间充质干细胞在类风湿性关节炎治疗中的免疫调节作用
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摘要
背景:间充质干细胞拥有强大的抗炎和免疫调节功能,有关其治疗类风湿性关节炎的实验研究已经深入开展,其可能成为临床治疗类风湿性关节炎的新方法,但具体的分子机制有待阐明。目的:为更好地理解间充质干细胞治疗类风湿性关节炎的分子机制,进一步补充间充质干细胞对炎症性关节炎保护作用方面的最新进展,探讨间充质干细胞移植治疗类风湿性关节炎效果的差异,期待这些成果能为开发精准化靶点治疗类风湿性关节炎的药物提供新思路。方法:检索PubMed、Elsevier、CNKI和万方数据库,查阅2008至2019年期间国内外有关类风湿性关节炎与间充质干细胞的文献。检索词分别为"类风湿性关节炎,间充质干细胞"和"mesenchymal stem cells,rheumatoid arthritis"。最后选择55篇文献纳入结果分析。结果与结论:类风湿性关节炎发病机制涉及多种免疫细胞的增殖、分化及多种炎症因子的失衡。间充质干细胞具有免疫调节功能,且对类风湿性关节炎具有明显治疗效果,在抑制T细胞增殖、上调Treg细胞比例、抑制B细胞功能和减少B细胞数量、影响树突状细胞成熟、诱导M2型巨噬细胞产生、抑制M1型巨噬细胞活化方面有重要作用。
BACKGROUND: Mesenchymal stem cells possess powerful anti-inflammatory and immunoregulatory functions.Intensive studies on mesenchymal stem cells for the treatment of rheumatoid arthritis have been conducted. Mesenchymal stem cells may become a new method for the treatment of clinical rheumatoid arthritis; however, the specific molecular mechanism remains to be elucidated.OBJECTIVE: To explore the therapeutic efficacy of mesenchymal stem cell transplantation on rheumatoid arthritis in a bid to better understand its molecular mechanism and further clarify the recent advances in its protective role in inflammatory arthritis, providing new ideas for the development of targeted drugs for the treatment of rheumatoid arthritis.METHODS: PubMed database, Elsevier, CNKI and WanFang databases were searched to review literatures on rheumatoid arthritis and mesenchymal stem cells published from 2008 to 2019. The search terms were "rheumatoid arthritis, mesenchymal stem cells" in English and Chinese. Finally, 55 articles were selected for inclusion in the results analysis.RESULTS AND CONCLUSION: The pathogenesis of rheumatoid arthritis involves the proliferation and differentiation of various immune cells and the imbalance of various inflammatory factors. Mesenchymal stem cells have immunoregulatory functions and exert considerable therapeutic effects on rheumatoid arthritis. These cells have important roles in inhibiting T cell proliferation, up-regulating Treg cell ratio,suppressing B cell function, reducing B cell number, affecting dendritic cell maturation, inducing M2 type macrophage production, and hindering M1 type macrophage activation.
BACKGROUND: Mesenchymal stem cells possess powerful anti-inflammatory and immunoregulatory functions.Intensive studies on mesenchymal stem cells for the treatment of rheumatoid arthritis have been conducted. Mesenchymal stem cells may become a new method for the treatment of clinical rheumatoid arthritis; however, the specific molecular mechanism remains to be elucidated.OBJECTIVE: To explore the therapeutic efficacy of mesenchymal stem cell transplantation on rheumatoid arthritis in a bid to better understand its molecular mechanism and further clarify the recent advances in its protective role in inflammatory arthritis, providing new ideas for the development of targeted drugs for the treatment of rheumatoid arthritis.METHODS: PubMed database, Elsevier, CNKI and WanFang databases were searched to review literatures on rheumatoid arthritis and mesenchymal stem cells published from 2008 to 2019. The search terms were "rheumatoid arthritis, mesenchymal stem cells" in English and Chinese. Finally, 55 articles were selected for inclusion in the results analysis.RESULTS AND CONCLUSION: The pathogenesis of rheumatoid arthritis involves the proliferation and differentiation of various immune cells and the imbalance of various inflammatory factors. Mesenchymal stem cells have immunoregulatory functions and exert considerable therapeutic effects on rheumatoid arthritis. These cells have important roles in inhibiting T cell proliferation, up-regulating Treg cell ratio,suppressing B cell function, reducing B cell number, affecting dendritic cell maturation, inducing M2 type macrophage production, and hindering M1 type macrophage activation.
