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

Martino, Mikaël M.  ,  Maruyama, Kenta  ,  Kuhn, Gisela A.  ,  Satoh, Takashi  ,  Takeuchi, Osamu  ,  Müller, Ralph  ,  Akira, Shizuo

72016-03-22 , Nature Publishing Group
ISSN:2041-1723
Description
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.
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http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/210219/1/ncomms11051.pdf

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