1. Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration.
- Author
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Martino MM, Maruyama K, Kuhn GA, Satoh T, Takeuchi O, Müller R, and Akira S
- Subjects
- Animals, Bone Regeneration immunology, Cell Differentiation, Cell Movement, Cell Proliferation, Chondrocytes, Cytokines immunology, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Macrophages immunology, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells physiology, Mice, Mice, Knockout, Monocytes immunology, Osteoblasts physiology, Proto-Oncogene Proteins c-akt metabolism, Regeneration genetics, Regeneration immunology, Signal Transduction, Skull diagnostic imaging, Toll-Like Receptors immunology, Wnt Signaling Pathway, X-Ray Microtomography, beta Catenin metabolism, Bone Regeneration genetics, Interleukin-1beta immunology, Mesenchymal Stem Cells immunology, Myeloid Differentiation Factor 88 genetics, Osteoblasts metabolism, Receptors, Interleukin-1 Type I genetics, Skull injuries
- 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.
- Published
- 2016
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