title: Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction.
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.
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kanda
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Toshinao
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Mei Lan
authors.initials: ML
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Kondou
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Goro
authors.initials: G
authors.lastname: Sashida
authors.affiliation: Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D053612:Janus Kinases / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D050791:STAT Transcription Factors / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050791:STAT Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases