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Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration

Author

Listed:
  • Mikaël M. Martino

    (WPI Immunology Frontier Research Center, Osaka University)

  • Kenta Maruyama

    (WPI Immunology Frontier Research Center, Osaka University)

  • Gisela A. Kuhn

    (Institute for Biomechanics)

  • Takashi Satoh

    (WPI Immunology Frontier Research Center, Osaka University)

  • Osamu Takeuchi

    (WPI Immunology Frontier Research Center, Osaka University
    Institute for Virus Research, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan)

  • Ralph Müller

    (Institute for Biomechanics)

  • Shizuo Akira

    (WPI Immunology Frontier Research Center, Osaka University)

Abstract

Tissue injury and the healing response lead to the release of endogenous danger signals including Toll-like receptor (TLR) and interleukin-1 receptor, type 1 (IL-1R1) ligands, which modulate the immune microenvironment. Because TLRs and IL-1R1 have been shown to influence the repair process of various tissues, we explored their role during bone regeneration, seeking to design regenerative strategies integrating a control of their signalling. Here we show that IL-1R1/MyD88 signalling negatively regulates bone regeneration, in the mouse. Furthermore, IL-1β which is released at the bone injury site, inhibits the regenerative capacities of mesenchymal stem cells (MSCs). Mechanistically, IL-1R1/MyD88 signalling impairs MSC proliferation, migration and differentiation by inhibiting the Akt/GSK-3β/β-catenin pathway. Lastly, as a proof of concept, we engineer a MSC delivery system integrating inhibitors of IL-1R1/MyD88 signalling. Using this strategy, we considerably improve MSC-based bone regeneration in the mouse, demonstrating that this approach may be useful in regenerative medicine applications.

Suggested Citation

  • Mikaël M. Martino & Kenta Maruyama & Gisela A. Kuhn & Takashi Satoh & Osamu Takeuchi & Ralph Müller & Shizuo Akira, 2016. "Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11051
    DOI: 10.1038/ncomms11051
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