MicroRNA-181a Regulates Local Immune Balance by Inhibiting Proliferation and Immunosuppressive Properties of Mesenchymal Stem Cells§

Authors

  • Liu Liu,

    1. Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical BiotechnologyNanjing University, Nanjing, People's Republic of China
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  • Yaping Wang,

    1. Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical BiotechnologyNanjing University, Nanjing, People's Republic of China
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  • Hongye Fan,

    1. Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical BiotechnologyNanjing University, Nanjing, People's Republic of China
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  • Xiaoyin Zhao,

    1. Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical BiotechnologyNanjing University, Nanjing, People's Republic of China
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  • Dan Liu,

    1. Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical BiotechnologyNanjing University, Nanjing, People's Republic of China
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  • Yali Hu,

    Corresponding author
    1. The affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
    • Yali Hu, The affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, People's Republic of China

      Jianxin Bao, Department of Otolaryngology, Washington University School of Medicine, 4560 Clayton Avenue, St. Louis, Missouri 63110, USA

      Yayi Hou, Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China

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    • Telephone: +86-025-83321980

  • Ambrose R. Kidd III,

    1. Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA
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  • Jianxin Bao,

    Corresponding author
    1. Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA
    • Yali Hu, The affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, People's Republic of China

      Jianxin Bao, Department of Otolaryngology, Washington University School of Medicine, 4560 Clayton Avenue, St. Louis, Missouri 63110, USA

      Yayi Hou, Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China

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    • Telephone: 314-747-7199; Fax: 314-747-7201

  • Yayi Hou

    Corresponding author
    1. Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical BiotechnologyNanjing University, Nanjing, People's Republic of China
    2. Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, People's Republic of China
    • Yali Hu, The affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, People's Republic of China

      Jianxin Bao, Department of Otolaryngology, Washington University School of Medicine, 4560 Clayton Avenue, St. Louis, Missouri 63110, USA

      Yayi Hou, Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China

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    • Telephone: +86-025-83686441


  • Author contributions: L.L.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; Y.W.: collection and/or assembly of data and provision of study material or patients; H.F.: conception and design, and data analysis and interpretation; X.Z.: provision of study material or patients; D.L.: administrative support; Y. Hu: provision of study material or patients; A.R.K. and J.B.: manuscript writing; Y. Hou: conception and design, financial support, manuscript writing, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS June 19, 2012.

Abstract

Mesenchymal stem cells (MSCs) exhibit extensive self-renewal potential and can modulate immunocyte activation. Our previous study reported that miR-181a expression was significantly increased in placenta from women with severe preeclampsia (PE), but the mechanisms by which miR-181a regulates MSCs are unknown. In this study, we asked if and how miR-181a regulates MSCs' proliferation and immunosuppressive properties. We found that the expression of miR-181a in the MSCs derived from the umbilical cord and decidua of PE patients increased relative to MSCs derived from normal patients. Transfection with miR-181a oligos prevented MSCs proliferation but did not affect MSCs apoptosis. Overexpression of miR-181a blocked activation of the TGF-β signaling pathway and caused downregulation of target gene (TGFBR1 and TGFBRAP1) mRNA and protein expression. Reporter genes with putative miR-181a binding sites from the TGFBR1 and TGFBRAP1 3′-untranslated regions (3′-UTRs) were downregulated in the presence of miR-181a, suggesting that miR-181a binds to TGFBR1 and TGFBRAP1 3′-UTRs. In contrast, transfection of MSCs with miR-181a oligo enhanced expression of IL-6 and indoleamine 2,3-dioxygenase by activating p38 and JNK signaling pathways, respectively. MSCs transfected with miR-181a also enhanced the proliferation of T cells in a short-term culture. Additionally, treatment with control MSCs, but not miR-181a transfected MSCs, improved dextran sulfate sodium-induced experimental colitis, suggesting that miR-181a attenuates the immunosuppressive properties of MSCs in vivo. Together, our data demonstrate that miR-181a is an important endogenous regulator in the proliferation and immunosuppressive properties of MSCs. STEM Cells2012;30:1756–1770

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