Published online before print January 11, 2007, doi: 10.1161/01.RES.0000257774.55970.f4
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© 2007 American Heart Association, Inc.
Molecular Medicine |
High-Mobility Group Box 1 Activates Integrin-Dependent Homing of Endothelial Progenitor Cells
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.
Correspondence to Stefanie Dimmeler, PhD, Molecular Cardiology Department of Internal Medicine III, J. W. Goethe University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler{at}em.uni-frankfurt.de
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Abstract |
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Endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. Integrins contribute to 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 ß1 and ß2 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 ß2 integrins or RAGE. 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. 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 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 a link between HMGB1 and integrin functions of 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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Introduction |
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The term vasculogenesis describes the de novo formation of new vessels from angioblasts during embryonic development.1 Vasculogenesis, which can be mediated by circulating bone marrow (BM)-derived endothelial progenitor or hematopoietic stem cells, is important in postnatal neovascularization of adult ischemic tissues.2–6 Ischemia or cytokines such as vascular endothelial growth factor (VEGF) lead to mobilization of endothelial progenitor cells (EPCs) from the BM7 and support the neovascularization of ischemic tissues or tumors.7–9 Therapeutic administration of EPCs increases the neovascularization of ischemic myocardium and limbs and improves left ventricular function after myocardial infarction.10–13 EPCs are preferentially recruited to sites of ischemia and improve neovascularization by being directly incorporated into vascular structures and differentiating to endothelial cells and/or by eliciting paracrine effects.2,4,6,7,10,14 Both the paracrine effects and the differentiation of EPCs to endothelial cells depend on the homing of EPCs to ischemic sites. In an in vivo intravital microscopy study, EPCs embryonic arrested within tumor microvessels, extravasated into the interstitium, and incorporated into neovessels, suggesting that adhesion and transendothelial migration are involved in the recruitment of EPCs.15
Recent evidence supports the involvement of integrins for the homing of EPCs to sites of active neovascularization. Specifically, we found that ß2 integrins mediate the endothelial adhesion and transendothelial migration of human adult peripheral blood–derived EPCs in vitro and the homing of murine BM Sca-1+/Lin– hematopoietic progenitor cells and murine VEGFR2+/Lin– BM EPCs to ischemic tissues in vivo.16 Interestingly, the blockade of another integrin, the 
4ß1 integrin, does not inhibit homing of BM EPCs to ischemic tissues but increases mobilization of BM-derived progenitor cells and enhances the progenitor cell–mediated neovascularization in the context of ischemia.17 Nevertheless, in a tumor model, the inhibition of 4ß1 integrin decreased the homing of BM progenitor cells to sites of active tumor angiogenesis.18 Others have demonstrated the accumulation of progenitor cells in fibronectin-rich regions in the hypoxia-induced remodeled pulmonary artery vessel wall.19 Thus, it is conceivable that different integrins may play distinct context- and tissue-specific roles for the homing of progenitor cells. However, the regulation of integrin activity and, more importantly, the influence of factors of the ischemic environment on integrin-dependent functions of EPCs are unclear.
High-mobility group box-1 (HMGB1), or amphoterin, is a highly conserved ubiquitously expressed nuclear protein20 that is released into the extracellular space on cell necrosis but not apoptosis.21 In addition, HMGB1 is actively secreted on activation of cells by inflammatory cytokines.22,23 Extracellular HMGB1 acts chemotactically on inflammatory cells, smooth muscle cells, and stem cells.24–26 The receptor for advanced glycation end products (RAGE) and members of the Toll-like receptor (TLR) family are cellular receptors of HMGB1.27–29
In a murine model of myocardial infarction, exogenously administrated HMGB1 in the periinfarcted left ventricle led to recovery of left ventricular function through regeneration of cardiomyocytes from resident cardiac c-Kit+ progenitor cells,30 suggesting that HMGB1 may have therapeutic relevance. Because necrosis and inflammation are hallmarks of ischemic tissues, we determined the effect of HMGB1 on the homing of EPCs in vitro and in vivo. In the present work, we provide evidence for integrin-activity regulation by chemokines in EPCs. Specifically, our results show that HMGB1 increases adhesion and migration of EPCs in a manner dependent on integrins and RAGE and stimulates the homing of EPCs into tumor and ischemic tissues in vivo.
