Inhibition of IL-1R1/MyD88 Signalling Promotes Mesenchymal Stem Cell-driven Tissue Regeneration

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Mar 23

PMID 27001940

Citations 64

Authors

Mikael M Martino

Kenta Maruyama

Gisela A Kuhn

Takashi Satoh

Osamu Takeuchi

Ralph Muller

Shizuo Akira

Affiliations

Soon will be listed here.

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.

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