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Zhao DZ, Yang RL, Wei HX, Yang K, Yang YB, Wang NX, Zhang Q, Chen F, Zhang T. Advances in the research of immunomodulatory mechanism of mesenchymal stromal/stem cells on periodontal tissue regeneration. Front Immunol 2025; 15:1449411. [PMID: 39830512 PMCID: PMC11739081 DOI: 10.3389/fimmu.2024.1449411] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 12/13/2024] [Indexed: 01/22/2025] Open
Abstract
Periodontal disease is a highly prevalent disease worldwide that seriously affects people's oral health, including gingivitis and periodontitis. Although the current treatment of periodontal disease can achieve good control of inflammation, it is difficult to regenerate the periodontal supporting tissues to achieve a satisfactory therapeutic effect. In recent years, due to the good tissue regeneration ability, the research on Mesenchymal stromal/stem cells (MSCs) and MSC-derived exosomes has been gradually deepened, especially its ability to interact with the microenvironment of the body in the complex immunoregulatory network, which has led to many new perspectives on the therapeutic strategies for many diseases. This paper systematically reviews the immunomodulatory (including bone immunomodulation) properties of MSCs and their role in the periodontal inflammatory microenvironment, summarizes the pathways and mechanisms by which MSCs and MSC-EVs have promoted periodontal regeneration in recent years, lists potential areas for future research, and describes the issues that should be considered in future basic research and the direction of development of "cell-free therapies" for periodontal regeneration.
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Affiliation(s)
- De-Zhi Zhao
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Rui-Lin Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Han-Xiao Wei
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Kang Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Yi-Bing Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Nuo-Xin Wang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Qian Zhang
- Department of Human Anatomy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Fang Chen
- Department of Prosthetics, Affiliated Stomatology Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
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Wang X, Shi T, Jiao Y, Geng Q, Zhao H, Deng T, Xiao C. Human umbilical mesenchymal stem cell-derived exosomes alleviate bone destruction and regulate bone immunity via the aryl hydrocarbon receptor to treat rheumatoid arthritis. Int Immunopharmacol 2024; 143:113340. [PMID: 39418734 DOI: 10.1016/j.intimp.2024.113340] [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: 07/31/2024] [Revised: 09/29/2024] [Accepted: 10/04/2024] [Indexed: 10/19/2024]
Abstract
OBJECTIVE Rheumatoid arthritis (RA) can lead to joint deformity, loss of function, and even disability. Bone erosion is a common cause of disability in individuals with RA; bone resorption by osteoclasts (OCs) and bone immunity by regulatory T cells (Tregs) play key roles in this process. Human umbilical mesenchymal stem cells (HUMSCs) can be used to treat RA; however, the regulation of Tregs and OCs by HUMSCs and their therapeutic effects on RA have not been fully elucidated. This study aimed to reveal the effects of exosomes derived from HUMSCs carrying miRNA-150-5p on Tregs and OCs in individuals with RA and to provide innovative evidence for the ability of HUMSCs to alleviate RA. METHODS First, we used collagen-induced arthritis (CIA) model mice to verify the efficacy of miR-150-5pmimic-Exos and explored their effects on bone erosion in mouse joints and on Tregs in the lymph nodes. Subsequently, miR-150-5pmimic-Exos and the aryl hydrocarbon receptor (AhR) inhibitor CH223191 were used in in vitro OCs, Tregs, and OC-Treg coculture systems to determine whether miR-150-5pmimic-Exos regulate bone immune microenvironment homeostasis via AhR. RESULTS Treatment with miR-150-5pmimic-Exos effectively alleviated bone damage to the ankle and knee joints in CIA model mice, inhibited OC differentiation, activated the immunosuppressive function of Tregs, and regulated bone immunity by increasing the expression of AhR/CYP1A1 signalling pathway genes such as Ahr, Arnt, Ahrr, Cyp1a1/1a2 and Cyp1b1 in OCs and Tregs. By coculturing Tregs and OCs, the ability of the miR-150-5pmimic-Exos to inhibit OC differentiation was further strengthened. CONCLUSIONS This study confirmed that miR-150-5pmimic-Exos can reduce bone destruction in mice with CIA. We first showed that miR-150-5pmimic-Exos acted on a Treg-OC coculture system to alleviate bone erosion and regulate bone immunity. This study is expected to provide new ideas for the treatment of RA.
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Affiliation(s)
- Xing Wang
- Beijing University of Chinese Medicine, School of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China; Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China
| | - Tong Shi
- China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Yi Jiao
- Beijing University of Chinese Medicine, School of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China; Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China
| | - Qishun Geng
- China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Hongyan Zhao
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Tingting Deng
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China.
| | - Cheng Xiao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China; Department of Emergency, China-Japan Friendship Hospital, Beijing 100029, China.
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Niu Q, Hao J, Li Z, Zhang H. Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review). Mol Med Rep 2024; 30:215. [PMID: 39370806 PMCID: PMC11450432 DOI: 10.3892/mmr.2024.13339] [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: 07/17/2024] [Accepted: 09/06/2024] [Indexed: 10/08/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease whose etiology is not fully understood. Defective peripheral immune tolerance and subsequent mis‑differentiation and aberrant infiltration of synovium by various immune cells, especially helper T (Th) cells, play an important role in the development of RA. There are significant sex differences in RA, but the results of studies on the effects of sex hormones on RA have been difficult to standardize and hormone replacement therapy has been limited by the potential for serious side effects. Existing research has amply demonstrated that cellular immune responses are largely determined by sex and that sex hormones play a key role in Th cell responses. Based on the aforementioned background and the plasticity of Th cells, it is reasonable to hypothesize that the action of sex hormones on Th cells will hopefully become a therapeutic target for RA. The present review discussed the role of various Th cell subsets in the pathogenesis of RA and also explored the role of sex hormones on the phenotype and function of these aberrantly regulated immune cells in RA as well as other pathologic effects on RA.
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Affiliation(s)
- Quanjun Niu
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Junhang Hao
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Zhen Li
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Huiping Zhang
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
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Li C, Sun Y, Xu W, Chang F, Wang Y, Ding J. Mesenchymal Stem Cells-Involved Strategies for Rheumatoid Arthritis Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305116. [PMID: 38477559 PMCID: PMC11200100 DOI: 10.1002/advs.202305116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/13/2023] [Indexed: 03/14/2024]
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints and bone destruction. Because of systemic administration and poor targeting, traditional anti-rheumatic drugs have unsatisfactory treatment efficacy and strong side effects, including myelosuppression, liver or kidney function damage, and malignant tumors. Consequently, mesenchymal stem cells (MSCs)-involved therapy is proposed for RA therapy as a benefit of their immunosuppressive and tissue-repairing effects. This review summarizes the progress of MSCs-involved RA therapy through suppressing inflammation and promoting tissue regeneration and predicts their potential clinical application.
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Affiliation(s)
- Chaoyang Li
- Department of OrthopedicsThe Second Hospital of Jilin University4026 Yatai StreetChangchun130041P. R. China
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
| | - Yifu Sun
- Department of OrthopedicsThe Second Hospital of Jilin University4026 Yatai StreetChangchun130041P. R. China
| | - Weiguo Xu
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
| | - Fei Chang
- Department of OrthopedicsThe Second Hospital of Jilin University4026 Yatai StreetChangchun130041P. R. China
| | - Yinan Wang
- Department of BiobankDivision of Clinical ResearchThe First Hospital of Jilin University1 Xinmin StreetChangchun130061P. R. China
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of EducationThe First Hospital of Jilin University1 Xinmin StreetChangchun130061P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
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Bakinowska E, Bratborska AW, Kiełbowski K, Ćmil M, Biniek WJ, Pawlik A. The Role of Mesenchymal Stromal Cells in the Treatment of Rheumatoid Arthritis. Cells 2024; 13:915. [PMID: 38891047 PMCID: PMC11171813 DOI: 10.3390/cells13110915] [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: 04/20/2024] [Revised: 05/15/2024] [Accepted: 05/23/2024] [Indexed: 06/20/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterised by the formation of a hyperplastic pannus, as well as cartilage and bone damage. The pathogenesis of RA is complex and involves broad interactions between various cells present in the inflamed synovium, including fibroblast-like synoviocytes (FLSs), macrophages, and T cells, among others. Under inflammatory conditions, these cells are activated, further enhancing inflammatory responses and angiogenesis and promoting bone and cartilage degradation. Novel treatment methods for RA are greatly needed, and mesenchymal stromal cells (MSCs) have been suggested as a promising new regenerative and immunomodulatory treatment. In this paper, we present the interactions between MSCs and RA-FLSs, and macrophages and T cells, and summarise studies examining the use of MSCs in preclinical and clinical RA studies.
