoted the regulatory effects of hPMSCs by enhancing the generation of CD4+IL-10+IFN-γ+ T cells from activated PBMC. Activation occurred through increases in the expression of programmed death ligand 2 (PDL2) in hPMSCs via the JAK/STAT signaling pathway. These findings indicated that hPMSCs could alleviate GVHD mice symptoms by upregulating the production of CD4+IL-10+IFN-γ+ T cells in the spleen and liver and downregulating serum levels of IL-27. In turn, the ability of hPMSCs to induce the generation of CD4+IL-10+IFN-γ+ T cells could be promoted by IL-27 through increases in PDL2 expression in hPMSCs. The results of this study will be of benefit for the application of hPMSCs in clinical trials.
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Affiliation(s)
- Junzhu Yi
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264003, China
| | - Zhenghua Chen
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong Province 264100, China
| | - Fenghuang Xu
- The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570102, China
| | - ZhuoYa Wang
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264003, China
| | - Aiping Zhang
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264003, China
| | - Tongshen Liu
- Department of Histology and Embryology, Binzhou Medical University, Yantai, Shandong Province 264003, China
| | - Nannan Zhao
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264003, China
| | - Yanlian Xiong
- Department of Anatomy, Binzhou Medical University, Yantai, Shandong Province 264003, China
| | - Guosheng Jiang
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264003, China
| | - Junjie Ma
- Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong Province 264000, China; and
| | - Xiying Luan
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264003, China; .,Taishan Scholar Immunology Program, Binzhou Medical University, Yantai, Shandong Province 264003, China
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22
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Effect of a Combination of Prednisone or Mycophenolate Mofetil and Mesenchymal Stem Cells on Lupus Symptoms in MRL. Faslpr Mice. Stem Cells Int 2018; 2018:4273107. [PMID: 30057623 PMCID: PMC6051060 DOI: 10.1155/2018/4273107] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 05/10/2018] [Accepted: 06/03/2018] [Indexed: 01/27/2023] Open
Abstract
The combination of immunosuppressants and mesenchymal stem cells (MSCs) is a promising therapeutic strategy for systemic lupus erythematosus, since this approach reduces doses of immunosuppressants while maintaining the same therapeutic outcome. However, it is unavoidable for MSCs to be exposed to immunosuppressants. Here, we examined the combination effect of prednisone (PD) or mycophenolate mofetil (MMF) and MSCs. We showed that PD or MMF in combination with MSCs showed better therapeutic effect than single therapy in lupus-prone MRL.Faslpr mice, as assessed by using the following readouts: prolongation of survival, decrease in anti-dsDNA and total IgG levels in serum, decrease in cytokine gene expression in spleen cells, and decrease in inflammatory cell infiltration into the kidney. In vitro, immunosuppressants and MSCs inhibited T cell proliferation in a synergistic manner. However, immunosuppressants did not affect MSC viability and functions such as TGF-β1 and PGE2 production, migration, and immunosuppressive capacity. In summary, our study demonstrates that a combination of immunosuppressants and MSCs is a good strategy to reduce the side effects of PD and MMF without the loss of therapeutic outcome.
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23
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Kaundal U, Bagai U, Rakha A. Immunomodulatory plasticity of mesenchymal stem cells: a potential key to successful solid organ transplantation. J Transl Med 2018; 16:31. [PMID: 29448956 PMCID: PMC5815241 DOI: 10.1186/s12967-018-1403-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 02/07/2018] [Indexed: 02/06/2023] Open
Abstract
Organ transplantation remains to be a treatment of choice for patients suffering from irreversible organ failure. Immunosuppressive (IS) drugs employed to maintain the allograft have shown excellent short-term graft survival, but, their long-term use could contribute to immunological and non-immunological risk factors, resulting in graft dysfunctionalities. Upcoming IS regimes have highlighted the use of cell-based therapies, which can eliminate the risk of drug-borne toxicities while maintaining efficacy of the treatment. Mesenchymal stem cells (MSCs) have been considered as an invaluable cell type, owing to their unique immunomodulatory properties, which makes them desirable for application in transplant settings, where hyper-activation of the immune system is evident. The immunoregulatory potential of MSCs holds true for preclinical studies while achieving it in clinical studies continues to be a challenge. Understanding the biological factors responsible for subdued responses of MSCs in vivo would allow uninhibited use of this therapy for countless conditions. In this review, we summarize the variations in the preclinical and clinical studies utilizing MSCs, discuss the factors which might be responsible for variability in outcome and propose the advancements likely to occur in future for using this as a "boutique/personalised therapy" for patient care.
