Background-Administration of cardiac progenitor cells (CPCs) 4 hours after reperfusion ameliorates left ventricular function in rats with acute myocardial infarction (MI). Clinically, however, this approach is not feasible, because expansion of autologous CPCs after acute MI requires several weeks. Therefore, we sought to determine whether CPCs are beneficial in the more clinically relevant setting of an old MI (scar). Methods and Results-One month after coronary occlusion/reperfusion, rats received an intracoronary infusion of vehicle or enhanced green fluorescent protein-labeled CPCs. Thirty-five days later, CPC-treated rats exhibited more viable myocardium in the risk region, less fibrosis in the noninfarcted region, and improved left ventricular function. Cells that stained positive for enhanced green fluorescent protein that expressed cardiomyocyte, endothelial, and vascular smooth muscle cell markers were observed only in 7 of 17 treated rats and occupied only 2.6% and 1.1% of the risk and noninfarcted regions, respectively. Transplantation of CPCs was associated with increased proliferation and expression of cardiac proteins by endogenous CPCs. Conclusions-Intracoronary administration of CPCs in the setting of an old MI produces beneficial structural and functional effects. Although exogenous CPCs can differentiate into new cardiac cells, this mechanism is not sufficient to explain the benefits, which suggests paracrine effects; among these, the present data identify activation of endogenous CPCs. This is the first report that CPCs are beneficial in the setting of an old MI when given by intracoronary infusion, the most widely applicable therapeutic approach in patients. Furthermore, this is the first evidence that exogenous CPC administration activates endogenous CPCs. These results open the door to new therapeutic applications for the use of autologous CPCs in patients with old MI and chronic ischemic cardiomyopathy. (Circulation. 2010;121:293-305.)Key Words: regeneration Ⅲ progenitor cells Ⅲ myocardial infarction Ⅲ reperfusion Ⅲ stem cells C ell-based therapies have the potential to alleviate left ventricular (LV) dysfunction and remodeling after acute myocardial infarction (MI) in experimental animal models 1 and in humans. 2,3 Among the various cells used, c-kitpositive (c-kit pos ) cardiac progenitor cells (CPCs) are attractive because they normally reside in the heart and presumably are responsible for replenishing the pool of cardiac myocytes and coronary vessels under normal conditions. 4 -6 The practical utility of CPCs is further supported by the fact that these cells can be isolated from small fragments of cardiac tissue and expanded for subsequent autologous administration. 5,6 Clinical Perspective on p 305Transplantation of autologous or syngeneic CPCs has been found to be effective in limiting LV dysfunction and remodeling in rodent models of acute MI, both in the setting of a permanent coronary occlusion 4 -6 and in that of a transient occlusion followed by reperfusion. 7 Clinically, how...

ABSTRACT

Abstract-We systematically investigated the comparative efficacy of three different cytokine regimens, administered after a reperfused myocardial infarction, in regenerating cardiac tissue and improving left ventricular (LV) function. Wild-type (WT) mice underwent a 30-minute coronary occlusion followed by reperfusion and received vehicle, granulocyte colony-stimulating factor (G-CSF)ϩFlt-3 ligand (FL), G-CSFϩstem cell factor (SCF), or G-CSF alone starting 4 hours after reperfusion. In separate experiments, chimeric mice generated by reconstitution of radioablated WT mice with bone marrow from enhanced green fluorescent protein (EGFP) transgenic mice underwent identical protocols. Mice were euthanized 5 weeks later. Echocardiographically, LV function was improved in G-CSFϩFL-and G-CSFϩSCF-treated but not in G-CSF-treated mice, whereas LV end-diastolic dimensions were smaller in all three groups. Morphometrically, cytokine-treated hearts had smaller LV diameter and volume. Numerous EGFP-positive cardiomyocytes, capillaries, and arterioles were noted in the infarcted region in cytokine-treated chimeric mice treated with G-CSFϩFL or G-CSFϩSCF, but the numbers were much smaller in G-CSF-treated mice. G-CSFϩFL therapy mobilized bone marrow-derived cells exhibiting increased expression of surface antigens (CD62L and CD11a) that facilitate homing. We conclude that postinfarct cytokine therapy with G-CSFϩFL or G-CSFϩSCF limits adverse LV remodeling and improves LV performance by promoting cardiac regeneration and probably also by exerting other beneficial actions unrelated to regeneration, and that G-CSF alone is less effective. , no therapies are currently available to restore dead myocardium. Although mobilization of bone marrow cells (BMCs) by cytokines has been suggested to regenerate cardiac tissue after MI and to produce functional improvement, the reports on the effects of cytokine treatment are conflicting. [1][2][3][4][5][6] Furthermore, previous studies of cytokines have used models of permanent coronary ligation 1-3,5 that do not reflect the fact that most patients with acute MI undergo coronary reperfusion. In addition, these studies have administered cytokines as a pretreatment 1,2 or performed splenectomy 1,2,5 or both, 1,2 neither of which would be clinically feasible. Although various cytokines have been tested, the relative efficacy of different treatments or combinations of treatments has not been elucidated. Finally, the mechanism whereby cytokines improve left ventricular (LV) function and structure after MI remains obscure. It has been proposed that cytokines mobilize BMCs with subsequent homing to the infarcted tissue and transdifferentiation into cardiac lineage, 1-3 but this hypothesis remains unproven. Thus, numerous unresolved issues persist regarding the use of cytokines as a strategy to achieve cardiac repair after MI.Accordingly, in the present study, we examined the effect of three cytokines (granulocyte colony-stimulating factor [G-CSF], stem cell factor [SCF], and Flt-3 ligand [FL]) on ca...