The resident cardiac progenitor cells (CPCs) have been identified in the adult myocardium, however, the CPC pool is rapidly depleted after acute myocardial infarction (AMI). The strategy to home ex vivo cultured CPCs to ischemic myocardium might be an important strategy to replenish resident CPC pool, and improve cardiac function. The CXC chemokine SDF-1α and its receptor CXCR4 have been identified as critical mediator for the ischemia-specific recruitment of progenitor cells, yet the level of CXCR4 expression in CPCs is quite low in normal conditions. Our previous studies showed that hypoxia can optimize CPCs via inducing functional CXCR4 expression in vitro, therefore, in this study, we want to investigate whether the transplantation of hypoxia treated CPCs (Hypo:CPCs) have the benefit of improving cardiac function resulted from increased cell homing in ischemic myocardium through mechanisms of hypoxia induced CXCR4 expression. To compare the homing capability between CPCs and Hypo:CPCs in response to endogenous SDF-1 signal in acute ischemic myocardium, we used retrovirus (pCL-MFG-β-gal) to label c-kit
+
Lin
−
CPCs with β-gal, and then injected labeled CPCs and Hypo:CPCs (1×10
6
) intravenously via intra-jugular vein to mice 10 min after induction of MI in the C56BL/6 mice. We harvested the hearts 1d after cell transplantation to quantify the cell retention by chemiluminescent β-galactosidase assay. We observed that hypoxia treatment resulted in about 2.5 fold increase in β-gal cell recruitment in ischemic hearts (p<0.001, n=7– 8/group), however, AMD3100 can partially reduce Hypo:CPCs homing, therefore, the beneficial effects of Hypo:CPCs transplantation were mediated primarily through increasing cell homing via SDF-1:CXCR4 binding within the ischemic hearts. In addtion, the infusion of Hypo:CPCs also led to improved left ventricular performance, as assessed by LV development pressure by Millar catheter, by 23.67% compared with CPCs at 1 month after cell therapy (p<0.001, n=6/group). These results indicate that replenish CPC pool after AMI using ex vivo cultured CPC transplantation has significant beneficial effects on injured heart function dependent of hypoxia induced CXCR4 upregulation.
C-Kit Promotes Growth and Migration of Human Cardiac Progenitor Cells via the PI3K-AKT and MEK-ERK Pathways