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Published online 26 January 2004. doi:10.1083/jcb.200304135
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 3, 441-449
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Article

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

Roberta Palumbo1, Maurilio Sampaolesi2, Francesco De Marchis1, Rossana Tonlorenzi2, Sara Colombetti3, Anna Mondino3, Giulio Cossu2,4,5, and Marco E. Bianchi6

1 Department of Molecular Biology and Functional Genomics, 2 Stem Cell Research Institute, and 3 Cancer Immunotherapy and Gene Therapy Program, San Raffaele Research Institute, 20132 Milan, Italy
4 Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, 00128 Rome, Italy
5 Department of Histology and Medical Embryology, University La Sapienza, 00161 Rome, Italy
6 San Raffaele University, 20132 Milan, Italy

Address correspondence to Marco E. Bianchi, San Raffaele University, via Olgettina 58, 20132 Milan, Italy. Tel.: 39-3477975788. Fax: 39-0226434861. email: bianchi.marco{at}hsr.it

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.

Key Words: cell migration; cytokine; inflammation; stem cell; tissue damage

R. Palumbo and M. Sampaolesi contributed equally to this paper.

Abbreviations used in this paper: {alpha}-SG, {alpha}-sarcoglycan; DiI, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; dnRAGE, dominant-negative mutant of RAGE; HMGB1, high mobility group box 1; lin-, murine lineage negative; LPS, lipopolysaccharide; RAGE, receptor for advanced glycation end products.


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