Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation.
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.
Palumbo
Roberta
R
Department of Molecular Biology and Functional Genomics, San Raffaele Research Institute, Milan, Italy.
Sampaolesi
Maurilio
M
De Marchis
Francesco
F
Tonlorenzi
Rossana
R
Colombetti
Sara
S
Mondino
Anna
A
Cossu
Giulio
G
Bianchi
Marco E
ME
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D017690:Cell Transplantation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D049031:Sarcoglycans; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D003598:Cytoskeletal Proteins; D024243:HMGB1 Protein; D008562:Membrane Glycoproteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D049031:Sarcoglycans