title: Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis.
abstract: Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e.g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4(+) T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy.
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China.
authors.forename: Shipeng
authors.initials: S
authors.lastname: Dang
authors.affiliation: Department of Endocrinology and Metabolism; Shanghai Jiao Tong University Affiliated First People's Hospital; Shanghai, China.
authors.forename: Huanbai
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China.
authors.forename: Congfeng
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Infectious Diseases; Ruijin Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China.
authors.forename: Yiji
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Cardiology; Affiliated Hospital of Nanjing Medical University in Wuxi; Wuxi People's Hospital; Wuxi, China.
authors.forename: Ru-Xing
authors.initials: RX
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism; Shanghai Jiao Tong University Affiliated First People's Hospital; Shanghai, China.
authors.forename: Yongde
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine; University of Michigan; Ann Arbor, MI USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China; The First People's Hospital of Changzhou and the Third Affiliated Hospital of Soochow University; Changzhou, Jiangsu China.
authors.forename: Changping
authors.initials: C
authors.lastname: Wu
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China; The First People's Hospital of Changzhou and the Third Affiliated Hospital of Soochow University; Changzhou, Jiangsu China.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: He
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wan
authors.affiliation: Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM); and Shanghai Institute of Immunology; Institutes of Medical Sciences; SJTUSM; Shanghai, China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C025946:3-methyladenine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000225:Adenine
keywords: autophagy; experimental autoimmune encephalomyelitis; immunosuppression; mesenchymal stem cells; mitogen-activated protein kinase 1/3; prostaglandin-endoperoxide synthase 2; reactive oxygen species