引文
[1]Niu X,Chen G.Clinical biomarkers and pathogenic-related cytokines in rheumatoid arthritis.J Immunol Res.2014;2014:698192.
[2]肖瑶,方宁,陈代雄,等.人羊膜间充质干细胞对大鼠胶原性关节炎的疗效及免疫调节作用[J].免疫学杂志,2013,29(6):461-466.
[3]Fiehn C,Holle J,Iking-Konert C,et al.S2e guideline:treatment of rheumatoid arthritis with disease-modifying drugs.Z Rheumatol.2018;77(Suppl 2):35-53.
[4]McInnes IB,Schett G.The pathogenesis of rheumatoid arthritis.N Engl J Med.2011;365(23):2205-2219.
[5]McInnes IB,Buckley CD,Isaacs JD.Cytokines in rheumatoid arthritisshaping the immunological landscape.Nat Rev Rheumatol.2016;12(1):63-68.
[6]Chastek B,Becker LK,Chen CI,et al.Outcomes of tumor necrosis factor inhibitor cycling versus switching to a disease-modifying anti-rheumatic drug with a new mechanism of action among patients with rheumatoid arthritis.J Med Econ.2017;20(5):464-473.
[7]Bongartz T,Sutton AJ,Sweeting MJ,et al.Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies:systematic review and meta-analysis of rare harmful effects in randomized controlled trials.JAMA.2006;295(19):2275-2285.
[8]Salliot C,Gossec L,Ruyssen-Witrand A,et al.Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in daily practice:a systematic retrospective study of 709 patients.Rheumatology(Oxford).2007;46(2):327-334.
[9]Castro-Manrreza ME,Montesinos JJ.Immunoregulation by mesenchymal stem cells:biological aspects and clinical applications.JImmunol Res.2015;2015:394917.
[10]刘荣霞,杨炳,余丽梅,等.不同来源间充质干细胞治疗卵巢早衰的作用及机制研究进展[J].山东医药,2018,58(40):106-110.
[11]罗欣,余丽梅.外泌体在间充质干细胞治疗骨性关节炎中的作用:新策略与新思路[J].中国组织工程研究,2018,22(1):140-145.
[12]Munir H,McGettrick HM.Mesenchymal Stem Cell Therapy for Autoimmune Disease:Risks and Rewards.Stem Cells Dev.2015;24(18):2091-2100.
[13]Baharlou R,Ahmadi-Vasmehjani A,Faraji F,et al.Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis:Regulatory effects on peripheral blood mononuclear cells activation.Int Immunopharmacol.2017;47:59-69.
[14]Vasilev G,Ivanova M,Ivanova-Todorova E,et al.Secretory factors produced by adipose mesenchymal stem cells downregulate Th17 and increase Treg cells in peripheral blood mononuclear cells from rheumatoid arthritis patients.Rheumatol Int.2019;39(5):819-826.
[15]Park KH,Mun CH,Kang MI,et al.Treatment of Collagen-Induced Arthritis Using Immune Modulatory Properties of Human Mesenchymal Stem Cells.Cell Transplant.2016;25(6):1057-1072.
[16]Greish S,Abogresha N,Abdel-Hady Z,et al.Human umbilical cord mesenchymal stem cells as treatment of adjuvant rheumatoid arthritis in a rat model.World J Stem Cells.2012;4(10):101-109.
