Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation

TLDR

HMGB1 is a chromatin protein that functions as a cytokine when released extracellularly by necrotic and inflammatory cells, and its potential to promote muscle regeneration remains to be clarified. The study aims to determine whether exogenous HMGB1 can stimulate mesoangioblast migration and proliferation to support tissue regeneration. Extracellular HMGB1 and its receptor RAGE drive mesoangioblast migration and proliferation, disrupt endothelial barrier function, and in vivo mesoangioblasts home to HMGB1‑laden beads, but in dystrophic muscle mesoangioblasts still migrate even when RAGE is disabled, indicating that HMGB1‑RAGE signaling is sufficient but not required and that alternative pathways may exist.

Abstract

High mobility group box 1 (HMGB1) is an abundant chromatin protein that acts as a cytokine when released in the extracellular milieu by necrotic and inflammatory cells. Here, we show that extracellular HMGB1 and its receptor for advanced glycation end products (RAGE) induce both migration and proliferation of vessel-associated stem cells (mesoangioblasts), and thus may play a role in muscle tissue regeneration. In vitro, HMGB1 induces migration and proliferation of both adult and embryonic mesoangioblasts, and disrupts the barrier function of endothelial monolayers. In living mice, mesoangioblasts injected into the femoral artery migrate close to HMGB1-loaded heparin-Sepharose beads implanted in healthy muscle, but are unresponsive to control beads. Interestingly, alpha-sarcoglycan null dystrophic muscle contains elevated levels of HMGB1; however, mesoangioblasts migrate into dystrophic muscle even if their RAGE receptor is disabled. This implies that the HMGB1-RAGE interaction is sufficient, but not necessary, for mesoangioblast homing; a different pathway might coexist. Although the role of endogenous HMGB1 in the reconstruction of dystrophic muscle remains to be clarified, injected HMGB1 may be used to promote tissue regeneration.