Essential Role of ICAM-1/CD18 in Mediating EPC Recruitment, Angiogenesis, and Repair to the Infarcted Myocardium

Abstract

Abstract-Bone marrow-derived endothelial progenitor cells (EPCs) have the ability to migrate to ischemic organs.However, the signals that mediate trafficking and recruitment of these cells are not well understood. Using a functional genomics strategy, we determined the genes that were upregulated in the ischemic myocardium and might be involved in EPC recruitment. Among them, CD18 and its ligand ICAM-1 are particularly intriguing because CD18 and its heterodimer binding chains CD11a and CD11b were correspondingly expressed in ex vivo-expanded EPCs isolated from rat and murine bone marrows. To further verify the functional role of CD18 in mediating EPC recruitment and repair to the infarcted myocardium, we used neutralizing antibody to block CD18. Blockade of CD18 in EPCs significantly inhibited their attachment capacity in vitro and reduced their recruitment to the ischemic myocardium in vivo by 95%. Moreover, mice receiving EPCs that were treated with control isotype IgG exhibited significantly increased capillary density in the infarct border zone, reduced cardiac dilatation, ventricular wall thinning, and fibrosis when compared with myocardial infarction mice receiving PBS and CD18 blockade reversed the EPC-mediated improvements to the infarcted heart. Thus, our results suggest an essential role of CD18 in mediating EPC recruitment and the subsequent functional effects on the infarcted heart. (Circ Res. 2006;99:315-322.)Key Words: CD18 Ⅲ EPC Ⅲ recruitment Ⅲ myocardial infarction Ⅲ heart repair P revious studies have suggested that bone marrowderived endothelial progenitor cells (EPCs) could migrate to the foci of ischemia and promote repair of the injured organs. 1 In animal models of myocardial infarction (MI), injection of ex vivo-expanded EPCs significantly improved blood flow and cardiac function and reduced left ventricular (LV) scarring. [2][3][4] Similarly, infusion of ex vivo-expanded EPCs improved the neovascularization in hind limb ischemia models. 4,5 Moreover, pilot trials using progenitor cells acquired from bone marrow or peripheral blood have shown benefit in improving blood supply of the ischemic tissue. 6,7 However, the benefit of ex vivoexpanded EPCs to the damaged organs along with the number of EPCs recruited to the damaged tissues varies considerably in the previous studies, 8 -10 suggesting that a better understanding of the mediators and receptors responsible for the process of EPC trafficking and recruitment would be crucial to enhancing EPC-mediated therapeutic effect.In this study, we developed a functional genomics strategy to identify the mediators of bone marrow-derived stem cell recruitment to the infarcted myocardium. We defined the term recruitment hereby that includes chemoattraction, adhesion, migration, retention, and accumulation. We generated expression profiles of MI heart and identified 16 chemokines, cytokines, and adhesion molecules that were significantly upregulated in myocardial ischemic injury whose complementary receptors were also expressed in EPCs. Accordingly,...

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

“…This is supported by observations that the augmentation of neovascularizations in MI hearts was closely associated with the prevention of cardiac remodeling (20,43). It is very interesting to evaluate the volume of infarct size over time following the transplantation of CSCs in the MI heart, which is the limitation in our observation.…”

Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia

“…Despite the lack of effect of DMOG-treated cells alone, the combination of IV DMOGtreated BMDACs and IM AdCA5 induced functional recovery and limb salvage in old mice, in which angiogenic responses are impaired as compared to young mice (4, 16), thus more closely resembling patients with critical limb ischemia. Finally, in addition to the synergistic therapeutic effects of IM AdCA5 and IV DMOG-treated BMDACs, stable retention of BMDACs in ischemic tissue is further aided by hypoxia-induced expression in vascular endothelial cells of ICAM-1 and E-selectin, which are known to interact with ␤ 2 integrins, and were recently shown to be involved in BMDAC homing to ischemic myocardium (35) and muscle (36,37).…”

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…SDF-1 induces integrin expression on EPCs [18] in addition to vascular cell adhesion molecule-1 on the endothelium [52]. Other crucial integrins mediating the incorporation of EPCs include β2 integrins, lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1 [53][54][55]. In addition, Massberg et al have demonstrated that SDF-1 released from platelets supports the recruitment of EPCs and facilitates their adhesion to the injured vascular wall [34].…”

“…In addition, Massberg et al have demonstrated that SDF-1 released from platelets supports the recruitment of EPCs and facilitates their adhesion to the injured vascular wall [34]. Finally, membrane-bound KitL (mKitL) in atherosclerotic lesions induces the adhesion and recruitment of EPCs, which could be indirectly driven by the activation of the SDF-1-CXCR4 pathway [54]. [20,21,30].…”