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Affiliation(s)
- Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
| | | | - Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
| | - Maciej Ćmil
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
| | - Wojciech Jerzy Biniek
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
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Pignatti E, Maccaferri M, Pisciotta A, Carnevale G, Salvarani C. A comprehensive review on the role of mesenchymal stromal/stem cells in the management of rheumatoid arthritis. Expert Rev Clin Immunol 2024; 20:463-484. [PMID: 38163928 DOI: 10.1080/1744666x.2023.2299729] [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: 09/18/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease with systemic manifestations. Although the success of immune modulatory drug therapy is considerable, about 40% of patients do not respond to treatment. Mesenchymal stromal/stem cells (MSCs) have been demonstrated to have therapeutic potential for inflammatory diseases. AREAS COVERED This review provides an update on RA disease and on pre-clinical and clinical studies using MSCs from bone marrow, umbilical cord, adipose tissue, and dental pulp, to regulate the immune response. Moreover, the clinical use, safety, limitations, and future perspective of MSCs in RA are discussed. Using the PubMed database and ClincalTrials.gov, peer-reviewed full-text papers, abstracts and clinical trials were identified from 1985 through to April 2023. EXPERT OPINION MSCs demonstrated a satisfactory safety profile and potential for clinical efficacy. However, it is mandatory to deepen the investigations on how MSCs affect the proinflammatory deregulated RA patients' cells. MSCs are potentially good candidates for severe RA patients not responding to conventional therapies but a long-term follow-up after stem cells treatment and standardized protocols are needed. Future research should focus on well-designed multicenter randomized clinical trials with adequate sample sizes and properly selected patients satisfying RA criteria for a valid efficacy evaluation.
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Affiliation(s)
- Elisa Pignatti
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Monia Maccaferri
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Pisciotta
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Gianluca Carnevale
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Salvarani
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
- Rheumatology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
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Bakinowska E, Kiełbowski K, Pawlik A. The Role of Extracellular Vesicles in the Pathogenesis and Treatment of Rheumatoid Arthritis and Osteoarthritis. Cells 2023; 12:2716. [PMID: 38067147 PMCID: PMC10706487 DOI: 10.3390/cells12232716] [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: 10/26/2023] [Revised: 11/24/2023] [Accepted: 11/25/2023] [Indexed: 12/18/2023] Open
Abstract
Cells can communicate with each other through extracellular vesicles (EVs), which are membrane-bound structures that transport proteins, lipids and nucleic acids. These structures have been found to mediate cellular differentiation and proliferation apoptosis, as well as inflammatory responses and senescence, among others. The cargo of these vesicles may include immunomodulatory molecules, which can then contribute to the pathogenesis of various diseases. By contrast, EVs secreted by mesenchymal stem cells (MSCs) have shown important immunosuppressive and regenerative properties. Moreover, EVs can be modified and used as drug carriers to precisely deliver therapeutic agents. In this review, we aim to summarize the current evidence on the roles of EVs in the progression and treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), which are important and prevalent joint diseases with a significant global burden.
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Affiliation(s)
| | | | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.)
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Yu H, Pan Y, Dai M, Wang X, Chen H. Mesenchymal Stem Cell-Originated Exosomal Lnc A2M-AS1 Alleviates Hypoxia/Reperfusion-Induced Apoptosis and Oxidative Stress in Cardiomyocytes. Cardiovasc Drugs Ther 2023; 37:891-904. [PMID: 35543792 DOI: 10.1007/s10557-022-07339-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-derived exosomes play significant roles in ameliorating cardiac damage after myocardial ischemia-reperfusion (I/R) injury. Long non-coding RNA alpha-2-macroglobulin antisense RNA 1 (Lnc A2M-AS1) was found that might protect against myocardial I/R. However, whether Lnc A2M-AS1 delivery via MSC-derived exosomes could also regulate myocardial I/R injury remains unknown. METHODS Exosomes were isolated by ultracentrifugation, and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Hypoxia/reoxygenation (H/R) treatment in human cardiomyocytes was used to mimic the process of myocardial I/R in vitro. The viability and apoptosis of cardiomyocytes were detected using cell counting kit-8, flow cytometry, and Western blot assays. The contents of lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) were evaluated using corresponding commercial kits. The quantitative real-time polymerase chain reaction and Western blot were used to determine the expression levels of Lnc A2M-AS1, microRNA (miR)-556-5p, and X-linked inhibitor of apoptosis protein (XIAP). The binding interaction between miR-556-5p and Lnc A2M-AS1 or XIAP was confirmed by the dual-luciferase reporter, RIP and pull-down assays. RESULTS Exosomes isolated from hMSCs (hMSCs-exo) attenuated H/R-induced apoptosis and oxidative stress in cardiomyocytes. Lnc A2M-AS1 was lowly expressed in AMI patients and H/R-induced cardiomyocytes. Besides, Lnc A2M-AS1 was detectable in hMSCs-exo, exosomes derived from Lnc A2M-AS1-transfected hMSCs weakened H/R-induced apoptosis and oxidative stress, and enhanced the protective action of hMSCs-exo on H/R-induced cardiomyocytes. Further mechanism analysis showed that Lnc A2M-AS1 acted as a sponge for miR-556-5p to increase XIAP expression level. Importantly, miR-556-5p overexpression or XIAP knockdown reversed the action of exosomal Lnc A2M-AS1 on H/R-induced cardiomyocytes. CONCLUSION Lnc A2M-AS1 delivery via MSC-derived exosomes ameliorated H/R-induced cardiomyocyte apoptosis and oxidative stress via regulating miR-556-5p/XIAP, opening a new window into the pathogenesis of myocardial I/R injury.
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Affiliation(s)
- Hang Yu
- Department of Cardiovascular Surgery Intensive Care Unit, The Second Affiliated Hospital of Hainan Medical College, Haikou City, Hainan Province, China
| | - Yuxiang Pan
- Department of Critical Care Medicine, The Second Affiliated Hospital of Hainan Medical College, Haikou City, Hainan Province, China
| | - Mingming Dai
- Department of Neurology Three Areas, The Second Affiliated Hospital of Hainan Medical College, Haikou City, Hainan Province, China
| | - Xiaoqi Wang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Hainan Medical College, No. 368 Yehai Avenue, Longhua District, Haikou City, 570105, Hainan Province, China.
| | - Haibo Chen
- Department of Blood Transfusion, The Second Affiliated Hospital of Hainan Medical College, No. 368 Yehai Avenue, Longhua District, Haikou City, 570105, Hainan Province, China.
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Riekert M, Almanzar G, Schmalzing M, Schütze N, Jakob F, Prelog M. Mesenchymal stem cells modulate IL-17 and IL-9 production induced by Th17-inducing cytokine conditions in autoimmune arthritis: an explorative analysis. Adv Rheumatol 2023; 63:37. [PMID: 37525265 DOI: 10.1186/s42358-023-00317-z] [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: 12/08/2022] [Accepted: 07/19/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND The importance of proinflammatory T-cells and their cytokine production in patients with autoimmune arthritis has been widely described. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have come into focus as a potential therapeutic concept. The aim of this study was to investigate the influence of MSCs on the phenotype, cytokine profile, and functionality of naive and non-naive CD4+ T-cells from healthy donors (HD) and patients with autoimmune arthritis under Th17-cytokine polarizing conditions in an explorative way using a transwell system prohibiting any cell-cell-contact. METHODS Magnetically isolated naive and non-naive CD4+ T-cells were stimulated under Th17-polarizing proinflammatory cytokine conditions in presence and absence of bone marrow derived mesenchymal stromal cells (MSCs). After an incubation period of 6 days, the proportions of the T-cell subpopulations TEMRA (CD45RA+CD27-), memory (CD45RA-CD27+), effector (CD45RA-CD27-) and naive cells (CD45RA+CD27+) were determined. Quantitative immunofluorescence intensity was used as a measure for IL-9, IL-17 and IFN-γ production in each subpopulation. RESULTS In isolated naive CD4+ T-cells from HD and patients, MSCs suppressed the differentiation of naive towards an effector phenotype while memory and naive cells showed higher percentages in culture with MSCs. In patients, MSCs significantly decreased the proportion of IL-9 and IL-17 producing effector T-cells. MSCs also reduced IFN-γ production in the naive and memory phenotype from HD. CONCLUSION The results of the study indicate significant immunomodulatory properties of MSCs, as under Th17-polarizing conditions MSCs are still able to control T-cell differentiation and proinflammatory cytokine production in both HD and patients with autoimmune arthritis.
