Abstract 3286: IGF-2 Enhances Human Cardiac Progenitor Cell Differentiation and Myocardial Regeneration After Infarction
The reconstitution of muscle mass by cell implantation after infarction is limited by two factors: number of cells engrafted into the recipient myocardium and modest differentiation of the cardiomyocyte progeny. The IGF system exerts powerful growth promoting and cell survival effects, suggesting that progenitor cells expressing the IGF-1 receptor (IGF-1R) may be more effective in promoting cardiac repair following ischemic myocardial damage. The IGF system consists of two ligands, IGF-1 and IGF-2, which both activate IGF-1R, although the cellular response to these two ligands may differ significantly. Therefore, hCPCs were isolated from myocardial samples collected from 8 patients and the presence and absence of IGF-1R was documented at the mRNA and protein level by quantitative RT-PCR, Western blotting and immunocytochemistry. Subsequently, two populations of hCPCs were obtained by FACS: IGF-1RPOS and IGF-1RNEG. In vitro, non-stimulated IGF-1RPOS-hCPCs had a population doubling time that was 2-fold shorter than in IGF-1RNEG-hCPCs. IGF-1 and IGF-2 enhanced further the proliferative response of IGF-1RPOS-hCPCs due to longer telomeres and higher level of telomerase activity. Additionally, IGF-2 increased dramatically the expression of markers of myocyte differentiation pointing to this ligand as a critical variable for the maturation of the committed myocyte progeny. Based on these observations, we tested whether IGF-1RPOS-hCPCs pre-treated with IGF-2 led to a striking expansion of the myocyte mass in the acutely infarcted heart of immunosuppressed rats. In comparison with IGF-1RPOS-hCPCs not exposed to IGF-2, growth factor activated IGF-1RPOS-hCPCs resulted in a larger magnitude of myocardial regeneration mediated by a nearly 2.5-fold significant increase in myocyte volume; the newly formed cardiomyocytes tended to acquire a more mature adult phenotype. These observations, obtained 16 days after coronary occlusion and the delivery of IGF-2 stimulated IGF-1RPOS-hCPCs, were accompanied by a 10 point increase in ejection fraction, attenuation in ventricular dilation and thickening of the ventricular wall. Thus, activation of IGF-1RPOS-hCPCs by IGF-2 potentiates cardiac repair and improves the performance of the infarcted heart.