Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells

Authors

  • Yi Zhang,

    1. Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM, Shanghai, China
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    • These authors contributed equally to this work.

  • Wei Cai,

    1. Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM, Shanghai, China
    2. Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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    • These authors contributed equally to this work.

  • Qingrong Huang,

    1. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Yuting Gu,

    1. Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM, Shanghai, China
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  • Yufang Shi,

    1. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Jiefang Huang,

    1. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Fang Zhao,

    1. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Qiang Liu,

    1. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Xunbin Wei,

    1. Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
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  • Min Jin,

    1. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Changping Wu,

    1. Department of Oncology, Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
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  • Qing Xie,

    1. Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Yi Zhang,

    1. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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  • Bing Wan,

    Corresponding author
    1. Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM, Shanghai, China
    • Address reprint requests to: Yanyun Zhang, M.D., Ph.D., or Bing Wan, M.D., Ph.D., Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, China. E-mail: yyzhang@sibs.ac.cn or bingwan@shsmu.edu.cn; fax: +86-21-63852705.

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  • Yanyun Zhang

    Corresponding author
    1. Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM, Shanghai, China
    • Address reprint requests to: Yanyun Zhang, M.D., Ph.D., or Bing Wan, M.D., Ph.D., Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, China. E-mail: yyzhang@sibs.ac.cn or bingwan@shsmu.edu.cn; fax: +86-21-63852705.

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  • Potential conflict of interest: Nothing to report.

  • Supported by the Ministry of Science and Technology of China 2011CB966200 (to Y.Z.), Strategic Priority Research Program of the Chinese Academy of Sciences XDA01040000 (to Y.Z.), National Natural Science Foundation of China 81130057, 81071748 (to Y.Z.), the Program of Science and Technology Commission of Shanghai Municipality 11JC1411400, 11431920900 (to Y.Z.) and 11ZR1422400 (to W.C.), the Program of Chinese Academy of Science KSCX2-YW-R-245, KSCX2-YW-R-175 (to Y.Z.), and Leading Academic Discipline Project of Shanghai Municipal Education Commission J50207 (to Y.Z.).

Abstract

Fulminant hepatic failure (FHF) is a clinical syndrome characterized by sudden and severe impairment of liver function. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for FHF. In this study we used Propionibacterium acnes (P. acnes)-primed, lipopolysaccharide (LPS)-induced liver injury in mice as an animal model of human FHF. We demonstrated that administration of MSCs significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS-induced FHF. Allogeneic MSCs showed similar treatment efficacy as autologous MSCs did in FHF. Treatment efficacy of MSCs could be attributed to decreased infiltration and activation of CD4+ T cells in the liver, inhibition of T helper 1 cells, and induction of regulatory T cells (Tregs). Moreover, decreased DNA copies of P. acnes were detected in the liver of MSC-treated mice. Intriguingly, a distinct liver population of CD11c+MHCIIhiCD80loCD86lo regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor-β production. Further mechanistic studies demonstrated that MSC-derived prostaglandin E2 and one of its receptors, EP4, played essential roles in the differentiation of CD11c+B220 DC precursors into regulatory DCs in a phosphoinositide 3-kinase-dependent manner. Conclusion: MSCs induce regulatory DCs from CD11c+B220 DC precursors. This study elucidates an immunoregulatory mechanism of MSCs and lays a foundation for application of MSCs in FHF therapy. (Hepatology 2014;59:671–682)

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