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Affiliation(s)
- Maximilian Riekert
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany.
- Department of Oral and Craniomaxillofacial and Plastic Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Straße 62, 50924, Cologne, Germany.
| | - Giovanni Almanzar
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Marc Schmalzing
- Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany
| | - Norbert Schütze
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Franz Jakob
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Martina Prelog
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
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Sardana Y, Bhatti GK, Singh C, Sharma PK, Reddy PH, Bhatti JS. Progression of pre-rheumatoid arthritis to clinical disease of joints: Potential role of mesenchymal stem cells. Life Sci 2023; 321:121641. [PMID: 36997059 DOI: 10.1016/j.lfs.2023.121641] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/16/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023]
Abstract
Rheumatoid arthritis (RA) related autoimmunity is developed at mucosal sites due to the interplay between genetic risk factors and environmental triggers. The pre-RA phase that leads to anti-citrullinated protein antibodies, rheumatoid factor, and other autoantibodies spread in the systemic circulation may not affect articular tissue for years until a mysterious second hit triggers the localization of RA-related autoimmunity in joints. Several players in the joint microenvironment mediate the synovial innate and adaptive immunological processes, eventually leading to clinical synovitis. There still exists a gap in the early phase of RA pathogenesis, i.e., the progression of diseases from the systemic circulation to joints. The lack of better understanding of these events results in the inability to answer questions about why only after a certain point of time the disease appears in joints and why in some cases, it simply remains latent and doesn't affect joints at all. In the current review, we focused on the immunomodulatory and regenerative role of mesenchymal stem cells and associated exosomes in RA pathology. We also highlighted the age-related dysregulations in activities of mesenchymal stem cells and how that might trigger homing of systemic autoimmunity to joints.
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Affiliation(s)
- Yogesh Sardana
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India
| | - Charan Singh
- Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University, Uttarakhand, India
| | | | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA.
| | - Jasvinder Singh Bhatti
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
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Abo-Aziza FAM, Wasfy BM, Wahba SMR, Abd-Elhalem SS. Mesenchymal Stem Cells and Myeloid-Derived Suppressor Cells Interplay in Adjuvant-Induced Arthritis Rat Model. Int Immunopharmacol 2023; 120:110300. [PMID: 37192553 DOI: 10.1016/j.intimp.2023.110300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/27/2023] [Accepted: 05/05/2023] [Indexed: 05/18/2023]
Abstract
There has not been much researchs on the biological relationship between myeloid-derived suppressor cells (MDSCs) and mesenchymal stem cells (MSCs). The goal of the current work is to examine how these cells cooperate with one another in a rat model of adjuvant-induced arthritis (AIA). Three groups of equal numbers of rats were created; the first group served as the control. Complete Freund's adjuvant (CFA) was injected into the second group to induce AIA. The third group underwent MSCstreatment. Three weeks later, ANA, IL-1β, IL-4, IL-6, IL-10, TNF-α, IFN-γ, M-CSF, iNOS and Arg-1 were determined using ELISA. Flowcytometric studies for MDSCs using CD11bc + and His48 + antibodies were performed. Current results showed significantly higher levels of WBCs, ANA, IL-1, IL-4, IL-6, IL-10, TNF-α, M-CSF, iNOS and Arg-1 along with a significant rise in MDSCs % in the AIA group compared to the control group. As opposed to AIA animals, MSCs administration resulted in a considerable improvement in cytokine levels, supporting the immunomodulation function of MSCs. Histological examination of the joints in the AIA group revealed articular cartilage degradation as well as infiltration of inflammatory cells and fibroplasia. These several evidences suggested that MDSCs may perform various roles in autoimmunity. Understanding how MDSCs and MSCs contribute to arthritis may help their prospective application in immunotherapy. Therefore, the reciprocal collaboration of MSCs and MDSCs must therefore be the subject of new investigations, which can offer new platforms for the development of more effective and individualized therapies for the treatment of immunological illnesses.
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Affiliation(s)
- Faten A M Abo-Aziza
- Department of Parasitology and Animal Diseases, Veterinary Research Institute, National Research Centre, 12622 Cairo, Egypt.
| | - Basma M Wasfy
- Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, 11757 Cairo, Egypt
| | - Sanaa M R Wahba
- Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, 11757 Cairo, Egypt
| | - Sahar S Abd-Elhalem
- Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, 11757 Cairo, Egypt
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12
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Laranjeira P, dos Santos F, Salvador MJ, Simões IN, Cardoso CMP, Silva BM, Henriques-Antunes H, Corte-Real L, Couceiro S, Monteiro F, Santos C, Santiago T, da Silva JAP, Paiva A. Umbilical-Cord-Derived Mesenchymal Stromal Cells Modulate 26 Out of 41 T Cell Subsets from Systemic Sclerosis Patients. Biomedicines 2023; 11:1329. [PMID: 37239000 PMCID: PMC10215673 DOI: 10.3390/biomedicines11051329] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/20/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Systemic sclerosis (SSc) is an immune-mediated disease wherein T cells are particularly implicated, presenting a poor prognosis and limited therapeutic options. Thus, mesenchymal-stem/stromal-cell (MSC)-based therapies can be of great benefit to SSc patients given their immunomodulatory, anti-fibrotic, and pro-angiogenic potential, which is associated with low toxicity. In this study, peripheral blood mononuclear cells from healthy individuals (HC, n = 6) and SSc patients (n = 9) were co-cultured with MSCs in order to assess how MSCs affected the activation and polarization of 58 different T cell subsets, including Th1, Th17, and Treg. It was found that MSCs downregulated the activation of 26 out of the 41 T cell subsets identified within CD4+, CD8+, CD4+CD8+, CD4-CD8-, and γδ T cells in SSc patients (HC: 29/42) and affected the polarization of 13 out of 58 T cell subsets in SSc patients (HC: 22/64). Interestingly, SSc patients displayed some T cell subsets with an increased activation status and MSCs were able to downregulate all of them. This study provides a wide-ranging perspective of how MSCs affect T cells, including minor subsets. The ability to inhibit the activation and modulate the polarization of several T cell subsets, including those implicated in SSc's pathogenesis, further supports the potential of MSC-based therapies to regulate T cells in a disease whose onset/development may be due to immune system's malfunction.
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Affiliation(s)
- Paula Laranjeira
- Flow Cytometry Unit, Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal;
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal
| | - Francisco dos Santos
- Stemlab S.A., Famicord Group, 3060-197 Cantanhede, Portugal; (F.d.S.); (I.N.S.); (C.M.P.C.); (H.H.-A.); (L.C.-R.); (S.C.); (F.M.); (C.S.)
| | - Maria João Salvador
- Rheumatology Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal; (M.J.S.); (T.S.)
| | - Irina N. Simões
- Stemlab S.A., Famicord Group, 3060-197 Cantanhede, Portugal; (F.d.S.); (I.N.S.); (C.M.P.C.); (H.H.-A.); (L.C.-R.); (S.C.); (F.M.); (C.S.)
| | - Carla M. P. Cardoso
- Stemlab S.A., Famicord Group, 3060-197 Cantanhede, Portugal; (F.d.S.); (I.N.S.); (C.M.P.C.); (H.H.-A.); (L.C.-R.); (S.C.); (F.M.); (C.S.)
| | - Bárbara M. Silva
- Algarve Biomedical Center (ABC), Universidade do Algarve, 8005-139 Faro, Portugal;
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, 8005-139 Faro, Portugal
- Doctoral Program in Biomedical Sciences, Faculty of Medicine and Biomedical Sciences, Universidade do Algarve, 8005-139 Faro, Portugal
| | - Helena Henriques-Antunes
- Stemlab S.A., Famicord Group, 3060-197 Cantanhede, Portugal; (F.d.S.); (I.N.S.); (C.M.P.C.); (H.H.-A.); (L.C.-R.); (S.C.); (F.M.); (C.S.)
