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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Regeneration / genetics*
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Bone Regeneration / immunology
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Cell Differentiation
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Cell Movement
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Cell Proliferation
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Chondrocytes
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Cytokines / immunology
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Interleukin-1beta / immunology*
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Macrophages / immunology
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Mesenchymal Stem Cells / immunology*
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Mesenchymal Stem Cells / metabolism
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Mesenchymal Stem Cells / physiology
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Mice
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Mice, Knockout
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Monocytes / immunology
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Myeloid Differentiation Factor 88 / genetics*
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Osteoblasts / metabolism*
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Osteoblasts / physiology
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Interleukin-1 Type I / genetics*
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Regeneration / genetics
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Regeneration / immunology
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Signal Transduction
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Skull / diagnostic imaging
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Skull / injuries*
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Toll-Like Receptors / immunology
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Wnt Signaling Pathway
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X-Ray Microtomography
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beta Catenin / metabolism
Substances
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Cytokines
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IL1B protein, mouse
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IL1R1 protein, mouse
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Interleukin-1beta
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Interleukin-1 Type I
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Toll-Like Receptors
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beta Catenin
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3