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

Mikaël M. Martino (), Kenta Maruyama, Gisela A. Kuhn, Takashi Satoh, Osamu Takeuchi, Ralph Müller and Shizuo Akira ()
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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
Ralph Müller: Institute for Biomechanics
Shizuo Akira: WPI Immunology Frontier Research Center, Osaka University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11051

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