| | - Luísa Corte-Real
- Stemlab S.A., Famicord Group, 3060-197 Cantanhede, Portugal; (F.d.S.); (I.N.S.); (C.M.P.C.); (H.H.-A.); (L.C.-R.); (S.C.); (F.M.); (C.S.)
| | - Sofia Couceiro
- Stemlab S.A., Famicord Group, 3060-197 Cantanhede, Portugal; (F.d.S.); (I.N.S.); (C.M.P.C.); (H.H.-A.); (L.C.-R.); (S.C.); (F.M.); (C.S.)
| | - Filipa Monteiro
- Stemlab S.A., Famicord Group, 3060-197 Cantanhede, Portugal; (F.d.S.); (I.N.S.); (C.M.P.C.); (H.H.-A.); (L.C.-R.); (S.C.); (F.M.); (C.S.)
| | - Carolina Santos
- Stemlab S.A., Famicord Group, 3060-197 Cantanhede, Portugal; (F.d.S.); (I.N.S.); (C.M.P.C.); (H.H.-A.); (L.C.-R.); (S.C.); (F.M.); (C.S.)
| | - Tânia Santiago
- Rheumatology Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal; (M.J.S.); (T.S.)
| | - José A. P. da Silva
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Rheumatology Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal; (M.J.S.); (T.S.)
| | - Artur Paiva
- Flow Cytometry Unit, Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal;
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal;
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, 3046-854 Coimbra, Portugal
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Arshad M, Jalil F, Jaleel H, Ghafoor F. Bone marrow derived mesenchymal stem cells therapy for rheumatoid arthritis - a concise review of past ten years. Mol Biol Rep 2023; 50:4619-4629. [PMID: 36929285 DOI: 10.1007/s11033-023-08277-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/11/2023] [Indexed: 03/18/2023]
Abstract
Rheumatoid arthritis is an autoimmune disorder characterized by swelling in synovial joints and erosion of bones. The disease is normally treated with conventional drugs which provide only temporary relief to the symptoms. Over the past few years, mesenchymal stromal cells have become the center of attention for treating this disease due to their immuno-modulatory and anti-inflammatory characteristics. Various studies on treatment of rheumatoid arthritis by using these cells have shown positive outcomes in terms of reduction in the level of pain as well as improvement of the function and structure of joints. Mesenchymal stromal cells can be derived from multiple sources, however, the ones derived from bone marrow are considered most beneficial for treating several disorders including rheumatoid arthritis on account of being safer and more effective. This review summarizes all the preclinical and clinical studies which were conducted over the last ten years for therapy of rheumatoid arthritis utilizing these cells. The literature was reviewed using the terms "mesenchymal stem/stromal cells and rheumatoid arthritis'' and "bone marrow derived mesenchymal stromal cells and therapy of rheumatoid arthritis''. Data was extracted to enable the readers to have access to the most relevant information regarding advancement in therapeutic potential of these stromal cells. Additionally, this review will also help in fulfilling any gap in current knowledge of readers about the outcome of using these cells in animal models, cell line and in patients suffering from rheumatoid arthritis and other autoimmune disorders as well.
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Affiliation(s)
- Maria Arshad
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan.
| | - Fazal Jalil
- Department of Biotechnology, Abdul Wali Khan University, Mardan, Pakistan
| | - Hadiqa Jaleel
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan
| | - Farkhanda Ghafoor
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan
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14
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Hackel A, Vollmer S, Bruderek K, Lang S, Brandau S. Immunological priming of mesenchymal stromal/stem cells and their extracellular vesicles augments their therapeutic benefits in experimental graft-versus-host disease via engagement of PD-1 ligands. Front Immunol 2023; 14:1078551. [PMID: 36875112 PMCID: PMC9978482 DOI: 10.3389/fimmu.2023.1078551] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/09/2023] [Indexed: 02/18/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) exert profound anti-inflammatory and regenerative effects in inflammation and tissue damage, which makes them an attractive tool for cellular therapies. In this study we have assessed the inducible immunoregulatory properties of MSCs and their EVs upon stimulation with different combinations of cytokines. First, we found that MSCs primed with IFN-γ, TNF-α and IL-1β, upregulate the expression of PD-1 ligands, as crucial mediators of their immunomodulatory activity. Further, primed MSCs and MSC-EVs, compared to unstimulated MSCs and MSC-EVs, had increased immunosuppressive effects on activated T cells and mediated an enhanced induction of regulatory T cells, in a PD-1 dependent manner. Importantly, EVs derived from primed MSCs reduced the clinical score and prolonged the survival of mice in a model of graft-versus-host disease. These effects could be reversed in vitro and in vivo by adding neutralizing antibodies directed against PD-L1 and PD-L2 to both, MSCs and their EVs. In conclusion, our data reveal a priming strategy that potentiates the immunoregulatory function of MSCs and their EVs. This concept also provides new opportunities to improve the clinical applicability and efficiency of cellular or EV-based therapeutic MSC products.
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Affiliation(s)
- Alexander Hackel
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sebastian Vollmer
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Kirsten Bruderek
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Stephan Lang
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sven Brandau
- Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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15
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Fu Y, Li J, Zhang Z, Ren F, Wang Y, Jia H, Liu J, Chang Z. Umbilical cord mesenchymal stem cell-derived exosomes alleviate collagen-induced arthritis by balancing the population of Th17 and regulatory T cells. FEBS Lett 2022; 596:2668-2677. [PMID: 35918178 DOI: 10.1002/1873-3468.14460] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/20/2022] [Accepted: 07/13/2022] [Indexed: 11/07/2022]
Abstract
Exosomes released by mesenchymal stem cells (MSCs) are thought to function as extensions of the MSCs. However, it remains unclear whether exosomes derived from human umbilical cord MSCs (HUMSCs) possess immunoregulatory functions in rheumatoid arthritis. We report that when mice with collagen-induced arthritis were injected with exosomes derived from HUMSC (HUMSC-Exo), their paws became less swollen, and they had lower serum pro-inflammatory cytokine and anti-collagen IgG levels, and decreased synovial hyperplasia. The HUMSC-Exo appeared to restore the balance between Th17 and Treg cells, and this effect was accompanied by reduced IL-17 and enhanced TGF-β and IL-10 levels. These findings suggest that HUMSC-Exo function as important regulator of the balance between Th1/Th17 and Treg cells during immune and inflammatory responses.
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Affiliation(s)
- Yanxia Fu
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, China
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Jun Li
- TsCell Biotech Inc., Beijing, China
| | - Ziyu Zhang
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Fangli Ren
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Yinyin Wang
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Huihui Jia
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Jihe Liu
- Beijing No. 2 Middle School, China
| | - Zhijie Chang
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
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16
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Wu X, Ma J. miR-568 Regulates Bone Marrow Mesenchymal Stem Cells (BMSCs) Homing into Joint Tissue in Rheumatoid Arthritis (RA). J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
This study assessed the biological molecular mechanism of miR-568 on bone marrow mesenchymal stem cells (BMSCs) homing into joint tissue in RA. BMSCs in joint tissue of RA patients was isolated and cultured. The form of BMSCs was observed with microscope and the surface antigen was
identified with flow cytometry. The level of miRNA-568, NFATc4, SOX5 and CD17 was detected. The binding relation between SOX5 and miRNA-568 was predicted and validated with multiple kinds of bioinformatics software including Targetscan, miRWalk and miRDB. The level of miRNA-568 in group with
BMSCS homing into joint tissue was higher than normal. SOX5 level in RA patients was lower than normal adults. There was a binding relationship between miRNA-568 and SOX5. Overexpression of miR-568 significantly reduced SOX5, NFATc4 and CD17 level. In conclusion, the BMSCs homing into joint
tissue could be regulated by miRNA-568 through targeting on SOX5 so as to develop effect on retraining the inflammatory response.