[17]álvaro-Gracia JM,Jover JA,García-Vicu?a R,et al.Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis(Cx611):results of a multicentre,dose escalation,randomised,single-blind,placebo-controlled phase Ib/IIa clinical trial.Ann Rheum Dis.2017;76(1):196-202.
[18]Ghoryani M,Shariati-Sarabi Z,Tavakkol-Afshari J,et al.Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow-derived mesenchymal stem cells:A successful clinical trial in Iran.Biomed Pharmacother.2019;109:1834-1840.
[19]Park EH,Lim HS,Lee S,et al.Intravenous Infusion of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Rheumatoid Arthritis:APhase Ia Clinical Trial.Stem Cells Transl Med.2018;7(9):636-642.
[20]Shadmanfar S,Labibzadeh N,Emadedin M,et al.Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement:Results of a randomized,triple-blind,placebo-controlled phase 1/2clinical trial.Cytotherapy.2018;20(4):499-506.
[21]Uccelli A,de Rosbo NK.The immunomodulatory function of mesenchymal stem cells:mode of action and pathways.Ann N Y Acad Sci.2015;1351:114-126.
[22]Yan X,Cen Y,Wang Q.Mesenchymal stem cells alleviate experimental rheumatoid arthritis through microRNA-regulated IκBexpression.Sci Rep.2016;6:28915.
[23]MacDonald GI,Augello A,De Bari C.Role of mesenchymal stem cells in reestablishing immunologic tolerance in autoimmune rheumatic diseases.Arthritis Rheum.2011;63(9):2547-2557.
[24]Toupet K,Maumus M,Luz-Crawford P,et al.Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis.PLoS One.2015;10(1):e0114962.
[25]Nam Y,Jung SM,Rim YA,et al.Intraperitoneal infusion of mesenchymal stem cell attenuates severity of collagen antibody induced arthritis.PLoS One.2018;13(6):e0198740.
[26]Zhang L,Wang XY,Zhou PJ,et al.Use of immune modulation by human adipose-derived mesenchymal stem cells to treat experimental arthritis in mice.Am J Transl Res.2017;9(5):2595-2607.
[27]Baharlou R,Rashidi N,Ahmadi-Vasmehjani A,et al.Immunomodulatory Effects of Human Adipose Tissue-derived Mesenchymal Stem Cells on TCell Subsets in Patients with Rheumatoid Arthritis.Iran J Allergy Asthma Immunol.2019;18(1):114-119.
[28]Usha Shalini P,Vidyasagar JV,Kona LK,et al.In vitro allogeneic immune cell response to mesenchymal stromal cells derived from human adipose in patients with rheumatoid arthritis.Cell Immunol.2017;314:18-25.
[29]Liu R,Li X,Zhang Z,et al.Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis.Sci Rep.2015;5:12777.
[30]Rosado MM,Bernardo ME,Scarsella M,et al.Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells.Stem Cells Dev.2015;24(1):93-103.
[31]Liu Y,Yin Z,Zhang R,et al.MSCs inhibit bone marrow-derived DCmaturation and function through the release of TSG-6.Biochem Biophys Res Commun.2014;450(4):1409-1415.
[32]Spaggiari GM,Moretta L.Cellular and molecular interactions of mesenchymal stem cells in innate immunity.Immunol Cell Biol.2013;91(1):27-31.
[33]Shin TH,Kim HS,Kang TW,et al.Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis.Cell Death Dis.2016;7(12):e2524.
[34]Zhang S,Chu WC,Lai RC,et al.Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration.Osteoarthritis Cartilage.2016;24(12):2135-2140.
[35]Feng Z,Zhai Y,Zheng Z,et al.Loss of A20 in BM-MSCs regulates the Th17/Treg balance in Rheumatoid Arthritis.Sci Rep.2018;8(1):427.
