Abstract
Cardiac stem cells or precursor cells regenerate cardiomyocytes; however, the mechanism underlying this effect remains unclear. We generated CreLacZ mice in which more than 99.9% of the cardiomyocytes in the left ventricular field were positive for 5-bromo-4-chloro-3-indolyl-β-d-galactoside (X-gal) staining immediately after tamoxifen injection. Three months after myocardial infarction (MI), the MI mice had more X-gal-negative (newly generated) cells than the control mice (3.04 ± 0.38/mm2, MI; 0.47 ± 0.16/mm2, sham; p < 0.05). The cardiac side population (CSP) cell fraction contained label-retaining cells, which differentiated into X-gal-negative cardiomyocytes after MI. We injected a leukemia inhibitory factor (LIF)-expression construct at the time of MI and identified a significant functional improvement in the LIF-treated group. At 1 month after MI, in the MI border and scar area, the LIF-injected mice had 31.41 ± 5.83 X-gal-negative cardiomyocytes/mm2, whereas the control mice had 12.34 ± 2.56 X-gal-negative cardiomyocytes/mm2 (p < 0.05). Using 5-ethynyl-2'-deoxyurinide (EdU) administration after MI, the percentages of EdU-positive CSP cells in the LIF-treated and control mice were 29.4 ± 2.7% and 10.6 ± 3.7%, respectively, which suggests that LIF influenced CSP proliferation. Moreover, LIF activated the Janus kinase (JAK)signal transducer and activator of transcription (STAT), mitogen-activated protein kinase/extracellular signal-regulated (MEK)extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)–AKT pathways in CSPs in vivo and in vitro. The enhanced green fluorescent protein (EGFP)-bone marrow-chimeric CreLacZ mouse results indicated that LIF did not stimulate cardiogenesis via circulating bone marrow-derived cells during the 4 weeks following MI. Thus, LIF stimulates, in part, stem cell-derived cardiomyocyte regeneration by activating cardiac stem or precursor cells. This approach may represent a novel therapeutic strategy for cardiogenesis.
Highlights
Progress in the treatment of heart failure has improved survival rates in previous decades; it remains one of the leading causes of morbidity and mortality worldwide [1]
The cardiomyocytes, which were characterized by sarcomere formation and surrounding laminin, exhibited X-gal-positive staining in the left ventricle (LV) (Fig 1B). β-galactosidase expression in the cardiomyocytes was confirmed by immunofluorescence using an anti-β-galactosidase antibody (S1 Fig)
Using a genetic fate-mapping system, we identified more newly formed cardiomyocytes in injured myocardium compared with normal myocardium
Summary
Progress in the treatment of heart failure has improved survival rates in previous decades; it remains one of the leading causes of morbidity and mortality worldwide [1]. The most established strategy for cardiac regenerative therapy has been the delivery of exogenous cells, i.e., cell-based therapy. The adult mammalian heart possesses several types of cardiac stem cells (CSCs) or progenitor cells (CPCs), which have the ability to differentiate into cardiomyocytes [6]. Recent radioisotope studies have demonstrated homeostatic endogenous cardiomyocyte regeneration in the adult mammalian heart [7].
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