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      Mesenchymal stem cells alleviate experimental autoimmune cholangitis through immunosuppression and cytoprotective function mediated by galectin-9

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          Abstract

          Background

          Mesenchymal stem cells (MSCs) play an anti-inflammatory role by secreting certain bioactive molecules to exert their therapeutic effects for disease treatment. However, the underlying mechanism of MSCs in chronic autoimmune liver diseases—primary biliary cholangitis (PBC), for example—remains to be elucidated.

          Methods

          Human umbilical cord–derived MSCs (UC-MSCs) were injected intravenously into 2-octynoic acid coupled to bovine serum albumin (2OA-BSA)-induced autoimmune cholangitis mice. Serum levels of biomarkers and autoantibodies, histologic changes in the liver, diverse CD4 + T-cell subsets in different tissues, and chemokine activities were analyzed. Moreover, we investigated galectin-9 (Gal-9) expression and its function in UC-MSCs.

          Results

          In this study, UC-MSC transplantation (UC-MSCT) significantly ameliorated liver inflammation, primarily by diminishing T helper 1 (Th1) and Th17 responses as well as modifying liver chemokine activities in experimental autoimmune cholangitis mice. Mechanistically, UC-MSCs significantly repressed the proliferation of CD4 + T cells and suppressed the differentiation of Th1 and Th17 cells, which was likely dependent on Gal-9. Furthermore, the signal transducer and activator of transcription (STAT) and c-Jun N-terminal kinase (JNK) signaling pathways were involved in the production of Gal-9 in UC-MSCs.

          Conclusions

          These results suggest that Gal-9 contributes significantly to UC-MSC–mediated therapeutic effects and improve our understanding of the immunomodulatory mechanisms of MSCs in the treatment of PBC.

          Electronic supplementary material

          The online version of this article (10.1186/s13287-018-0979-x) contains supplementary material, which is available to authorized users.

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          Most cited references37

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          Mesenchymal Stem Cell-Based Tissue Regeneration is Governed by Recipient T Lymphocyte via IFN-γ and TNF-α

          Stem cell-based regenerative medicine is a promising approach for tissue reconstruction. Here, we showed that pro-inflammatory T cells in the recipients inhibited bone marrow mesenchymal stem cell (BMMSC)-mediated bone formation via T helper 1 (Th1) cytokine interferon (IFN)-γ induced down-regulation of runt-related transcription factor 2 (Runx-2) pathway and tumor necrosis factor (TNF)-α-regulated BMMSC apoptosis. TNF-α converted IFN-γ-activated non-apoptotic Fas to a caspase 3/8-associated apoptotic signaling in BMMSCs through inhibition of nuclear factor kappa B (NFκB), resulting in BMMSC apoptosis. Conversely, reduction of IFN-γ and TNF-α levels by systemic infusion of Foxp3+ regulatory T cells (Tregs) markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL6 mice. Furthermore, we showed that local administration of aspirin reduced levels of IFN-γ and TNF-α at the implantation site and significantly improved BMMSC-based calvarial defect repair. These data collectively uncover a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.
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            Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair.

            Mesenchymal stem cells (MSCs) have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-gamma with TNF-alpha, IL-1alpha or IL-1beta. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression: immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide (NO), whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase (IDO). Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.
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              Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis.

              The effects of galectin-9 on a mouse collagen-induced arthritis (CIA) model were assessed to clarify whether galectin-9 suppresses CIA by regulating T cell immune responses. Galectin-9 suppressed CIA in a dose-dependent manner, and such suppression was observed even when treatment was started on 7 days after the booster, indicating its preventive and therapeutic effects. Galectin-9 induced the decreased levels of pro-inflammatory cytokines, IL-17, IL-12, and IFNgamma in the joint. Galectin-9 induced the decreased number of CD4(+) TIM-3(+) T cells in peripheral blood. Galectin-9-deficient mice became susceptible to CIA may be by increased number of CD4(+) TIM-3(+) T cells and decreased number of Treg cells. We further found that galectin-9 induces differentiation of naive T cells to Treg cells, and it suppresses differentiation to Th17 cells in vitro. The present results suggested that galectin-9 ameliorates CIA by suppressing the generation of Th17, promoting the induction of regulatory T cells.
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                Author and article information

                Contributors
                fjy707@163.com
                xjtang09@163.com
                wangqian198886@163.com
                gerardzhang@126.com
                wushufang_nju@126.com
                lorna_li@126.com
                shan_liu_shan@163.com
                yaogenhong@126.com
                +86-25-68182422 , chenhw02@hotmail.com
                +86-25-68182422 , lingyunsun@nju.edu.cn
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                17 September 2018
                17 September 2018
                2018
                : 9
                : 237
                Affiliations
                [1 ]ISNI 0000 0004 1765 1045, GRID grid.410745.3, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, , Nanjing University of Chinese Medicine, ; Nanjing, 210008 China
                [2 ]ISNI 0000 0004 1800 1685, GRID grid.428392.6, Department of Rheumatology and Immunology, , The Affiliated Drum Tower Hospital of Nanjing University Medical School, ; 321 Zhongshan Road, Nanjing, 210008 China
                Author information
                http://orcid.org/0000-0003-3392-0770
                Article
                979
                10.1186/s13287-018-0979-x
                6142687
                30223894
                b9249d19-21ae-4a91-9cb2-d31d0f944374
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 5 March 2018
                : 9 August 2018
                : 13 August 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 91442119
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Molecular medicine
                umbilical cord–derived mesenchymal stem cells,primary biliary cholangitis,galectin-9,inflammation

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