[36]Horai R,Saijo S,Tanioka H,et al.Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin1 receptor antagonist-deficient mice.J Exp Med.2000;191(2):313-320.
[37]Lee K,Park N,Jung H,et al.Mesenchymal stem cells ameliorate experimental arthritis via expression of interleukin-1 receptor antagonist.PLoS One.2018;13(2):e0193086.
[38]Headland SE,Jones HR,Norling LV,et al.Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis.Sci Transl Med.2015;7(315):315ra190.
[39]Chen Z,Wang H,Xia Y,et al.Therapeutic Potential of Mesenchymal Cell-Derived miRNA-150-5p-Expressing Exosomes in Rheumatoid Arthritis Mediated by the Modulation of MMP14 and VEGF.J Immunol.2018;201(8):2472-2482.
[40]Cosenza S,Toupet K,Maumus M,et al.Mesenchymal stem cellsderived exosomes are more immunosuppressive than microparticles in inflammatory arthritis.Theranostics.2018;8(5):1399-1410.
[41]张中原,余丽梅,王信.膝骨关节炎再生修复治疗新方法研究进展[J].实用医学杂志,2018,34(9):1561-1564.
[42]Zaiss MM,Frey B,Hess A,et al.Regulatory T cells protect from local and systemic bone destruction in arthritis.J Immunol.2010;184(12):7238-7246.
[43]Oshita K,Yamaoka K,Udagawa N,et al.Human mesenchymal stem cells inhibit osteoclastogenesis through osteoprotegerin production.Arthritis Rheum.2011;63(6):1658-1667.
[44]Varin A,Pontikoglou C,Labat E,et al.CD200R/CD200 inhibits osteoclastogenesis:new mechanism of osteoclast control by mesenchymal stem cells in human.PLoS One.2013;8(8):e72831.
[45]Garimella MG,Kour S,Piprode V,et al.Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis.J Immunol.2015;195(11):5136-5148.
[46]Chemel M,Brion R,Segaliny AI,et al.Bone Morphogenetic Protein 2and Transforming Growth Factorβ1 Inhibit the Expression of the Proinflammatory Cytokine IL-34 in Rheumatoid Arthritis Synovial Fibroblasts.Am J Pathol.2017;187(1):156-162.
[47]Le Blanc K,Tammik C,Rosendahl K,et al.HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.Exp Hematol.2003;31(10):890-896.
[48]Sakaguchi Y,Sekiya I,Yagishita K,et al.Comparison of human stem cells derived from various mesenchymal tissues:superiority of synovium as a cell source.Arthritis Rheum.2005;52(8):2521-2529.
[49]De Bari C,Dell'Accio F,Karystinou A,et al.A biomarker-based mathematical model to predict bone-forming potency of human synovial and periosteal mesenchymal stem cells.Arthritis Rheum.2008;58(1):240-250.
[50]Melief SM,Zwaginga JJ,Fibbe WE,et al.Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts.Stem Cells Transl Med.2013;2(6):455-463.
[51]Abdelmawgoud H,Saleh A.Anti-inflammatory and antioxidant effects of mesenchymal and hematopoietic stem cells in a rheumatoid arthritis rat model.Adv Clin Exp Med.2018;27(7):873-880.
[52]Abd Elhalem SS,Haggag NZ,El-Shinnawy NA.Bone marrow mesenchymal stem cells suppress IL-9 in adjuvant-induced arthritis.Autoimmunity.2018;51(1):25-34.
[53]Yu Y,Yoon KA,Kang TW,et al.Therapeutic effect of long-interval repeated intravenous administration of human umbilical cord blood-derived mesenchymal stem cells in DBA/1 mice with collagen-induced arthritis.Tissue Eng Regen Med.2019 Apr 8.doi:10.1002/term.2861.[Epub ahead of print]
[54]Kim KW,Kim HJ,Kim BM,et al.Epigenetic modification of mesenchymal stromal cells enhances their suppressive effects on the Th17 responses of cells from rheumatoid arthritis patients.Stem Cell Res Ther.2018;9(1):208.
[55]Yang Y,He X,Zhao R,et al.Serum IFN-γlevels predict the therapeutic effect of mesenchymal stem cell transplantation in active rheumatoid arthritis.J Transl Med.2018;16(1):165.
[2]肖瑶,方宁,陈代雄,等.人羊膜间充质干细胞对大鼠胶原性关节炎的疗效及免疫调节作用[J].免疫学杂志,2013,29(6):461-466.
[3]Fiehn C,Holle J,Iking-Konert C,et al.S2e guideline:treatment of rheumatoid arthritis with disease-modifying drugs.Z Rheumatol.2018;77(Suppl 2):35-53.
[4]McInnes IB,Schett G.The pathogenesis of rheumatoid arthritis.N Engl J Med.2011;365(23):2205-2219.
[5]McInnes IB,Buckley CD,Isaacs JD.Cytokines in rheumatoid arthritisshaping the immunological landscape.Nat Rev Rheumatol.2016;12(1):63-68.
[6]Chastek B,Becker LK,Chen CI,et al.Outcomes of tumor necrosis factor inhibitor cycling versus switching to a disease-modifying anti-rheumatic drug with a new mechanism of action among patients with rheumatoid arthritis.J Med Econ.2017;20(5):464-473.
[7]Bongartz T,Sutton AJ,Sweeting MJ,et al.Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies:systematic review and meta-analysis of rare harmful effects in randomized controlled trials.JAMA.2006;295(19):2275-2285.
[8]Salliot C,Gossec L,Ruyssen-Witrand A,et al.Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in daily practice:a systematic retrospective study of 709 patients.Rheumatology(Oxford).2007;46(2):327-334.
[9]Castro-Manrreza ME,Montesinos JJ.Immunoregulation by mesenchymal stem cells:biological aspects and clinical applications.JImmunol Res.2015;2015:394917.
[10]刘荣霞,杨炳,余丽梅,等.不同来源间充质干细胞治疗卵巢早衰的作用及机制研究进展[J].山东医药,2018,58(40):106-110.
[11]罗欣,余丽梅.外泌体在间充质干细胞治疗骨性关节炎中的作用:新策略与新思路[J].中国组织工程研究,2018,22(1):140-145.
[12]Munir H,McGettrick HM.Mesenchymal Stem Cell Therapy for Autoimmune Disease:Risks and Rewards.Stem Cells Dev.2015;24(18):2091-2100.
[13]Baharlou R,Ahmadi-Vasmehjani A,Faraji F,et al.Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis:Regulatory effects on peripheral blood mononuclear cells activation.Int Immunopharmacol.2017;47:59-69.
[14]Vasilev G,Ivanova M,Ivanova-Todorova E,et al.Secretory factors produced by adipose mesenchymal stem cells downregulate Th17 and increase Treg cells in peripheral blood mononuclear cells from rheumatoid arthritis patients.Rheumatol Int.2019;39(5):819-826.
[15]Park KH,Mun CH,Kang MI,et al.Treatment of Collagen-Induced Arthritis Using Immune Modulatory Properties of Human Mesenchymal Stem Cells.Cell Transplant.2016;25(6):1057-1072.
[16]Greish S,Abogresha N,Abdel-Hady Z,et al.Human umbilical cord mesenchymal stem cells as treatment of adjuvant rheumatoid arthritis in a rat model.World J Stem Cells.2012;4(10):101-109.
[17]álvaro-Gracia JM,Jover JA,García-Vicu?a R,et al.Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis(Cx611):results of a multicentre,dose escalation,randomised,single-blind,placebo-controlled phase Ib/IIa clinical trial.Ann Rheum Dis.2017;76(1):196-202.
