caa a22 4500 528785648 20190713030954.0 cr unu---uuuuu 180924s2016 xx s 000 0 eng 10.3929/ethz-b-000114095 doi 10.1038/ncomms11051 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/114095 Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration [Elektronische Daten] [Mikaël M. Martino, Kenta Maruyama, Gisela A. Kuhn, Takashi Satoh, Osamu Takeuchi, Ralph; id_orcid 0000-0002-5811-7725 Müller, Shizuo Akira] Nat Commun Open access ethresearch 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. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch Martino Mikaël M. joint author Maruyama Kenta joint author Kuhn Gisela A. joint author Satoh Takashi joint author Takeuchi Osamu joint author Müller Ralph; id_orcid 0000-0002-5811-7725 joint author Akira Shizuo joint author Nature Communications London : Nature Publishing Group 7, p. 11051 2041-1723 http://hdl.handle.net/20.500.11850/114095 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/114095 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Martino Mikaël M. joint author ETHRESEARCH 700 1- Maruyama Kenta joint author ETHRESEARCH 700 1- Kuhn Gisela A. joint author ETHRESEARCH 700 1- Satoh Takashi joint author ETHRESEARCH 700 1- Takeuchi Osamu joint author ETHRESEARCH 700 1- Müller Ralph; id_orcid 0000-0002-5811-7725 joint author ETHRESEARCH 700 1- Akira Shizuo joint author ETHRESEARCH 773 0- Nature Communications London : Nature Publishing Group 7, p. 11051 2041-1723 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access