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Affiliation(s)
- Xiaodong Wu
- Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, Jiangsu, 215001, China
| | - Jianjun Ma
- Department of Joint Surgery, Yudong Hospital, Chongqing, 404600, China
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17
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Adipose-Derived Stem Cell Exosomes as a Novel Anti-Inflammatory Agent and the Current Therapeutic Targets for Rheumatoid Arthritis. Biomedicines 2022; 10:biomedicines10071725. [PMID: 35885030 PMCID: PMC9312519 DOI: 10.3390/biomedicines10071725] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/15/2022] [Accepted: 07/15/2022] [Indexed: 11/17/2022] Open
Abstract
Patients with rheumatoid arthritis (RA), a chronic inflammatory joint disorder, may not respond adequately to current RA treatments. Mesenchymal stem cells (MSCs) elicit several immunomodulatory and anti-inflammatory effects and, thus, have therapeutic potential. Specifically, adipose-derived stem cell (ADSC)-based RA therapy may have considerable potency in modulating the immune response, and human adipose tissue is abundant and easy to obtain. Paracrine factors, such as exosomes (Exos), contribute to ADSCs’ immunomodulatory function. ADSC-Exo-based treatment can reproduce ADSCs’ immunomodulatory function and overcome the limitations of traditional cell therapy. ADSC-Exos combined with current drug therapies may provide improved therapeutic effects. Using ADSC-Exos, instead of ADSCs, to treat RA may be a promising cell-free treatment strategy. This review summarizes the current knowledge of medical therapies, ADSC-based therapy, and ADSC-Exos for RA and discusses the anti-inflammatory properties of ADSCs and ADSC-Exos. Finally, this review highlights the expanding role and potential immunomodulatory activity of ADSC-Exos in patients with RA.
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18
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Li YJ, Chen Z. Cell-based therapies for rheumatoid arthritis: opportunities and challenges. Ther Adv Musculoskelet Dis 2022; 14:1759720X221100294. [PMID: 35634355 PMCID: PMC9131381 DOI: 10.1177/1759720x221100294] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 04/26/2022] [Indexed: 11/18/2022] Open
Abstract
Rheumatoid arthritis (RA) is the most common immune-mediated inflammatory disease characterized by chronic synovitis that hardly resolves spontaneously. The current treatment of RA consists of nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, conventional disease-modifying antirheumatic drugs (cDMARDs), biologic and targeted synthetic DMARDs. Although the treat-to-target strategy has been intensively applied in the past decade, clinical unmet needs still exist since a substantial proportion of patients are refractory or even develop severe adverse effects to current therapies. In recent years, with the deeper understanding of immunopathogenesis of the disease, cell-based therapies have exhibited effective and promising interventions to RA. Several cell-based therapies, such as mesenchymal stem cells (MSC), adoptive transfer of regulatory T cells (Treg), and chimeric antigen receptor (CAR)-T cell therapy as well as their beneficial effects have been documented and verified so far. In this review, we summarize the current evidence and discuss the prospect as well as challenges for these three types of cellular therapies in RA.
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Affiliation(s)
- Yu-Jing Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Second Clinical Medical School, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Martinez-Arroyo O, Ortega A, Forner MJ, Cortes R. Mesenchymal Stem Cell-Derived Extracellular Vesicles as Non-Coding RNA Therapeutic Vehicles in Autoimmune Diseases. Pharmaceutics 2022; 14:pharmaceutics14040733. [PMID: 35456567 PMCID: PMC9028692 DOI: 10.3390/pharmaceutics14040733] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/17/2022] [Accepted: 03/26/2022] [Indexed: 02/07/2023] Open
Abstract
Autoimmune diseases (ADs) are characterized by the activation of the immune system against self-antigens. More common in women than in men and with an early onset, their incidence is increasing worldwide, and this, combined with their chronic nature, is contributing to an enlarged medical and economic burden. Conventional immunosuppressive agents are designed to alleviate symptoms but do not constitute an effective therapy, highlighting a need to develop new alternatives. In this regard, mesenchymal stem cells (MSCs) have demonstrated powerful immunosuppressive and regenerative effects. MSC-derived extracellular vesicles (MSC-EVs) have shown some advantages, such as less immunogenicity, and are proposed as novel therapies for ADs. In this review, we summarize current perspectives on therapeutic options for ADs based on MSCs and MSC-EVs, focusing particularly on their mechanism of action exerted through their non-coding RNA (ncRNA) cargo. A complete state-of-the-art review was performed, centralized on some of the most severe ADs (rheumatoid arthritis, autoimmune type 1 diabetes mellitus, and systemic lupus erythematosus), giving evidence that a promising field is evolving to overcome the current knowledge and provide new therapeutic possibilities centered on MSC-EVs and their role as ncRNA delivery vehicles for AD gene therapy.
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Affiliation(s)
- Olga Martinez-Arroyo
- Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (O.M.-A.); (M.J.F.)
| | - Ana Ortega
- Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (O.M.-A.); (M.J.F.)
- Correspondence: (A.O.); (R.C.); Tel.: +34-96398-3916 (R.C.); Fax: +34-96398-7860 (R.C.)
| | - Maria J. Forner
- Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (O.M.-A.); (M.J.F.)
- Internal Medicine Unit, Hospital Clinico Universitario, 46010 Valencia, Spain
| | - Raquel Cortes
- Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (O.M.-A.); (M.J.F.)
- Correspondence: (A.O.); (R.C.); Tel.: +34-96398-3916 (R.C.); Fax: +34-96398-7860 (R.C.)
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20
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Laranjeira P, Pedrosa M, Duarte C, Pedreiro S, Antunes B, Ribeiro T, dos Santos F, Martinho A, Fardilha M, Domingues MR, Abecasis M, Pereira da Silva JA, Paiva A. Human Bone Marrow Mesenchymal Stromal/Stem Cells Regulate the Proinflammatory Response of Monocytes and Myeloid Dendritic Cells from Patients with Rheumatoid Arthritis. Pharmaceutics 2022; 14:pharmaceutics14020404. [PMID: 35214136 PMCID: PMC8880255 DOI: 10.3390/pharmaceutics14020404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 12/15/2022] Open
Abstract
Rheumatoid arthritis (RA) is a disabling autoimmune disease whose treatment is ineffective for one-third of patients. Thus, the immunomodulatory potential of mesenchymal stromal/stem cells (MSCs) makes MSC-based therapy a promising approach to RA. This study aimed to explore the immunomodulatory action of human bone marrow (BM)-MSCs on myeloid dendritic cells (mDCs) and monocytes, especially on cytokines/chemokines involved in RA physiopathology. For that, LPS plus IFNγ-stimulated peripheral blood mononuclear cells from RA patients (n = 12) and healthy individuals (n = 6) were co-cultured with allogeneic BM-MSCs. TNF-α, CD83, CCR7 and MIP-1β protein levels were assessed in mDCs, classical, intermediate, and non-classical monocytes. mRNA expression of other cytokines/chemokines was also evaluated. BM-MSCs effectively reduced TNF-α, CD83, CCR7 and MIP-1β protein levels in mDCs and all monocyte subsets, in RA patients. The inhibition of TNF-α production was mainly achieved by the reduction of the percentage of cellsproducing this cytokine. BM-MSCs exhibited a remarkable suppressive action over antigen-presenting cells from RA patients, potentially affecting their ability to stimulate the immune adaptive response at different levels, by hampering their migration to the lymph node and the production of proinflammatory cytokines and chemokines. Accordingly, MSC-based therapies can be a valuable approach for RA treatment, especially for non-responder patients.
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Affiliation(s)
- Paula Laranjeira
- Flow Cytometry Unit, Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, Av. Bissaya Barreto, Bloco de Celas, 3000-075 Coimbra, Portugal;
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; (C.D.); (J.A.P.d.S.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Polo 1, 1.° Piso, FMUC, Rua Larga, 3004-504 Coimbra, Portugal
| | - Mónia Pedrosa
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
- Signal Transduction Laboratory, Center of Cellular Biology, SACS and Department of Biology, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;
- Enzifarma—Diagnostica e Farmacêutica, S.A., Estrada da Luz, n.° 90, 2° F, 1600-160 Lisbon, Portugal
| | - Cátia Duarte
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; (C.D.); (J.A.P.d.S.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Rheumatology Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal
| | - Susana Pedreiro
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
| | - Brígida Antunes
- Cell2B Advanced Therapeutics, SA, Biocant Park, Núcleo 04, Lote 4A, 3060-197 Cantanhede, Portugal; ; (B.A.); (T.R.); (F.d.S.)
| | - Tânia Ribeiro
- Cell2B Advanced Therapeutics, SA, Biocant Park, Núcleo 04, Lote 4A, 3060-197 Cantanhede, Portugal; ; (B.A.); (T.R.); (F.d.S.)
| | - Francisco dos Santos
- Cell2B Advanced Therapeutics, SA, Biocant Park, Núcleo 04, Lote 4A, 3060-197 Cantanhede, Portugal; ; (B.A.); (T.R.); (F.d.S.)