[18]Ghoryani M,Shariati-Sarabi Z,Tavakkol-Afshari J,et al.Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow-derived mesenchymal stem cells:A successful clinical trial in Iran.Biomed Pharmacother.2019;109:1834-1840.
[19]Park EH,Lim HS,Lee S,et al.Intravenous Infusion of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Rheumatoid Arthritis:APhase Ia Clinical Trial.Stem Cells Transl Med.2018;7(9):636-642.
[20]Shadmanfar S,Labibzadeh N,Emadedin M,et al.Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement:Results of a randomized,triple-blind,placebo-controlled phase 1/2clinical trial.Cytotherapy.2018;20(4):499-506.
[21]Uccelli A,de Rosbo NK.The immunomodulatory function of mesenchymal stem cells:mode of action and pathways.Ann N Y Acad Sci.2015;1351:114-126.
[22]Yan X,Cen Y,Wang Q.Mesenchymal stem cells alleviate experimental rheumatoid arthritis through microRNA-regulated IκBexpression.Sci Rep.2016;6:28915.
[23]MacDonald GI,Augello A,De Bari C.Role of mesenchymal stem cells in reestablishing immunologic tolerance in autoimmune rheumatic diseases.Arthritis Rheum.2011;63(9):2547-2557.
[24]Toupet K,Maumus M,Luz-Crawford P,et al.Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis.PLoS One.2015;10(1):e0114962.
[25]Nam Y,Jung SM,Rim YA,et al.Intraperitoneal infusion of mesenchymal stem cell attenuates severity of collagen antibody induced arthritis.PLoS One.2018;13(6):e0198740.
[26]Zhang L,Wang XY,Zhou PJ,et al.Use of immune modulation by human adipose-derived mesenchymal stem cells to treat experimental arthritis in mice.Am J Transl Res.2017;9(5):2595-2607.
[27]Baharlou R,Rashidi N,Ahmadi-Vasmehjani A,et al.Immunomodulatory Effects of Human Adipose Tissue-derived Mesenchymal Stem Cells on TCell Subsets in Patients with Rheumatoid Arthritis.Iran J Allergy Asthma Immunol.2019;18(1):114-119.
[28]Usha Shalini P,Vidyasagar JV,Kona LK,et al.In vitro allogeneic immune cell response to mesenchymal stromal cells derived from human adipose in patients with rheumatoid arthritis.Cell Immunol.2017;314:18-25.
[29]Liu R,Li X,Zhang Z,et al.Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis.Sci Rep.2015;5:12777.
[30]Rosado MM,Bernardo ME,Scarsella M,et al.Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells.Stem Cells Dev.2015;24(1):93-103.
[31]Liu Y,Yin Z,Zhang R,et al.MSCs inhibit bone marrow-derived DCmaturation and function through the release of TSG-6.Biochem Biophys Res Commun.2014;450(4):1409-1415.
[32]Spaggiari GM,Moretta L.Cellular and molecular interactions of mesenchymal stem cells in innate immunity.Immunol Cell Biol.2013;91(1):27-31.
[33]Shin TH,Kim HS,Kang TW,et al.Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis.Cell Death Dis.2016;7(12):e2524.
[34]Zhang S,Chu WC,Lai RC,et al.Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration.Osteoarthritis Cartilage.2016;24(12):2135-2140.
[35]Feng Z,Zhai Y,Zheng Z,et al.Loss of A20 in BM-MSCs regulates the Th17/Treg balance in Rheumatoid Arthritis.Sci Rep.2018;8(1):427.
[36]Horai R,Saijo S,Tanioka H,et al.Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin1 receptor antagonist-deficient mice.J Exp Med.2000;191(2):313-320.
[37]Lee K,Park N,Jung H,et al.Mesenchymal stem cells ameliorate experimental arthritis via expression of interleukin-1 receptor antagonist.PLoS One.2018;13(2):e0193086.