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Materials and Methods |
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Cell Culture
Peripheral blood mononuclear cells (MNCs) from healthy human volunteers were isolated by density-gradient centrifugation with Ficoll as described.16 Immediately after isolation, total MNCs were plated on culture dishes coated with human fibronectin (10 µg/mL; Sigma) and maintained in endothelial basal medium (Cambrex) supplemented with 1 µg/mL hydrocortisone, 12 µg/mL bovine brain extract, 50 µg/mL gentamycin, 50 ng/mL amphotericin B, 10 ng/mL epidermal growth factor, and 20% FCS. After 3 days, nonadherent cells were removed and adherent cells were incubated for another 24 hours before the experiments were performed. EPCs were characterized by dual-staining for 1,1'-dioctadecyl-3,3',3'-tetramethylindo-carbocyanine–labeled acetyl-low-density lipoprotein (Dil) and lectin and expression of endothelial markers kinase insert domain receptor, vascular endothelial cadherin, and von Willebrand factor.6 Human umbilical vein endothelial cells (HUVECs) were purchased from Cambrex and cultured until the third passage, as described.31
Cell Migration
Transwell membranes (8 µm; Costar) were coated on both sides with fibronectin (2.5 µg/mL; Roche, Mannheim, Germany) or fibrinogen (2.5 µg/mL; Hemochrom Diagnostica, Essen, Germany) overnight at 4°C. Ex vivo–expanded human EPCs were stained with CellTracker Green 5-chloromethylfluorescein diacetate (Molecular Probes, Eugene, Ore) for 30 minutes at 37°C. EPCs were detached by trypsinization, and after neutralization of trypsin, cells were resuspended in serum-free RPMI 1640 containing 0.05% BSA. Serum-free RPMI 1640 (600 µL) with 0.05% BSA containing the indicated concentrations of HMGB1 was placed in the lower chambers. Full-length HMGB1 was expressed and purified as described32 (HMGBiotech, Milano, Italy) or commercially purchased (R&D Systems, Wiesbaden, Germany). Both preparations had similar effects in functional assays. HMGB1 was free of lipopolysaccharide. EPCs (120 000) in 100 µL of serum-free RPMI 1640 containing 0.05% BSA were incubated in the upper chamber at 37°C in 5% CO2 for 16 to 18 hours. For inhibition experiments, EPCs were preincubated for 30 minutes at 4°C with the following: 40 µg/mL control goat IgG (R&D Systems), murine isotype control IgG (Alexis Biochemicals, Gruenberg, Germany), or anti-RAGE (R&D Systems); or 5 µg/mL soluble RAGE (kindly provided by Dr M. Nagashima, Berlex Biosciences, Richmond, Calif), anti-TLR2 (clone TL2.1, Biolegend, San Diego, Calif), anti-TLR4 (clone HTA125, Biolegend), anti–ß1 integrin (clone 6S6, Chemicon, Temecula, Calif), or anti–ß2 integrin (clone IB4, Alexis Biochemicals). Cells remaining on the upper surface of the filters were mechanically removed, and cells that had migrated to the lower surface were fixed with 4% formaldehyde and counted in 5 fields using a fluorescence microscope (Axiovert 100, Carl Zeiss, Jena, Germany).
Fluorescence-activated sell-sorting (FACS) analysis, cell–cell adhesion, cell–matrix adhesion, and the murine model of hindlimb ischemia were performed as described previously.16 The details, as well as the methods to detect activation epitopes of integrins, integrin polarization, Rap1 activity assay, intravital videomicroscopy, and statistical analysis are described in detail in the expanded Materials and Methods section, available in the online data supplement at http://circres.ahajournals.org.