- Stemlab SA, Biocant Park, Núcleo 04, Lote 2, 3060-197 Cantanhede, Portugal
| | - António Martinho
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
| | - Margarida Fardilha
- Signal Transduction Laboratory, Center of Cellular Biology, SACS and Department of Biology, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;
- Laboratory of Signal Transduction, Institute of Biomedicine—iBiMED, Department of Medical Sciences, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - M. Rosário Domingues
- Mass Spectrometry Centre, LAQV REQUIMTE, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal;
- Centre for Environmental and Marine Studies (CESAM), Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal
| | - Manuel Abecasis
- Serviço de Transplantação de Progenitores Hematopoiéticos (UTM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Rua Professor Lima Basto, 1099-023 Lisbon, Portugal;
- Instituto Português do Sangue e da Transplantação—CEDACE, Alameda das Linhas de Torres, 117, 1769-001 Lisbon, Portugal
| | - José António Pereira da Silva
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; (C.D.); (J.A.P.d.S.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Rheumatology Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal
| | - Artur Paiva
- Flow Cytometry Unit, Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, Av. Bissaya Barreto, Bloco de Celas, 3000-075 Coimbra, Portugal;
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; (C.D.); (J.A.P.d.S.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, Rua 5 de Outubro, 3046-854 Coimbra, Portugal
- Correspondence: ; Tel.: +351-239-488-700
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Ma L, Wei J, Zeng Y, Liu J, Xiao E, Kang Y, Kang Y. Mesenchymal stem cell-originated exosomal circDIDO1 suppresses hepatic stellate cell activation by miR-141-3p/PTEN/AKT pathway in human liver fibrosis. Drug Deliv 2022; 29:440-453. [PMID: 35099348 PMCID: PMC8812765 DOI: 10.1080/10717544.2022.2030428] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Liver fibrosis is a common pathologic stage of the development of liver failure. It has showed that exosomes loaded with therapeutic circRNAs can be manufactured in bulk by exosome secreted cells in vitro, thus enabling personalized treatment. This study aimed to investigate the role of exosome-based delivery of circDIDO1 in liver fibrosis. Levels of genes and proteins were examined by qRT-PCR and Western blot. Cell proliferation, apoptosis, and cell cycle were analyzed by using cell counting kit-8 (CCK-8) assay, EdU assay, and flow cytometry, respectively. The binding between circDIDO1 and miR-141-3p was confirmed by dual-luciferase reporter, RNA pull-down and RIP assays. Exosomes were isolated by ultracentrifugation, and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. CircDIDO1 overexpression or miR-141-3p inhibition suppressed the proliferation, reduced pro-fibrotic markers, and induced apoptosis as well as cell cycle arrest in hepatic stellate cells (HSCs) by blocking PTEN/AKT pathway. Mechanistically, circDIDO1 acted as an endogenous sponge for miR-141-3p, further rescue experiments showed that circDIDO1 suppressed HSC activation by targeting miR-141-3p. Extracellular circDIDO1 could be incorporated into exosomes isolated from mesenchymal stem cells (MSCs), and transmitted to HSCs to restrain HSC activation. Clinically, low levels of serum circDIDO1 in exosome were correlated with liver failure, and serum exosomal circDIDO1 had a well diagnostic value for liver fibrosis in liver failure patients. Transfer of circDIDO1 mediated by MSC-isolated exosomes suppressed HSC activation through the miR-141-3p/PTEN/AKT pathway, gaining a new insight into the prevention of liver fibrosis in liver failure patients.
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Affiliation(s)
- Li Ma
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China
| | - Junfeng Wei
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China
| | - Yanli Zeng
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China
| | - Junping Liu
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China
| | - Erhui Xiao
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China
| | - Yuehua Kang
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China
| | - Yi Kang
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China
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22
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Liu Y, Peng L, Li L, Huang C, Shi K, Meng X, Wang P, Wu M, Li L, Cao H, Wu K, Zeng Q, Pan H, Lu WW, Qin L, Ruan C, Wang X. 3D-bioprinted BMSC-laden biomimetic multiphasic scaffolds for efficient repair of osteochondral defects in an osteoarthritic rat model. Biomaterials 2021; 279:121216. [PMID: 34739982 DOI: 10.1016/j.biomaterials.2021.121216] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 10/13/2021] [Accepted: 10/20/2021] [Indexed: 01/09/2023]
Abstract
Osteochondral defect repair in osteoarthritis (OA) remains an unsolved clinical problem due to the lack of enough seed cells in the defect and chronic inflammation in the joint. To address this clinical need, we designed a bone marrow-derived mesenchymal stem cell (BMSC)-laden 3D-bioprinted multilayer scaffold with methacrylated hyaluronic acid (MeHA)/polycaprolactone incorporating kartogenin and β-TCP for osteochondral defect repair within each region. BMSC-laden MeHA was designed to actively introduce BMSCs in situ, and diclofenac sodium (DC)-incorporated matrix metalloproteinase-sensitive peptide-modified MeHA was induced on the BMSC-laden scaffold as an anti-inflammatory strategy. BMSCs in the scaffolds survived, proliferated, and produced large amounts of cartilage-specific extracellular matrix in vitro. The effect of BMSC-laden scaffolds on osteochondral defect repair was investigated in an animal model of medial meniscectomy-induced OA. BMSC-laden scaffolds facilitated chondrogenesis by promoting collagen II and suppressed interleukin 1β in osteochondral defects of the femoral trochlea. Congruently, BMSC-laden scaffolds significantly improved joint function of the injured leg with respect to the ground support force, paw grip force, and walk gait parameters. Therefore, this research demonstrates the potential of 3D-bioprinted BMSC-laden scaffolds to simultaneously inhibit joint inflammation and promote cartilage defect repair in OA joints.
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Affiliation(s)
- Yanzhi Liu
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Medical Research Institute, Guangdong Medical University, Zhanjiang, 524023, China
| | - Liuqi Peng
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Lingli Li
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Cuishan Huang
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Keda Shi
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Xiangbo Meng
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Pinpin Wang
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Mingming Wu
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Ling Li
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Huijuan Cao
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Kefeng Wu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Medical Research Institute, Guangdong Medical University, Zhanjiang, 524023, China
| | - Qingqiang Zeng
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Haobo Pan
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - William Weijia Lu
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Department of Orthopaedic and Traumatology, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China
| | - Ling Qin
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Changshun Ruan
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
| | - Xinluan Wang
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
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Zou H, Zhou N, Huang Y, Luo A, Sun J. Phenotypes, roles, and modulation of regulatory lymphocytes in periodontitis and its associated systemic diseases. J Leukoc Biol 2021; 111:451-467. [PMID: 33884656 DOI: 10.1002/jlb.3vmr0321-027rrr] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Periodontitis is a common chronic inflammatory disease that can result in tooth loss and poses a risk to systemic health. Lymphocytes play important roles in periodontitis through multiple mechanisms. Regulatory lymphocytes including regulatory B cells (Bregs) and T cells (Tregs) are the main immunosuppressive cells that maintain immune homeostasis, and are critical to our understanding of the pathogenesis of periodontitis and the development of effective treatments. In this review, we discuss the phenotypes, roles, and modulating strategies of regulatory lymphocytes including Bregs and Tregs in periodontitis and frequently cooccurring inflammatory diseases such as rheumatoid arthritis, Alzheimer disease, diabetes mellitus, and stroke. The current evidence suggests that restoring immune balance through therapeutic targeting of regulatory lymphocytes is a promising strategy for the treatment of periodontitis and other systemic inflammatory diseases.
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Affiliation(s)
- Hang Zou
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Niu Zhou
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Guangzhou Zoo, Guangzhou, China
| | - Yilian Huang
- School of Nursing, Guangdong Pharmaceutical University, Guangzhou, China
| | - Aoxiang Luo
- School of Nursing, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jianbo Sun
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
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Zhu HS, Li D, Li C, Huang JX, Chen SS, Li LB, Shi Q, Ju XL. Prior transfusion of umbilical cord mesenchymal stem cells can effectively alleviate symptoms of motion sickness in mice through interleukin 10 secretion. World J Stem Cells 2021; 13:177-192. [PMID: 33708346 PMCID: PMC7933988 DOI: 10.4252/wjsc.v13.i2.177] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/31/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Motion sickness (MS) is a disease that occurs during unbalanced movement, characterized by gastrointestinal symptoms and autonomic nervous system activation. Current clinical treatments for MS are limited. Recent evidence indicates that the levels of pro-inflammatory cytokines increase during MS and are associated with an inner ear immune imbalance. In the present study, mesenchymal stem cells (MSCs) have been shown to exert strong immuno-suppressive effects.