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Affiliation(s)
- Urvashi Kaundal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
- Department of Zoology, Panjab University, Sector 14, Chandigarh, India
| | - Upma Bagai
- Department of Zoology, Panjab University, Sector 14, Chandigarh, India
| | - Aruna Rakha
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
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24
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Casiraghi F, Perico N, Remuzzi G. Mesenchymal stromal cells for tolerance induction in organ transplantation. Hum Immunol 2017; 79:304-313. [PMID: 29288697 DOI: 10.1016/j.humimm.2017.12.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 12/06/2017] [Accepted: 12/18/2017] [Indexed: 12/20/2022]
Abstract
The primary challenge in organ transplantation continues to be the need to suppress the host immune system long-term to ensure prolonged allograft survival. Long-term non-specific immunosuppression can, however, result in life-threatening complications. Thus, efforts have been pursued to explore novel strategies that would allow minimization of maintenance immunosuppression, eventually leading to transplant tolerance. In this scenario, bone marrow-derived mesenchymal stromal cells (MSC), given their unique immunomodulatory properties to skew the balance between regulatory and memory T cells, have emerged as potential candidates for cell-based therapy to promote immune tolerance. Here, we review our initial clinical experience with bone marrow-derived MSC in living-donor kidney transplant recipients and provide an overview of the available results of other clinical programs with MSC in kidney and liver transplantation, highlighting hurdles and success of this innovative cell-based therapy.
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Affiliation(s)
| | - Norberto Perico
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
| | - Giuseppe Remuzzi
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST), Papa Giovanni XXIII, Bergamo, Italy; L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
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25
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Javorkova E, Vackova J, Hajkova M, Hermankova B, Zajicova A, Holan V, Krulova M. The effect of clinically relevant doses of immunosuppressive drugs on human mesenchymal stem cells. Biomed Pharmacother 2017; 97:402-411. [PMID: 29091890 DOI: 10.1016/j.biopha.2017.10.114] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/17/2017] [Accepted: 10/21/2017] [Indexed: 12/15/2022] Open
Abstract
Immunosuppressive drugs are used to suppress graft rejection after transplantation and for the treatment of various diseases. The main limitations of their use in clinical settings are severe side effects, therefore alternative approaches are desirable. In this respect, mesenchymal stem cells (MSCs) possess a regenerative and immunomodulatory capacity that has generated considerable interest for their use in cell-based therapy. Currently, MSCs are tested in many clinical trials, including the treatment of diseases which require simultaneous immunosuppressive treatment. Since the molecular targets of immunosuppressive drugs are also present in MSCs, we investigated whether immunosuppressive drugs interact with the activity of MSCs. Human MSCs isolated from the bone marrow (BM) or adipose tissue (AT) were cultured in the presence of clinical doses of five widely used immunosuppressive drugs (cyclosporine A, mycophenolate mofetil, rapamycin, prednisone and dexamethasone), and the influence of these drugs on several factors related to the immunosuppressive properties of MSCs, including the expression of immunomodulatory enzymes, various growth factors, cytokines, chemokines, adhesion molecules and proapoptotic ligands, was assessed. Glucocorticoids, especially dexamethasone, showed the most prominent effects on both types of MSCs and suppressed the expression of the majority of the factors that were tested. A significant increase of hepatocyte growth factor production in AT-MSCs and of indoleamine 2,3-dioxygenase expression in both types of MSCs were the only exceptions. In conclusion, clinically relevant doses of inhibitors of calcineurin, mTOR and IMPDH and glucocorticoids interfere with MSC functions, but do not restrain their immunosuppressive properties. These findings should be taken into account before preparing immunosuppressive strategies combining the use of immunosuppressive drugs and MSCs.
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Affiliation(s)
- Eliska Javorkova
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague 2, 128 44, Czech Republic; Department of Transplantation Immunology, The Czech Academy of Sciences, Institute of Experimental Medicine, Videnska 1083, Prague 4, 142 20, Czech Republic.
| | - Julie Vackova
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague 2, 128 44, Czech Republic.
| | - Michaela Hajkova
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague 2, 128 44, Czech Republic; Department of Transplantation Immunology, The Czech Academy of Sciences, Institute of Experimental Medicine, Videnska 1083, Prague 4, 142 20, Czech Republic.
| | - Barbora Hermankova
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague 2, 128 44, Czech Republic; Department of Transplantation Immunology, The Czech Academy of Sciences, Institute of Experimental Medicine, Videnska 1083, Prague 4, 142 20, Czech Republic.
| | - Alena Zajicova
- Department of Transplantation Immunology, The Czech Academy of Sciences, Institute of Experimental Medicine, Videnska 1083, Prague 4, 142 20, Czech Republic.
| | - Vladimir Holan
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague 2, 128 44, Czech Republic; Department of Transplantation Immunology, The Czech Academy of Sciences, Institute of Experimental Medicine, Videnska 1083, Prague 4, 142 20, Czech Republic.
| | - Magdalena Krulova
- Department of Cell Biology, Faculty of Science, Charles University, Vinicna 7, Prague 2, 128 44, Czech Republic; Department of Transplantation Immunology, The Czech Academy of Sciences, Institute of Experimental Medicine, Videnska 1083, Prague 4, 142 20, Czech Republic.
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