Abstract 3901: Doxorubicin-Induced Cardiomyopathy Is Partially Reversed by Cardiac Progenitor Cell Therapy
The objective of this study was to determine whether the injection of cardiac progenitor cells (CPCs) opposes the progression of doxorubicin (DOXO) induced cardiotoxicity, a major problem in cancer treatment. Therefore, Fischer rats were injected i.p. over a period of 14 days with six doses of DOXO, each 2.5 mg/kg. One week later, a significant impairment of left ventricular (LV) function was found; ejection fraction and fractional shortening were markedly reduced while LV diameters increased and wall thickness decreased. These parameters of LV function and anatomy were further altered at 6 weeks. Throughout the period of investigation, overall mortality in DOXO-treated rats reached 78%. DOXO treatment potentiated myocyte apoptosis. Conversely, myocyte regeneration measured by Ki67 labeling was modest and did not counteract the extent of cell death. Importantly, DOXO administration was associated with a 70% reduction in the number of resident LV CPCs. In fact, a larger number of CPCs was undergoing apoptosis and this phenomenon was associated with enhanced oxidative stress. Additionally, the fraction of senescent p16INK4a positive CPCs was dramatically increased and the percentage of Ki67-positive CPCs was severely reduced. Based on these findings, EGFP-labeled CPCs were injected intramyocardially in DOXO-treated rats. Rats were sacrificed 3 weeks later. Cardiac function was significantly enhanced and mortality was dramatically reduced in CPC-treated animals. The decrease in heart weight associated with the dilated myopathy was partly prevented by CPC therapy, suggesting that CPCs promoted cardiac repair. Large clusters of regenerated myocytes were detected throughout the LV wall. These cells were EGFP- and BrdU-positive, and expressed contractile proteins. Multiple foci of myocardial regeneration were detected in all animals treated with CPCs. Connexin 43 and N-cadherin were expressed between new myocytes and preexisting myocytes demonstrating that the formed cells were electrically and mechanically coupled. Regeneration also involved resistance arterioles and capillary structures. In conclusion, CPC treatment restores partly the structural and functional integrity of DOXO-mediated dilated cardiomyopathy.