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Results |
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Expression of HMGB1 Receptors in EPCs
The endothelial phenotype of the ex vivo cultivated EPCs was confirmed by immunostaining, FACS analysis, and functional response to shear stress, as previously described.10,33,34 As assessed by FACS analysis, EPCs expressed the HMGB1 receptors, RAGE, and TLR2, but not TLR4 (Figure 1A and 1B).
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Effect of HMGB1 on EPC Migration
HMGB1 may stimulate migration of various cell types.26,32,35 Because EPCs express HMGB1 receptors, we first explored whether HMGB1 may affect vasculogenesis-related functions of EPCs. Although HMGB1 did not affect proliferation, apoptosis, or endothelial differentiation of EPCs (data not shown), it dose-dependently increased the chemotactic migration of EPCs onto fibronectin and fibrinogen, with a maximal effect at 10 ng/mL, whereas higher concentrations of HMGB1 were less effective in stimulating migration (Figure 2A and 2B).
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P<0.05 vs control+goat IgG; *P<0.05 vs HMGB1+IgG) E and F, EPC migration on fibronectin (E) and fibrinogen (F) was stimulated with HMGB1 (10 ng/mL) or PBS (control). EPCs were preincubated with the neutralizing integrin antibodies or murine control antibodies before migration (E [n=9 to 10]: #P<0.05 vs control+IgG, *P<0.05 vs HMGB1+IgG; F [n=6]: #P<0.05 vs control+IgG, *P<0.05 vs HMGB1+IgG).To analyze the underlying mechanism of HMGB1-induced EPC migration, we engaged inhibitory antibodies against its receptors, RAGE, TLR2, and TLR4. A neutralizing anti-RAGE antibody, as well as soluble RAGE, significantly blocked the HMGB1-induced migration of EPCs on fibronectin and fibrinogen (Figure 2C and 2D), whereas neutralizing TLR2 and TLR4 antibodies did not significantly influence HMGB1-stimulated EPC migration (Figure 2C and 2D), suggesting that the migratory effect of HMGB1 on human EPCs is predominantly mediated by RAGE. The anti-RAGE antibodies did not affect survival of EPCs (data not shown).
Because integrins are essential for cell motility,36 we next studied the role of ß1 and ß2 integrins for HMGB1-induced migration of EPCs. HMGB1-induced migration of EPCs on fibronectin and fibrinogen was specifically inhibited by blocking antibodies to ß1 and ß2 integrins, respectively (Figure 2E and 2F). Together, our data indicate that HMGB1 stimulates EPC migration on matrix proteins in a RAGE- and an integrin-dependent manner.
HMGB1 Induces EPC Adhesion
Adhesion to endothelial cells is an essential step for the extravasation of inflammatory37 and progenitor cells to ischemic tissues.16 Therefore, we investigated whether HMGB1 can induce the adhesion of EPCs to mature endothelial cells. Remarkably, short-term prestimulation of EPCs (in suspension) with HMGB1 dose-dependently increased EPC adhesion to HUVEC monolayers, with a maximal effect at 300 ng/mL (Figure 3A). Because ß2 integrins mediate EPC adhesion to HUVECs,16 we studied the effect of neutralizing integrin antibodies. Two different inhibitory ß2 integrin antibodies abolished the proadhesive effect of HMGB1, suggesting that HMGB1-induced adhesion of EPCs to HUVECs is mediated by ß2 integrins (Figure 3B). Furthermore, EPC preincubation with a neutralizing anti-RAGE antibody significantly reduced the HMGB1-induced adhesion of EPCs to HUVEC monolayers (Figure 3C).
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To further decipher the HMGB1-induced stimulation of EPC/endothelial cell interactions, we investigated the effect of HMGB1 on EPC adhesion to immobilized recombinant human intercellular adhesion molecule (ICAM)-1, which functions as the major endothelial cell ligand for ß2 integrins.38 Short-term stimulation of EPCs with HMGB1 significantly increased the binding of EPCs to ICAM-1, and this effect of HMGB1 was prevented by an inhibitory anti-RAGE antibody, but not by an inhibitory anti-TLR2 antibody (Figure 4A). Furthermore, neutralizing antibodies against the subunits (CD11a or CD11b) of the ß2 integrins significantly inhibited the HMGB1-induced adhesion of EPCs to ICAM-1, consistent with the fact that adhesion to ICAM-1 is mediated by both the CD11a and the CD11b subunits (Figure 4B). We then investigated whether HMGB1 is capable of increasing the ß1-integrin–dependent EPC adhesion to fibronectin.38 Short-term stimulation of EPCs with HMGB1 significantly increased EPC adhesion to fibronectin. HMGB1-induced EPC adhesion to fibronectin was significantly reduced by a neutralizing anti-RAGE antibody but not by a neutralizing anti-TLR2 antibody (Figure 4C). These data demonstrate that HMGB1 can increase both ß1- and ß2-integrin–dependent adhesion of EPCs via RAGE.
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Effect of HMGB1 on Integrin Activity
Because short-term stimulation of EPCs with HMGB1 rapidly increases adhesion, we hypothesized that HMGB1 may affect integrin activity. Integrin activity is regulated by affinity and valency changes.39,40 First, we investigated the effect of HMGB1 on integrin affinity by using specific antibodies that recognize activation-dependent epitopes on integrins. Although the stimulation of EPCs with HMGB1 had no effect on the total protein expression of the ß2 or ß1 integrins (data not shown), it enhanced the expression of the activation-dependent epitopes mAb24 (epitope on the ß2 integrin I-like domain) and HUTS21 (on the ß1 integrin), suggesting that HMGB1 is able to increase integrin affinity by inducing the active conformation of ß2 and ß1 integrins (Figure 5A and 5B).
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Next, we investigated whether HMGB1 can affect the distribution of integrins on the surface of EPCs, thereby affecting integrin valency/avidity. EPCs were incubated in suspension for 15 minutes in the presence or absence of HMGB1, then immediately fixed and seeded on poly-L-lysine-coated glass slides. Immunofluorescence staining was performed for ß2 integrin and CD44. CD44 is an adhesion molecule that localizes at the rear of lymphocytes on stimulation with chemokines.41 In the absence of HMGB1, the ß2 integrin and CD44 were homogeneously distributed on the EPC surface. Strikingly, HMGB1 stimulation of EPCs resulted in polarization of the ß2 integrin subunit (CD18) and of CD44 (Figure 6A and 6B). These data demonstrate that HMGB1 induces the lateral motility of the ß2 integrins on the EPC surface, thereby increasing integrin valency.
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Effect of HMGB1 on the Activation of the Small GTPase Rap1 in Human EPCs
Rap1 is a small GTPase involved in the regulation of integrin activity in several cell types.42 Because HMGB1 rapidly stimulates integrin-dependent adhesive functions of EPCs by increasing integrin affinity and valency/avidity, we explored whether HMGB1 stimulates Rap1 activity. Indeed, HMGB1 rapidly increased the GTP-bound (active) form of Rap1 in EPCs (Figure 7A and 7B), suggesting that Rap1 could participate in mediating the proadhesive activity of HMGB1 in EPCs.
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Effect of HMGB1 on Initial Adhesion and Homing of EPCs at Sites of Active Tumor Neovascularization and to Ischemic Muscles
HMGB1 activates ß1 and ß2 integrins in EPCs and increases integrin-dependent functions such as adhesion and migration in vitro. Therefore, we questioned whether HMGB1 can affect EPC homing at sites of active neovascularization in vivo. For that purpose, we used intravital videomicroscopy in a model of tumor angiogenesis. Prestimulation of EPCs in suspension with HMGB1 for 15 minutes increased the initial arrest of EPCs in the tumor microvessels as compared with nonstimulated cells (Figure 8A). Moreover, prestimulation of EPCs with HMGB1 significantly increased the long-term homing of EPCs into the tumor tissue 2 days after their intraarterial injection by 3-fold (Figure 8B). In addition, prestimulation of EPCs with HMGB1 significantly enhanced the homing of EPCs to ischemic limbs in the murine model of hind limb ischemia (Figure 8C; Figure I in the online data supplement).
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Discussion |
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The present study provides novel evidence for the regulation of integrin-dependent homing functions of EPCs by HMGB1. Specifically, our investigations revealed that (1) EPCs express the HMGB1 receptors RAGE and TLR2; (2) HMGB1 induces the chemotactic migration of EPCs in a RAGE- and integrin-dependent manner; (3) HMGB1 rapidly increases RAGE- and integrin-dependently the adhesion of EPCs to mature endothelial cells, ICAM-1, and fibronectin; (4) HMGB1 activates ß1 and ß2 integrins by enhancing their affinity and induces the lateral motility of ß2 integrins on the EPC surface; and (5) prestimulation of EPCs with HMGB1 is able to enhance in vivo adhesion and homing of EPCs at sites of active angiogenesis and sites of ischemia. Therefore, the present study provides insights into the regulation of integrin activity in EPCs and unravels a new function of HMGB1 in the regulation of integrin-dependent homing of EPCs (Figure 8D).
Previous studies demonstrated that HMGB1 acts as a chemoattractant for smooth muscle cells, inflammatory cells, stem cells, and glioma cells.26,32,43 In line with these reports, the present study demonstrates that HMGB1 induces the chemotactic migration of adult human peripheral blood–derived EPCs. Our findings demonstrated RAGE as the major HMGB1 receptor mediating the chemotactic activity of HMGB1 on EPCs. Besides RAGE, we found that EPCs express TLR2. TLR2 and TLR4 have been reported to function as receptors for HMGB128,29; however, in our study, TLR did not participate in the HMGB1-induced cell migration of EPCs. The studies demonstrating a TLR dependency28,29 used higher HMGB1 concentrations. The lower HMGB1 concentrations of the present study are within the range of serum levels measured in patients or animals under pathological conditions.44–46 The present work additionally demonstrates that the chemotactic response of EPCs to HMGB1 on matrix proteins like fibrinogen and fibronectin is dependent on integrins. This is in accordance with the established role of integrins for cell motility.36 Moreover, in previous studies HMGB1 has been shown to induce proliferation of murine embryonic mesoangioblasts and cardiac c-Kit+ progenitor cells and differentiation of the latter to cardiomyocytes.30,32 However, in the present study, HMGB1 had no significant effect on the proliferation rate, apoptosis, or endothelial differentiation of EPCs in vitro (data not shown). A conceivable explanation for this discrepancy is that progenitor cell populations of different origin may display distinct responses on stimulation with cytokines.
The present work also demonstrates that HMGB1 rapidly enhances EPC adhesion via stimulation of integrin activity. Prestimulation with HMGB1 increased the adhesion of EPCs to mature endothelial cell monolayers, to immobilized ICAM-1, and to fibronectin in a manner dependent on both RAGE and integrins. Likewise, HMGB1 stimulated the expression of activation-dependent epitopes on ß1 and ß2 integrins, indicating an increase in integrin affinity. Additionally, HMGB1 affected the distribution of ß2 integrins on the surface of EPCs (integrin valency/avidity). Specifically, stimulation of EPCs in suspension with HMGB1 led to a polarized distribution of ß2 integrins and CD44 on the EPC surface, with ß2 integrins segregated to the pole opposite to the CD44 localization, a pattern reminiscent of the polarization of leukocytes,41,47 in which CD44 is localized at the uropod (rear of migrating cells).41,47 Because cell polarization is essential for cell migration,36 it is conceivable that the HMGB1-induced polarization of integrins may be involved in the promigratory effect of HMGB1 on EPCs. In summary, these effects of HMGB1 resemble the integrin affinity and valency regulation mediated by chemokines in leukocytes40,48–51 and support the notion that the homing of leukocytes to sites of inflammation and the homing of EPCs to sites of neovascularization share at least some common features.
An open question is how HMGB1 regulates integrin affinity and avidity changes. Binding of HMGB1 to RAGE may trigger intracellular inside–outside signaling indirectly affecting integrin function. Indeed, HMGB1 increased the activity of the small GTPase Rap1 in EPCs, which is involved in the stimulation of integrin affinity and avidity.42,51 Moreover, during cell migration, small GTPases such as Cdc42 and Rac may affect the cell polarization and surface distribution of integrins, respectively.36 Dominant negative Rac and Cdc42 inhibit the outgrowth of neurites induced by RAGE-HMGB1 interaction.52 HMGB1 may also directly affects RAGE-dependent integrin activity. Further studies are required to clarify the mechanism of HMGB1-induced integrin activation.
In accordance with our in vitro data regarding the proadhesive effect of HMGB1, short-term prestimulation of EPCs with HMGB1 increased initial adhesion/arrest of EPCs in tumor vessels and their homing in the tumor tissue. Moreover, prestimulation of EPCs with HMGB1 enhanced the initial homing of EPCs to ischemic muscles in the murine model of hindlimb ischemia. These observations in combination with the integrin-stimulating activity of HMGB1 are in line with our previous findings demonstrating that integrin activation of EPCs by activating ß2 integrin antibodies is sufficient to increase homing and neovascularization capacity of EPCs.16 Together with its previously reported ability to increase the differentiation and proliferation of cardiac stem cells and to improve left ventricular ejection fraction after myocardial infarction30 and its proangiogenic activity,53,54 HMGB1-mediated stimulation of EPC homing may indeed have therapeutic relevance for patients with ischemic disorders.
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Acknowledgments |
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We thank Dr N. Hogg for providing the antibody mAb24.
Sources of Funding
This work was supported by the Deutsche Forschungsgemeinschaft (Transregional Collaborative Research Center SFB/TR23; Project A2 to E.C. and S.D. and Project C2 to P.V.), by the Sixth EU Framework Program (Anti-tumor Targeting; LSHC-CT-2005-518178 to P.V.), and by the Intramural Research Program of the NIH, National Cancer Institute (to T.C.).
Disclosures
Besides the scientific grants to E.C., S.D., P.V., and T.C. mentioned in the sources of funding, M.B. is the founder and owner of HMGBiotech, Milano, Italy (a biotechnology company specializing in HMG proteins). The value of these interests exceeds $10 000. A.M.Z., A.H., M.V., and G.C. have no interests to disclose.
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Footnotes |
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*Both authors contributed equally to this work.
Original received June 16, 2006; revision received December 14, 2006; accepted January 2, 2007.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000; 6: 389–395.[CrossRef][Medline] [Order article via Infotrieve]
2. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275: 964–967.
3. Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A, Fujita Y, Kothari S, Mohle R, Sauvage LR, Moore MA, Storb RF, Hammond WP. Evidence for circulating bone marrow-derived endothelial cells. Blood. 1998; 92: 362–367.
4. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999; 85: 221–228.
5. Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003; 9: 702–712.[CrossRef][Medline] [Order article via Infotrieve]
6. Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, Dimmeler S. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med. 2003; 9: 1370–1376.[CrossRef][Medline] [Order article via Infotrieve]
7. Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999; 5: 434–438.[CrossRef][Medline] [Order article via Infotrieve]
8. Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, Inai Y, Silver M, Isner JM. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 1999; 18: 3964–3972.[CrossRef][Medline] [Order article via Infotrieve]
9. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001; 7: 1194–1201.[CrossRef][Medline] [Order article via Infotrieve]
10. Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A. 2000; 97: 3422–3427.
11. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001; 7: 430–436.[CrossRef][Medline] [Order article via Infotrieve]
12. Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, Silver M, Ma H, Kearney M, Isner JM, Asahara T. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001; 103: 634–637.
13. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation. 2002; 106: 3009–3017.
14. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004; 95: 343–353.
15. Vajkoczy P, Blum S, Lamparter M, Mailhammer R, Erber R, Engelhardt B, Vestweber D, Hatzopoulos AK. Multistep nature of microvascular recruitment of ex vivo-expanded embryonic endothelial progenitor cells during tumor angiogenesis. J Exp Med. 2003; 197: 1755–1765.
16. Chavakis E, Aicher A, Heeschen C, Sasaki K, Kaiser R, El Makhfi N, Urbich C, Peters T, Scharffetter-Kochanek K, Zeiher AM, Chavakis T, Dimmeler S. Role of beta2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med. 2005; 201: 63–72.
17. Qin G, Ii M, Silver M, Wecker A, Bord E, Ma H, Gavin M, Goukassian DA, Yoon YS, Papayannopoulou T, Asahara T, Kearney M, Thorne T, Curry C, Eaton L, Heyd L, Dinesh D, Kishore R, Zhu Y, Losordo DW. Functional disruption of alpha4 integrin mobilizes bone marrow-derived endothelial progenitors and augments ischemic neovascularization. J Exp Med. 2006; 203: 153–163.
18. Jin H, Aiyer A, Su J, Borgstrom P, Stupack D, Friedlander M, Varner J. A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. J Clin Invest. 2006; 116: 652–662.[CrossRef][Medline] [Order article via Infotrieve]
19. Davie NJ, Crossno JT Jr, Frid MG, Hofmeister SE, Reeves JT, Hyde DM, Carpenter TC, Brunetti JA, McNiece IK, Stenmark KR. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol. 2004; 286: L668–L678.
20. Bianchi ME, Manfredi A. Chromatin and cell death. Biochim Biophys Acta. 2004; 1677: 181–186.[Medline] [Order article via Infotrieve]
21. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002; 418: 191–195.[CrossRef][Medline] [Order article via Infotrieve]
22. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003; 22: 5551–5560.[CrossRef][Medline] [Order article via Infotrieve]
23. Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 2002; 3: 995–1001.[CrossRef][Medline] [Order article via Infotrieve]
24. Palumbo R, Bianchi ME. High mobility group box 1 protein, a cue for stem cell recruitment. Biochem Pharmacol. 2004; 68: 1165–1170.[CrossRef][Medline] [Order article via Infotrieve]
25. Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005; 5: 331–342.[CrossRef][Medline] [Order article via Infotrieve]
26. Rouhiainen A, Kuja-Panula J, Wilkman E, Pakkanen J, Stenfors J, Tuominen RK, Lepantalo M, Carpen O, Parkkinen J, Rauvala H. Regulation of monocyte migration by amphoterin (HMGB1). Blood. 2004; 104: 1174–1182.
27. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D, Morser J, Stern D, Schmidt AM. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem. 1995; 270: 25752–25761.
28. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 2004; 279: 7370–7377.
29. Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A, Ishizaka A, Abraham E. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol. 2006; 290: C917–C924.
30. Limana F, Germani A, Zacheo A, Kajstura J, Di Carlo A, Borsellino G, Leoni O, Palumbo R, Battistini L, Rastaldo R, Muller S, Pompilio G, Anversa P, Bianchi ME, Capogrossi MC. Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation. Circ Res. 2005; 97: e73–e83.
31. Chavakis E, Dernbach E, Hermann C, Mondorf UF, Zeiher AM, Dimmeler S. Oxidized LDL inhibits vascular endothelial growth factor-induced endothelial cell migration by an inhibitory effect on the Akt/endothelial nitric oxide synthase pathway. Circulation. 2001; 103: 2102–2107.
32. Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A, Cossu G, Bianchi ME. Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol. 2004; 164: 441–449.
33. Kawamoto A, Asahara T, Losordo DW. Transplantation of endothelial progenitor cells for therapeutic neovascularization. Cardiovasc Radiat Med. 2002; 3: 221–225.[CrossRef][Medline] [Order article via Infotrieve]
34. Urbich C, Heeschen C, Aicher A, Dernbach E, Zeiher AM, Dimmeler S. Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells. Circulation. 2003; 108: 2511–2516.