AIM To explore whether umbilical cord-derived mesenchymal stem cells (UC-MSCs) can prevent the occurrence of MS, and the underlying mechanism regulated by MSCs in a mouse model of MS.
METHODS A total of 144 (equal numbers of males and females) 5wkold BALB/c mice were randomly divided into five groups: Normal group (n = 16), MS group (n = 32), MSCs group (n = 32), MS + MSCs group (n = 32), and MS + AS101/MSCs group (n = 32). The MSCs group (n = 32), MS + MSCs group (n = 32), and MS + AS101/MSCs group (n = 32) were preventively transplanted with UC-MSCs or AS101-treated UC-MSCs (1 × 106 cells/mouse). Mice in the MS (n = 32), MS + MSCs, and MS + AS101/MSCs groups were subjected to rotation on a centrifuge for 10 min at 8 × g/min for MS model establishment on days 3, 5, 8, and 10 after UC-MSCs injection. The Morris water maze (MWM) test was used to observe the symptom of dizziness. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect the levels of inflammatory cytokines in mice peripheral blood and the petrous part of the temporal bone samples. Western blot analysis was performed to analyze the JAK2/STAT3 signaling pathway in the cochlear tissues. Histological examination was performed by hematoxylin and eosin (HE) staining for conventional morphological evaluation in the petrous part of temporal bone samples.
RESULTS The MWM test demonstrated that UC-MSCs improved the symptoms of MS. The MS + MSCs group was faster than the MS group on days 3 and 5 (P = 0.036 and P = 0.002, respectively). ELISA and RT-qPCR showed that the serum and mRNA levels of interleukin-10 (IL-10) in the cochlear tissues were increased after transplantation with UC-MSCs (MS + MSCs group vs MS group at 3 and 5 d, P = 0.002 and cP < 0.001, respectively). RT-qPCR results confirmed a significant increase in IL-10 levels at four time points (MS + MSCs group vs MS group, P = 0.009, P = 0.009, P = 0.048, and P = 0.049, respectively). This suggested that UC-MSCs reduced the sensitivity of the vestibular microenvironment by secreting IL-10. Moreover, Western blot analysis showed that the MSCs activated the JAK2/STAT3 signaling pathway in the cochlear tissues. The levels of IL-10, IL-10RA, JAK2, STAT3, and phosphorylated JAK2 and STAT3 in the MS + MSCs group were increased compared to those of the MS group (P < 0.05). The morphological changes in the four groups showed no significant differences. The role of IL-10 secretion on the ability of UC-MSCs to successfully improve the symptoms of MS was confirmed by the diminished therapeutic effects associated with treatment with the IL-10 inhibitor ammonium trichloro (dioxoethylene-o,o′) tellurate (AS101).
CONCLUSION Prophylactic transplantation of UC-MSCs can alleviate the clinical symptoms of MS in mice, particularly at 3-5 d after preventive transplantation. The mechanism for UC-MSCs to reduce the sensitivity of vestibular cortex imbalance may be the secretion of IL-10. The next step is to demonstrate the possibility of curing MS in the vestibular environment by intermittent transplantation of MSCs. Above all, MSCs are expected to become a new method for the clinical prevention and treatment of MS.
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Affiliation(s)
- Hua-Su Zhu
- Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Dong Li
- Stem Cell and Regenerative Medicine Research Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Cong Li
- Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Jin-Xian Huang
- Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Shan-Shan Chen
- Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Lan-Bo Li
- Department of Animal Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Qing Shi
- Stem Cell and Regenerative Medicine Research Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Xiu-Li Ju
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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25
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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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Podestà MA, Remuzzi G, Casiraghi F. Mesenchymal Stromal Cell Therapy in Solid Organ Transplantation. Front Immunol 2021; 11:618243. [PMID: 33643298 PMCID: PMC7902912 DOI: 10.3389/fimmu.2020.618243] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/29/2020] [Indexed: 12/29/2022] Open
Abstract
Transplantation is the gold-standard treatment for the failure of several solid organs, including the kidneys, liver, heart, lung and small bowel. The use of tailored immunosuppressive agents has improved graft and patient survival remarkably in early post-transplant stages, but long-term outcomes are frequently unsatisfactory due to the development of chronic graft rejection, which ultimately leads to transplant failure. Moreover, prolonged immunosuppression entails severe side effects that severely impact patient survival and quality of life. The achievement of tolerance, i.e., stable graft function without the need for immunosuppression, is considered the Holy Grail of the field of solid organ transplantation. However, spontaneous tolerance in solid allograft recipients is a rare and unpredictable event. Several strategies that include peri-transplant administration of non-hematopoietic immunomodulatory cells can safely and effectively induce tolerance in pre-clinical models of solid organ transplantation. Mesenchymal stromal cells (MSC), non-hematopoietic cells that can be obtained from several adult and fetal tissues, are among the most promising candidates. In this review, we will focus on current pre-clinical evidence of the immunomodulatory effect of MSC in solid organ transplantation, and discuss the available evidence of their safety and efficacy in clinical trials.
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Affiliation(s)
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Bergamo, Italy
| | - Federica Casiraghi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Bergamo, Italy
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27
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Su Y, Liu Y, Ma C, Guan C, Ma X, Meng S. Mesenchymal stem cell-originated exosomal lncRNA HAND2-AS1 impairs rheumatoid arthritis fibroblast-like synoviocyte activation through miR-143-3p/TNFAIP3/NF-κB pathway. J Orthop Surg Res 2021; 16:116. [PMID: 33549125 PMCID: PMC7866436 DOI: 10.1186/s13018-021-02248-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
Background Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) was found to be elevated in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs). However, whether HAND2-AS1 functions as an exosomal lncRNA related to mesenchymal stem cells (MSCs) in RA progression is unknown. Methods The expression of HAND2-AS1, microRNA (miR)-143-3p, and tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) was detected using quantitative real-time polymerase chain reaction and Western blot. Cell proliferation, apoptosis, migration, and invasion were detected using cell counting kit-8, flow cytometry, and wound healing and transwell assays. The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL)-6 were analyzed using enzyme-linked immunosorbent assay. The level of phosphorylated-p65 was examined by Western blot. The binding interaction between miR-143-3p and HAND2-AS1 or TNFAIP3 was confirmed by the dual-luciferase reporter and RIP assays. Exosomes were isolated by ultracentrifugation and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Results HAND2-AS1 was lowly expressed in RA synovial tissues, and HAND2-AS1 re-expression suppressed the proliferation, motility, and inflammation and triggered the apoptosis in RA-FLSs via the inactivation of NF-κB pathway. Mechanistically, HAND2-AS1 directly sponged miR-143-3p and positively regulated TNFAIP3 expression, the target of miR-143-3p. Moreover, the effects of HAND2-AS1 on RA-FLSs were partially attenuated by miR-143-3p upregulation or TNFAIP3 knockdown. HAND2-AS1 could be packaged into hMSC-derived exosomes and absorbed by RA-FLSs, and human MSC-derived exosomal HAND2-AS1 also repressed above malignant biological behavior of RA-FLSs. Conclusion MSC-derived exosomes participated in the intercellular transfer of HAND2-AS1 and suppressed the activation of RA-FLSs via miR-143-3p/TNFAIP3/NF-κB pathway, which provided a novel insight into the pathogenesis and treatment of RA.
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Affiliation(s)
- Yuhua Su
- Department of Rheumatology and Immunology, Affiliated Hospital of Weifang Medical University, NO.2428 Yuhe Road, Kuiwen District, Weifang, 261000, Shandong, China
| | - Yajing Liu
- Department of Rheumatology and Immunology, Affiliated Hospital of Weifang Medical University, NO.2428 Yuhe Road, Kuiwen District, Weifang, 261000, Shandong, China
| | - Chao Ma
- Internal medicine, Yuncheng Hospital of traditional Chinese Medicine, Heze, 274700, Shandong, China
| | - Chunxiao Guan
- Department of Rheumatology and Immunology, Affiliated Hospital of Weifang Medical University, NO.2428 Yuhe Road, Kuiwen District, Weifang, 261000, Shandong, China
| | - Xiufen Ma
- Department of Rheumatology and Immunology, Affiliated Hospital of Weifang Medical University, NO.2428 Yuhe Road, Kuiwen District, Weifang, 261000, Shandong, China
| | - Shan Meng
- Department of Rheumatology and Immunology, Affiliated Hospital of Weifang Medical University, NO.2428 Yuhe Road, Kuiwen District, Weifang, 261000, Shandong, China.
