title: Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration.
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.
authors.affiliation: WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Mikaël M
authors.initials: MM
authors.lastname: Martino
authors.affiliation: WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Institute for Biomechanics, Leopold-Ruzicka-Weg 4, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Gisela A
authors.initials: GA
authors.lastname: Kuhn
authors.affiliation: WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.|Institute for Virus Research, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.affiliation: Institute for Biomechanics, Leopold-Ruzicka-Weg 4, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Müller
authors.affiliation: WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000235:genetics* / Q000276:immunology; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D019902:Chondrocytes; D016207:Cytokines / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D053583:Interleukin-1beta / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D010006:Osteoblasts / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics*; D012038:Regeneration / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D012886:Skull / Q000000981:diagnostic imaging / Q000293:injuries*; D051193:Toll-Like Receptors / Q000276:immunology; D060449:Wnt Signaling Pathway; D055114:X-Ray Microtomography; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016207:Cytokines; C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; D051193:Toll-Like Receptors; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3