Abstract 1386: Stem Cells Refresh Adult Mammalian Cardiomyocytes Following Injury: A Genetic Fate-Mapping Study
Background Two fundamental questions in cardiac regeneration that remain controversial are: Are cardiomyocytes constantly replaced by endogenous stem/precursor cells? Does injury lead to replacement with new cardiomyocytes from a stem/precursor pool?
Methods and Results We developed a genetic fate-mapping system that allowed “pulse-chase” studies of cardiomyocytes in mice. We crossed an inducible cardiomyocyte-specific Mer-Cre-Mer transgenic mouse with ZEG reporter mice. Using a high-efficiency 4-OH-tamoxifen regimen that induced Cre recombination and induction of GFP in cardiomyocytes only, the GFP labeling efficiency in cardiomyocytes from 8 week old mice was 82.7±5.5% (n=10), with no detectable GFP expression in non-cardiomyocytes. Cumulative GFP leakage in the absence of 4-OH-tamoxifen was 1.7 ±1.1% over 12 months. During normal aging, the percentage of GFP+ cardiomyocytes at 3, 6, and 12 months after 4-OH-tamoxifen pulse was 85±4% (n=5), 82±3% (n=6), and 83±4% (n=8), respectively (P=NS), demonstrating no significant stem/precursor cell contribution to cardiomyocyte turnover without injury. However, 3 months following myocardial infarction (MI) or pressure overload, GFP+ cardiomyocytes significantly decreased; 83±4% in sham (n=8), 68±7% at MI border (n=14, P<0.0001), 77±6% in MI remote areas (n=14, P<0.05) and 76±8% in pressure overload (n=13, P<0.05). 90% of BrdU+/cardiac troponin-T+ cardiomyocytes were GFP-negative with no differences between sham, MI and overload (P<0.05), suggesting that most actively dividing cardiomyocytes in injured myocardium arise from a stem/precursor pool.
Conclusion Genetic “pulse-chase” fate mapping demonstrates that stem/precursor cells significantly contribute to adult mammalian cardiomyocyte replacement following injury but do not contribute significantly to cardiomyocyte renewal during normal aging.