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Inhibition of Rheumatoid Arthritis Using Bark, Leaf, and Male Flower Extracts of Eucommia ulmoides. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:3260278. [PMID: 32855647 PMCID: PMC7443016 DOI: 10.1155/2020/3260278] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 05/21/2020] [Accepted: 07/10/2020] [Indexed: 12/29/2022]
Abstract
Eucommia ulmoides Oliv., a native Chinese plant species, has been used as a traditional Chinese medicine formulation to treat rheumatoid arthritis (RA), strengthen bones and muscles, and lower blood pressure. Various parts of this plant such as the bark, leaves, and flowers have been found to have anti-inflammatory properties. E. ulmoides has potential applications as a therapeutic agent against bone disorders, which were investigated in this study. In vitro, RA joint fibroblast-like synoviocytes (RA-FLS) were treated with different concentrations (0, 25, 50, 100, 200, 400, 800, and 1000 μg/mL) of E. ulmoides bark, leaf, and male flower alcoholic extracts (EB, EL, and EF, respectively) to determine their potential cytotoxicity. Tumor necrosis factor- (TNF-) α and nitric oxide (NO) levels in RA-FLS were quantified using enzyme-linked immunosorbent assay (ELISA). Furthermore, collagen-induced arthritis (CIA) rats were treated with EB, EL, EF, Tripterygium wilfordii polyglycoside (TG) or the normal control (Nor), and then ankle joint pathology, bone morphology, and serum and spleen inflammatory cytokine levels were evaluated. The results showed that, in RA-FLS, EB, EL, and EF were not cytotoxic; EB and EF reduced TNF-α supernatant levels; and EB, EL, and EF reduced NO levels. The results of in vivo experiments showed that EB, EL, and EF alleviated ankle swelling and joint inflammation, while all extracts diminished inflammatory cell infiltration, pannus and bone destruction, and bone erosion. All tested extracts inhibited interleukin- (IL-) 6, IL-17, and TNF-α mRNA in the spleen of CIA rats, while EB most effectively reduced osteoclasts and inhibited bone erosion. EF showed the most obvious inhibition of inflammatory factors and pannus. Thus, EB, EL, and EF may alleviate bone destruction by inhibiting inflammation.
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Yang JH, Liu FX, Wang JH, Cheng M, Wang SF, Xu DH. Mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles: Potential roles in rheumatic diseases. World J Stem Cells 2020; 12:688-705. [PMID: 32843922 PMCID: PMC7415241 DOI: 10.4252/wjsc.v12.i7.688] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/26/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been widely investigated in rheumatic disease due to their immunomodulatory and regenerative properties. Recently, mounting studies have implicated the therapeutic potency of MSCs mostly due to the bioactive factors they produce. Extracellular vesicles (EVs) derived from MSCs have been identified as a promising cell-free therapy due to low immunogenicity. Rheumatic disease, primarily including rheumatoid arthritis and osteoarthritis, is a group of diseases in which immune dysregulation and chronic progressive inflammation lead to irreversible joint damage. Targeting MSCs and MSC-derived EVs may be a more effective and promising therapeutic strategy for rheumatic diseases.
AIM To evaluate the potential therapeutic effectiveness of MSCs and EVs generated from MSCs in rheumatic diseases.
METHODS PubMed was searched for the relevant literature using corresponding search terms alone or in combination. Papers published in English language from January 1999 to February 2020 were considered. Preliminary screening of papers concerning analysis of "immunomodulatory function" or "regenerative function" by scrutinizing the titles and abstracts of the literature, excluded the papers not related to the subject of the article. Some other related studies were obtained by manually retrieving the reference lists of papers that comply with the selection criteria, and these studies were screened to meet the final selection and exclusion criteria.
RESULTS Eighty-six papers were ultimately selected for analysis. After analysis of the literature, it was found that both MSCs and EVs generated from MSCs have great potential in multiple rheumatic diseases, such as rheumatoid arthritis and osteoarthritis, in repair and regeneration of tissues, inhibition of inflammatory response, and regulation of body immunity via promoting chondrogenesis, regulating innate and adaptive immune cells, and regulating the secretion of inflammatory factors. But EVs from MSCs exhibit much more advantages over MSCs, which may represent another promising cell-free restorative strategy. Targeting MSCs and MSC-derived EVs may be a more efficient treatment for patients with rheumatic diseases.
CONCLUSION The enormous potential of MSCs and EVs from MSCs in immunomodulation and tissue regeneration offers a new idea for the treatment of rheumatism. However, more in-depth exploration is needed before their clinical application.
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Affiliation(s)
- Jing-Han Yang
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Feng-Xia Liu
- Department of Allergy, Weifang People’s Hospital, Weifang 261000, Shandong Province, China
| | - Jing-Hua Wang
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Min Cheng
- Department of Physiology, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Shu-Feng Wang
- Medical Experimental Training Center, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Dong-Hua Xu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
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Abstract
Mesenchymal stromal or stem cells (MSC) possess strong immunomodulatory properties. Due to their impressive potential to differentiate into various cell types they are capable of inducing mechanisms of tissue repair. Experimental data have demonstrated impaired MSC function in several rheumatic diseases in vitro; however, the relevance of these phenomena for the pathogenesis of rheumatic disorders has not been convincingly demonstrated. Nevertheless, allogeneic MSC transplantation (MSCT), and possibly autologous MSCT as well, could prove to be an interesting instrument for the treatment of autoimmune rheumatic diseases. The first clinical trials have demonstrated positive effects in systemic lupus erythematosus, systemic sclerosis and Sjogren's syndrome; however, questions regarding the long-term benefits and safety as well as the best source, the optimal cultivation technique and the most effective way of application of MSC are still unanswered.
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Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro. Stem Cell Res Ther 2020; 11:91. [PMID: 32111238 PMCID: PMC7049226 DOI: 10.1186/s13287-020-01612-y] [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: 11/14/2019] [Revised: 01/15/2020] [Accepted: 02/18/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction Mesenchymal stem cells (MSCs) exert immunomodulatory functions by inducing the development and differentiation of naive T cells into T cells with an anti-inflammatory regulatory T cell (Treg) phenotype. Our previous study showed that hepatocyte growth factor (HGF) secreted by MSCs had immunomodulatory effects in the context of lipopolysaccharide (LPS) stimulation. We hypothesized that HGF is a key factor in the MSC-mediated regulation of the T helper 17 (Th17) cell/regulatory T (Treg) cell balance. Methods We investigated the effects of MSCs on the differentiation of CD4+ T cells and the functions of Th17/Treg cells in response to LPS stimulation by performing in vitro coculture experiments. MSCs were added to the upper chambers of cell culture inserts, and CD4+ T cells were plated in the lower chambers, followed by treatment with LPS or an anti-HGF antibody. Th17 (CD4+CD3+RORrt+) and Treg (CD4+CD25+Foxp3+) cell frequencies were analysed by flow cytometry, and the expression of Th17 cell- and Treg cell-related cytokines in the CD4+ T cells or culture medium was measured by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Neutrophil functions were determined by flow cytometry after a coculture with Th17/Treg cells. Results The percentage of CD4+CD25+Foxp3+ cells was significantly increased in the CD4+ T cell population, while the percentage of CD4+CD3+RORrt+ cells was significantly decreased after MSC coculture. However, the MSC-induced effect was significantly inhibited by the anti-HGF antibody (p < 0.05). Furthermore, MSCs significantly inhibited the CD4+ T cell expression of IL-17 and IL-6 but increased the expression of IL-10 (p < 0.05 or p < 0.01); these effects were inhibited by the anti-HGF antibody (p < 0.05). In addition, CD4+ T cells cocultured with MSCs significantly inhibited neutrophil phagocytic and oxidative burst activities (p < 0.05 or p < 0.01); however, these MSC-induced effects were inhibited by the anti-HGF antibody (p < 0.05). Conclusion These data suggested that MSCs induced the conversion of fully differentiated Th17 cells into functional Treg cells and thereby modulated the Th17/Treg cell balance in the CD4+ T cell population, which was partly attributed to HGF secreted by the MSCs.
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