Abstract 11260: Leukemia Inhibitory Factor Activates JAK-STAT Pathway in Side Population Cells and Enhances Stem Cell-Derived Cardiomyocyte Renewal after Myocardial Infarction
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. 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. Flow cytometric analyses confirmed that LIF activates JAK-STA pathway in SP cells both in vivo and in vitro. Taken together, LIF may stimulate stem cell-derived cardiomyocyte regeneration in part by activating SPcells. We believe our findings will help provide a novel therapeutic strategy for cardiogenesis.
- © 2012 by American Heart Association, Inc.