35. Huttunen HJ, Rauvala H. Amphoterin as an extracellular regulator of cell motility: from discovery to disease. J Intern Med. 2004; 255: 351–366.[CrossRef][Medline] [Order article via Infotrieve]
36. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR. Cell migration: integrating signals from front to back. Science. 2003; 302: 1704–1709.
37. Muller WA. Leukocyte-endothelial cell interactions in the inflammatory response. Lab Invest. 2002; 82: 521–533.[CrossRef][Medline] [Order article via Infotrieve]
38. Plow EF, Haas TA, Zhang L, Loftus J, Smith JW. Ligand binding to integrins. J Biol Chem. 2000; 275: 21785–21788.
39. Carman CV, Springer TA. Integrin avidity regulation: are changes in affinity and conformation underemphasized. Curr Opin Cell Biol. 2003; 15: 547–556.[CrossRef][Medline] [Order article via Infotrieve]
40. van Kooyk Y, Figdor CG. Avidity regulation of integrins: the driving force in leukocyte adhesion. Curr Opin Cell Biol. 2000; 12: 542–547.[CrossRef][Medline] [Order article via Infotrieve]
41. Sanchez-Madrid F, del Pozo MA. Leukocyte polarization in cell migration and immune interactions. EMBO J. 1999; 18: 501–511.[CrossRef][Medline] [Order article via Infotrieve]
42. Bos JL. Linking Rap to cell adhesion. Curr Opin Cell Biol. 2005; 17: 123–128.[CrossRef][Medline] [Order article via Infotrieve]
43. Degryse B, Bonaldi T, Scaffidi P, Muller S, Resnati M, Sanvito F, Arrigoni G, Bianchi ME. The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol. 2001; 152: 1197–1206.
44. Wang H, Yang H, Czura CJ, Sama AE, Tracey KJ. HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med. 2001; 164: 1768–1773.
45. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al-Abed Y, Metz C, Miller EJ, Tracey KJ, Ulloa L. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004; 10: 1216–1221.[CrossRef][Medline] [Order article via Infotrieve]
46. Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, Lee ML, Andersson J, Tokics L, Treutiger CJ. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med. 2005; 33: 564–573.[CrossRef][Medline] [Order article via Infotrieve]
47. Katagiri K, Maeda A, Shimonaka M, Kinashi T. RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat Immunol. 2003; 4: 741–748.[CrossRef][Medline] [Order article via Infotrieve]
48. Chan JR, Hyduk SJ, Cybulsky MI. Chemoattractants induce a rapid and transient upregulation of monocyte alpha4 integrin affinity for vascular cell adhesion molecule 1 which mediates arrest: an early step in the process of emigration. J Exp Med. 2001; 193: 1149–1158.
49. Chan JR, Cybulsky MI. Detection of high-affinity alpha4-integrin upon leukocyte stimulation by chemoattractants or chemokines. Methods Mol Biol. 2004; 239: 261–268.[Medline] [Order article via Infotrieve]
50. Weber KS, Klickstein LB, Weber C. Specific activation of leukocyte beta2 integrins lymphocyte function-associated antigen-1 and Mac-1 by chemokines mediated by distinct pathways via the alpha subunit cytoplasmic domains. Mol Biol Cell. 1999; 10: 861–873.
51. Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol. 2005; 5: 546–559.[CrossRef][Medline] [Order article via Infotrieve]
52. Huttunen HJ, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem. 1999; 274: 19919–19924.
53. Schlueter C, Weber H, Meyer B, Rogalla P, Roser K, Hauke S, Bullerdiek J. Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule. Am J Pathol. 2005; 166: 1259–1263.
54. Mitola S, Belleri M, Urbinati C, Coltrini D, Sparatore B, Pedrazzi M, Melloni E, Presta M. Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol. 2006; 176: 12–15.
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