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

High mobility group box 1 (HMGB1) is an abundantchromatin protein that acts as a cytokine whenreleased in the extracellular milieu by necroticand inflammatory cells. Here, we show that extracellularHMGB1 and its receptor for advanced glycation endproducts (RAGE) induce both migration and proliferation ofvessel-associated stem cells (mesoangioblasts), and thusmay play a role in muscle tissue regeneration. In vitro,HMGB1 induces migration and proliferation of both adultand embryonic mesoangioblasts, and disrupts the barrierfunction of endothelial monolayers. In living mice, mesoangioblastsinjected into the femoral artery migrate close to HMGB1-loaded heparin-Sepharose beads implanted inhealthy muscle, but are unresponsive to control beads.Interestingly,-sarcoglycan null dystrophic muscle containselevated levels of HMGB1; however, mesoangioblastsmigrate into dystrophic muscle even if their RAGE receptoris disabled. This implies that the HMGB1–RAGE interactionis sufficient, but not necessary, for mesoangioblast homing;a different pathway might coexist. Although the role ofendogenous HMGB1 in the reconstruction of dystrophicmuscle remains to be clarified, injected HMGB1 may beused to promote tissue regeneration.