The Toll-like Receptor 3 Ligand, Poly(I:C), Improves Immunosuppressive Function and Therapeutic Effect of Mesenchymal Stem Cells on Sepsis via Inhibiting MiR-143

Authors

  • Xiaoyin Zhao,

    1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
    Search for more papers by this author
  • Dan Liu,

    1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
    Search for more papers by this author
  • Wei Gong,

    1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
    Search for more papers by this author
  • Guangfeng Zhao,

    1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
    Search for more papers by this author
  • Liu Liu,

    1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
    Search for more papers by this author
  • Liu Yang,

    1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
    Search for more papers by this author
  • Yayi Hou

    Corresponding author
    1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
    2. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China
    • Correspondence: Yayi Hou, Ph.D., The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China. Telephone: +86-25-83686441; e-mail: yayihou@nju.edu.cn

    Search for more papers by this author

Abstract

Mesenchymal stem cells (MSCs) are attractive candidates for clinical therapeutic applications. Recent studies indicate MSCs express active Toll-like receptors (TLRs), but their effect on MSCs and the underlying mechanisms remain unclear. In this study, we found that, after treating human umbilical cord MSCs with various TLR ligands, only TLR3 ligand, poly(I:C), could significantly increase the expression of cyclooxygenase-2 (COX-2). Furthermore, poly(I:C) could enhance MSCs' anti-inflammatory effect on macrophages. Next, we focused on the regulatory roles of microRNAs (miRNAs) in the process of poly(I:C) activating MSCs. Our experiments indicated that miR-143 expression was significantly decreased in MSCs with poly(I:C) treatment, and the expression level of miR-143 could regulate the effect of poly(I:C) on MSCs' immunosuppressive function. Subsequent results showed that the reporter genes with putative miR-143 binding sites from the transforming growth factor-β-activated kinase-1 (TAK1) and COX-2 3′ untranslated regions were downregulated in the presence of miR-143. In addition, mRNA and protein expression of TAK1 and COX-2 in MSCs was also downregulated with miR-143 overexpression, suggesting that TAK1 and COX-2 are target genes of miR-143 in MSCs. Consistent with miR-143 overexpression, TAK1 interference also attenuated MSCs' immunosuppressive function enhanced by poly(I:C). Additionally, it was shown that TLR3-activated MSCs could improve survival in cecal ligation and puncture (CLP)-induced sepsis, while miR-143 overexpression reduced the effectiveness of this therapy. These results proved that poly(I:C) improved the immunosuppressive abilities of MSCs, revealed the regulatory role of miRNAs in the process, and may provide an opportunity for potential novel therapies for sepsis. Stem Cells 2014;32:521–533

Ancillary