Abstract 2113: Age and Pathology Impair Cardiac Stem Cells

Cardiac stem cells (CSCs), expressing Oct-4, NANOG and Sox-2, displayed, in vitro, extensive growth capacity, telomerase activity, clonogenicity and wide multipotency. Aims: to verify if age and heart failure impair CSCs. Methods and results: an in vitro system aimed at studying both senescence-associated molecular changes and functional impairment of CSCs was developed. Human CSCs were obtained from 18 donor hearts (D-CSCs) and 23 recipient hearts (R-CSCS). When compared in terms of telomerase activity, D-CSCs displayed significantly higher levels of enzymatic activity (154±76 TPG units vs. 30±29 TPG units, p=0.0002), longer telomeres (32±9 vs 24±8, p=0.012), and a lower fraction of cells with telomere dysfunction-induced foci-TIFs- (31.5±9.1 vs 33.7±7.3%, p=0.012). In R-CSCs, the presence of TIFs was associated with an increase in phospho-p53ser15, p21 and p16. Since age could affect the analyzed parameters, we determined, by statistical analysis, that pathology was an inedependent predictor of telomerase activity (p=0.0001), and TIFs (p=0.012). Finally, age and gender matched R- (n=21) and D-CSCs (n=12) were evaluated in terms of expansion potential, differentiation capacity, and migration ability. As expected, D-CSCs displayed, with respect to D-CSCs, longer population doubling time (55±15 vs 36±4 hours) and reduced maximum cell population doubling number (52±5 vs 43±6, p=0.002). Moreover, R-CSCs displayed a significantly impaired ability to differentiate into myocytes and endothelial cells and to migrate along a chemotactic gradient. However, when R-CSCs were cloned at single cell level, the fraction of TIF-positive cells was 40% smaller in clonogenic than in polyclonal recipient cells and the cardiomyogenic potential of cells from explanted hearts was partly restored when clonogenic cells were employed. In conclusion: Although CSCs can be isolated and grown from atria of normal and pathological human hearts, pathological processes can functionally impair the resident cardiac stem cell reservoir. However, it is possible to isolate a rare population of clonogenic cells with unaffected potential. This rare population could represent the ideal cell source to be employed in autologous regenerative approaches.