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,...

Abstract-Clinical and experimental evidence suggest that the renin-angiotensin system (RAS) plays a role in metabolic syndrome. Adipogenesis is suggested to modulate obesity and obesity-related consequences, such as metabolic syndrome. Although mesenchymal stem cells (MSCs) are a major source of adipocyte generation, the influence of RAS on MSC differentiation to adipocyte is unknown. We evaluated the expression of endogenous RAS in human MSCs during its differentiation to adipocytes and studied the effects of angiotensin II (Ang II), Ang II type 1 receptor blocker Valsartan, and type 2 (AT 2 ) receptor blocker PD123319. Our data showed that differentiation was associated with an increase in cellular renin and AT 2 receptor expression and a concomitant decrease in angiotensinogen and angiotensin-converting enzyme expression. The net effect is an increase in endogenous cellular angiotensin II production. Incubation with Ang II (exogenous) inhibited adipogenesis. Combined treatment of exogenous Ang II and Valsartan further inhibited adipogenesis, whereas combined treatment of Ang II and PD123319 completely abolished the inhibition of adipogenesis, suggesting an important role for the AT 2 receptor. Blockade of endogenous angiotensin II effect by incubation with Valsartan alone inhibited adipogenesis, whereas PD123319 alone promoted adipogenesis, confirming the data using exogenous Ang II. The combination of Valsartan and PD123319 had no net effect. Our data demonstrate an important role of the expression of the local RAS in the regulation of human MSC differentiation to adipocytes. Elucidation of the molecular mechanism should provide important insight into the pathophysiology of the metabolic syndrome and the development of future therapeutics.