Abstract
Cardiac stem cells or precursor cells have the potential to regenerate cardiomyocytes, but their role in the efficacy of cardioprotective drugs remains controversial. Therefore, using a genetic fate-mapping model, we tested the hypothesis that leukemia inhibitory factor (LIF) influences cardiac stem cells and stimulates endogenous cardiomyocyte renewal after myocardial infarction (MI). 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 (5mg/kg/d for 2 weeks). Thus, every Xgal-negative cardiomyocyte was derived from a stem or precursor cell after tamoxifen administration. The number of Xgal-negative cardiomyocytes did not change during normal aging spanning 1 year. However, at 3 months after MI, the MI mice had more Xgal-negative cells than the control mice (57.0 ± 12.0 and 3.0 ± 2.6 cells per section, respectively; P < 0.01). The side population (SP) cell fraction contained label-retaining cells, which differentiated into Xgal-negative cardiomyocytes after MI. Among the cytokines secreted after MI, LIF expression increased to 130 fold in MI mice but rapidly decreased within 1 week. Therefore, we injected the LIF plasmid at the time of MI to keep blood LIF concentrations high and examined its effect on regeneration. At 1 month after MI, the MI + LIF group (118.6 ± 51.5 cells per section) had more Xgal-negative cells than the MI + PBS group (37.0 ± 5.5 cells per section; P < 0.05). Echocardiography showed significant recovery of fractional shortening in the LIF-treated group only. Next, we immunohistochemically analyzed the effect of LIF on SP cells. On BrdU administration at 1 week after MI, the percentages of BrdU-positive SP cells in LIF- and PBS-treated mice were 59%, and 35%, respectively, suggesting that LIF influenced SP cell proliferation. The percentages of Ki67- and phosphorylated histone-3-positive SP cells were also higher in LIF-treated mice. Taken together, LIF may stimulate stem cell-derived cardiomyocyte regeneration in part by activating SP cells. We believe our findings will help provide a novel therapeutic strategy for cardiogenesis.
Published Version
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