Published online before print January 11, 2007, doi: 10.1161/01.RES.0000257774.55970.f4
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Submitted on June 16, 2006
Revised on December 14, 2006
Accepted on January 2, 2007
High-Mobility Group Box 1 Activates Integrin-Dependent Homing of Endothelial Progenitor Cells
Emmanouil Chavakis ;
From the Molecular Cardiology (E.C., A.H., G.C., A.M.Z., S.D.), Department of Internal Medicine III, J. W. Goethe University, Frankfurt, Germany; Department of Neurosurgery (M.V., P.V.), Medical Faculty of the University of Heidelberg, Mannheim, Germany; Department of Molecular Biology and Functional Genomics (M.E.B.), San Raffaele University, Milan, Italy; and Experimental Immunology Branch (T.C.), National Cancer Institute, NIH, Bethesda, MD.
* To whom correspondence should be addressed. E-mail: Dimmeler{at}em.uni-frankfurt.de.
Endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization, and we recently demonstrated that EPCs engage 
2 integrins for EPC homing. High-mobility group box 1 (HMGB1) is a nuclear protein that is released extracellularly on cell necrosis and tissue damage, eliciting a proinflammatory response and stimulating tissue repair. In the present study, we investigated the effects of HMGB1 on EPC homing. EPCs express the HMGB1 receptors RAGE (receptor for advanced glycation end products) and TLR2 (Toll-like receptor 2). EPC migration was stimulated by HMGB1 in a RAGE-dependent manner. In addition, the HMGB1-induced migration of EPCs on fibronectin and fibrinogen was significantly inhibited by antibodies against 1 and 2 integrins, respectively. Short-term prestimulation of EPCs with HMGB1 also increased EPC adhesion to endothelial cell monolayers, and this effect was blocked by antibodies to 2 integrins or RAGE. Moreover, HMGB1 increased EPC adhesion to the immobilized integrin ligands intercellular adhesion molecule-1 and fibronectin in a RAGE-dependent manner. Strikingly, HMGB1 rapidly increased integrin affinity and induced integrin polarization. Moreover, using intravital microscopy in a tumor model of neovascularization, prestimulation of EPCs with HMGB1 enhanced the initial in vivo adhesion of EPCs to microvessels and the long-term recruitment of EPCs in the tumor tissue. In addition, prestimulation of EPCs with HMGB1 increased the homing of EPCs to ischemic muscles. In conclusion, these data represent the first link between HMGB1 and integrin functions of EPCs, provide the first evidence for the regulation of integrin activity in EPCs, and demonstrate that HMGB1 stimulates EPC homing to ischemic tissues. These results may provide a platform for the development of novel therapeutic approaches to improve EPC homing.
Key words: high-mobility group box 1 • endothelial progenitor cells • homing • integrins • migration
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