[38]Headland SE,Jones HR,Norling LV,et al.Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis.Sci Transl Med.2015;7(315):315ra190.
[39]Chen Z,Wang H,Xia Y,et al.Therapeutic Potential of Mesenchymal Cell-Derived miRNA-150-5p-Expressing Exosomes in Rheumatoid Arthritis Mediated by the Modulation of MMP14 and VEGF.J Immunol.2018;201(8):2472-2482.
[40]Cosenza S,Toupet K,Maumus M,et al.Mesenchymal stem cellsderived exosomes are more immunosuppressive than microparticles in inflammatory arthritis.Theranostics.2018;8(5):1399-1410.
[41]张中原,余丽梅,王信.膝骨关节炎再生修复治疗新方法研究进展[J].实用医学杂志,2018,34(9):1561-1564.
[42]Zaiss MM,Frey B,Hess A,et al.Regulatory T cells protect from local and systemic bone destruction in arthritis.J Immunol.2010;184(12):7238-7246.
[43]Oshita K,Yamaoka K,Udagawa N,et al.Human mesenchymal stem cells inhibit osteoclastogenesis through osteoprotegerin production.Arthritis Rheum.2011;63(6):1658-1667.
[44]Varin A,Pontikoglou C,Labat E,et al.CD200R/CD200 inhibits osteoclastogenesis:new mechanism of osteoclast control by mesenchymal stem cells in human.PLoS One.2013;8(8):e72831.
[45]Garimella MG,Kour S,Piprode V,et al.Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis.J Immunol.2015;195(11):5136-5148.
[46]Chemel M,Brion R,Segaliny AI,et al.Bone Morphogenetic Protein 2and Transforming Growth Factorβ1 Inhibit the Expression of the Proinflammatory Cytokine IL-34 in Rheumatoid Arthritis Synovial Fibroblasts.Am J Pathol.2017;187(1):156-162.
[47]Le Blanc K,Tammik C,Rosendahl K,et al.HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.Exp Hematol.2003;31(10):890-896.
[48]Sakaguchi Y,Sekiya I,Yagishita K,et al.Comparison of human stem cells derived from various mesenchymal tissues:superiority of synovium as a cell source.Arthritis Rheum.2005;52(8):2521-2529.
[49]De Bari C,Dell'Accio F,Karystinou A,et al.A biomarker-based mathematical model to predict bone-forming potency of human synovial and periosteal mesenchymal stem cells.Arthritis Rheum.2008;58(1):240-250.
[50]Melief SM,Zwaginga JJ,Fibbe WE,et al.Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts.Stem Cells Transl Med.2013;2(6):455-463.
[51]Abdelmawgoud H,Saleh A.Anti-inflammatory and antioxidant effects of mesenchymal and hematopoietic stem cells in a rheumatoid arthritis rat model.Adv Clin Exp Med.2018;27(7):873-880.
[52]Abd Elhalem SS,Haggag NZ,El-Shinnawy NA.Bone marrow mesenchymal stem cells suppress IL-9 in adjuvant-induced arthritis.Autoimmunity.2018;51(1):25-34.
[53]Yu Y,Yoon KA,Kang TW,et al.Therapeutic effect of long-interval repeated intravenous administration of human umbilical cord blood-derived mesenchymal stem cells in DBA/1 mice with collagen-induced arthritis.Tissue Eng Regen Med.2019 Apr 8.doi:10.1002/term.2861.[Epub ahead of print]
[54]Kim KW,Kim HJ,Kim BM,et al.Epigenetic modification of mesenchymal stromal cells enhances their suppressive effects on the Th17 responses of cells from rheumatoid arthritis patients.Stem Cell Res Ther.2018;9(1):208.
[55]Yang Y,He X,Zhao R,et al.Serum IFN-γlevels predict the therapeutic effect of mesenchymal stem cell transplantation in active rheumatoid arthritis.J Transl Med.2018;16(1):165.