Abstract
Introduction: Recent studies have contradicted the notion that the adult heart is a terminally differentiated organ. The source of cardiac regeneration and its relation with cardio-protective drugs remain controversial. Using a genetic fate-mapping model, we examined the rate of stem cell-derived cardiomyocyte renewal, focusing on the effect of leukemia inhibitory factor (LIF) on cardiac stem cells. Methods and Results: We generated MerCreMer-LacZ mice, in which more than 99.9% of the cardiomyocytes in the left ventricular field showed positive 5-bromo-4-chloro-3-indolyl-β-D-galactoside (Xgal) staining just after tamoxifen injection. Thus, every Xgal-negative cardiomyocyte was derived from a stem or precursor cell after tamoxifen administration. During normal aging spanning 1 year, the number of Xgal-negative cardiomyocytes in the mice did not change significantly: 2 weeks, 9.8 ± 3.8 cells per section; 1 year, 9.8 ± 5.2 cells per section. In contrast, at 6 months after myocardial infarction (MI), the MI mice had more Xgal-negative cells (41.0 ± 9.3 cells per section) than the control mice (8.0 ± 2.6 cells per section; P < 0.001) did. We injected the LIF plasmid or phosphate-buffered saline (PBS) at the time of MI. At 1 month after MI, the MI + LIF group (118.6 ± 51.5 cells per section) had a greater number of Xgal-negative cells than the MI + PBS group (37.0 ± 5.5 cells per section; P < 0.05) did. Echocardiography showed significant recovery of functional shortening in the LIF-treated group only. To detect the source of LIF-induced cardiomyocyte renewal, we studied cardiac side population (SP) cells. SP cells were found to have LIF receptors, and the percentage of phosphorylated signal transducers and activators of transcription 3-positive and cyclin D1-positive SP cells increased after LIF stimulation in vitro. In addition, continuous 5-bromodeoxyuridine (BrdU) administration during the first week after MI resulted in 68.9% BrdU-positive SP cells in LIF-treated mice, but only 30.5% in PBS-treated mice, suggesting that LIF influenced SP cell proliferation. Conclusion: LIF may stimulate stem cell-derived cardiomyocyte regeneration in part by activating SP cells. Our findings should help provide a novel strategy for therapeutic cardiogenesis.
Published Version
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