Abstract 17059: Genetic Ablation of c-kit Impairs Cardiac Stem Cell Function, Leading to Attenuated Cardiomyogenesis and Accelerated Myocardial Aging
The objective of this study was to determine whether defects in c-kit receptor tyrosine activity attenuate cardiac stem cell (CSC) growth, interfering with myocyte renewal and promoting myocardial aging. This possibility was tested in W/WV mice, which carry a mutated c-kit receptor characterized by 80-90% decrease in activity. Cardiac anatomy and function were studied echocardiographycally in conscious W/WV and WT mice from 2-3 to 9-11 months of age. At 2-3 months, LV systolic and diastolic diameters, wall thickness and ejection fraction were similar in the two groups of mice. However, at 6-7 and mostly at 9-11 months, LV cavitary diameters were larger in W/WV, resulting in a decrease in wall thickness-to-chamber radius ratio in these mice. Ejection fraction was preserved in WT up to 11 months, but decreased progressively with age in W/WV mice. Importantly, significant alterations in hematopoiesis were not present at this age interval. To establish whether the anatomical and functional modifications of the heart in W/WV mice were mediated by alterations in CSC growth, c-kit-positive CSCs were isolated from W/WV and WT mice. The fraction of BrdU-labeled CSCs was nearly 50% lower in W/WV, while apoptosis was 2.7-fold higher. The question was then whether these in vitro results had an equivalent counterpart in vivo. CSC niches were rarely seen in W/Wv mice. Niches correspond to the sites of active cardiomyogenesis suggesting that this process may be altered in W/Wv mice. At 2 months, WT and W/WV mice had the same number of LV myocytes which were essentially identical in volume. However, at 4 months, W/WV mice had a decreased number of LV myocytes, which were larger in volume. Cycling myocytes were 63% lower in W/WV mice and myocyte apoptosis was 3.6-fold higher in these mice. Following 1 week of BrdU administration, the fraction of BrdU-positive myocytes was 70% lower in W/WV mice. Importantly, a 2.4-fold and 2.1-fold increase in the percentage of CSCs and myocytes expressing the senescence-associated protein p16INK4a was observed in mutant mice. Thus, impaired growth reserve of CSCs in W/WV mice leads to defective myocyte turnover, accumulation of old CSCs and myocytes and enhanced cell death, which together condition premature cardiac aging and ventricular dysfunction.
- © 2013 by American Heart Association, Inc.