Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction
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)...
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| creator | Kanda, Masato Nagai, Toshio Takahashi, Toshinao Liu, Mei Lan Kondou, Naomichi Naito, Atsuhiko T Akazawa, Hiroshi Sashida, Goro Iwama, Atsushi Komuro, Issei Kobayashi, Yoshio |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0156562 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0156562</identifier><identifier>PMID: 27227407</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Animals ; Biology and Life Sciences ; Bone marrow ; Cardiomyocytes ; Cell cycle ; Cell Proliferation - drug effects ; Cellular signal transduction ; Cytokines ; Diagnosis ; Disease Models, Animal ; Extracellular signal-regulated kinase ; Fibroblasts ; Fluorescence ; Green fluorescent protein ; Green fluorescent proteins ; Heart ; Heart attack ; Heart attacks ; Heart cells ; Heart diseases ; Heart failure ; Janus kinase ; Janus Kinases - metabolism ; Laboratory animals ; Leukemia ; Leukemia inhibitory factor ; Leukemia Inhibitory Factor - pharmacology ; MAP kinase ; MAP Kinase Kinase Kinases - metabolism ; MAP Kinase Signaling System - drug effects ; Medicine ; Medicine and Health Sciences ; Mice ; Mice, Transgenic ; Myocardial infarction ; Myocardial Infarction - drug therapy ; Myocardial Infarction - metabolism ; Myocardium - metabolism ; Myocytes, Cardiac - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; Physiological aspects ; Precursors ; Protein kinase ; Proto-Oncogene Proteins c-akt - metabolism ; Regeneration ; Regeneration - drug effects ; Research and analysis methods ; Risk factors ; Rodents ; STAT Transcription Factors - metabolism ; Stem cell transplantation ; Stem cells ; Stem Cells - metabolism ; Tamoxifen ; Transcription ; Transgenic animals ; University graduates ; Ventricle</subject><ispartof>PloS one, 2016-05, Vol.11 (5), p.e0156562-e0156562</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Kanda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Kanda et al 2016 Kanda et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-c75299cb1134fbb3d64dbc2a0f596f73de86b90c96f2ab766f972d3a697561383</citedby><cites>FETCH-LOGICAL-c725t-c75299cb1134fbb3d64dbc2a0f596f73de86b90c96f2ab766f972d3a697561383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881916/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881916/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27227407$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Limana, Federica</contributor><creatorcontrib>Kanda, Masato</creatorcontrib><creatorcontrib>Nagai, Toshio</creatorcontrib><creatorcontrib>Takahashi, Toshinao</creatorcontrib><creatorcontrib>Liu, Mei Lan</creatorcontrib><creatorcontrib>Kondou, Naomichi</creatorcontrib><creatorcontrib>Naito, Atsuhiko T</creatorcontrib><creatorcontrib>Akazawa, Hiroshi</creatorcontrib><creatorcontrib>Sashida, Goro</creatorcontrib><creatorcontrib>Iwama, Atsushi</creatorcontrib><creatorcontrib>Komuro, Issei</creatorcontrib><creatorcontrib>Kobayashi, Yoshio</creatorcontrib><title>Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Bone marrow</subject><subject>Cardiomyocytes</subject><subject>Cell cycle</subject><subject>Cell Proliferation - drug effects</subject><subject>Cellular signal transduction</subject><subject>Cytokines</subject><subject>Diagnosis</subject><subject>Disease Models, Animal</subject><subject>Extracellular signal-regulated kinase</subject><subject>Fibroblasts</subject><subject>Fluorescence</subject><subject>Green fluorescent protein</subject><subject>Green fluorescent proteins</subject><subject>Heart</subject><subject>Heart attack</subject><subject>Heart attacks</subject><subject>Heart cells</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>Janus kinase</subject><subject>Janus Kinases - metabolism</subject><subject>Laboratory animals</subject><subject>Leukemia</subject><subject>Leukemia inhibitory factor</subject><subject>Leukemia Inhibitory Factor - pharmacology</subject><subject>MAP kinase</subject><subject>MAP Kinase Kinase Kinases - metabolism</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Myocardial infarction</subject><subject>Myocardial Infarction - drug therapy</subject><subject>Myocardial Infarction - metabolism</subject><subject>Myocardium - metabolism</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Physiological aspects</subject><subject>Precursors</subject><subject>Protein kinase</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Regeneration</subject><subject>Regeneration - drug effects</subject><subject>Research and analysis methods</subject><subject>Risk factors</subject><subject>Rodents</subject><subject>STAT Transcription Factors - metabolism</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Stem Cells - metabolism</subject><subject>Tamoxifen</subject><subject>Transcription</subject><subject>Transgenic animals</subject><subject>University graduates</subject><subject>Ventricle</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk22L1DAQx4so3nn6DUQLguiLXZukeXojHMudLqwcnA9vwzRJd3N2mzVpxf32pm7v2MqBUsjDzG_-SSczWfYcFXNEOHp34_vQQjPf-dbOC0QZZfhBdookwTOGC_LwaH2SPYnxpigoEYw9zk4wx5iXBT_N7Mr23-3WQb5sN65ynQ_7_BJ0mvOLdgOttjEtjF_b1vcxX0Awzm_3Xu87m1_bZLYBOufbHOrOhvxTcg0MNEmxhqAH39PsUQ1NtM_G-Sz7ennxZfFxtrr6sFycr2aaY9qlkWIpdYUQKeuqIoaVptIYippKVnNirGCVLHTaYKg4Y7Xk2BBgklOGiCBn2cuD7q7xUY0ZigpxiQTDtMSJWB4I4-FG7YLbQtgrD079MfiwVhA6pxurJEVGALGywHUpqBAWGWl5JZnRQEqTtN6Pp_XV1hpt2y5AMxGdelq3UWv_U5VCIIlYEngzCgT_o7exU1sXtW0aaG1KtkKiEIyKUsh_o1xiwqQgZUJf_YXen4iRWkP6V9fWPl1RD6LqvKSEEsLwcOz8Hip9JtWMTpVXu2SfBLydBCSms7-6NfQxquXn6_9nr75N2ddH7MZC022ib_qhuuIULA-gDj7GYOu790CFGhrnNhtqaBw1Nk4Ke3H8lndBt51CfgNu0RNh</recordid><startdate>20160526</startdate><enddate>20160526</enddate><creator>Kanda, Masato</creator><creator>Nagai, Toshio</creator><creator>Takahashi, Toshinao</creator><creator>Liu, Mei Lan</creator><creator>Kondou, Naomichi</creator><creator>Naito, Atsuhiko T</creator><creator>Akazawa, Hiroshi</creator><creator>Sashida, Goro</creator><creator>Iwama, Atsushi</creator><creator>Komuro, Issei</creator><creator>Kobayashi, Yoshio</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20160526</creationdate><title>Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction</title><author>Kanda, Masato ; Nagai, Toshio ; Takahashi, Toshinao ; Liu, Mei Lan ; Kondou, Naomichi ; Naito, Atsuhiko T ; Akazawa, Hiroshi ; Sashida, Goro ; Iwama, Atsushi ; Komuro, Issei ; Kobayashi, Yoshio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c725t-c75299cb1134fbb3d64dbc2a0f596f73de86b90c96f2ab766f972d3a697561383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Biology and Life Sciences</topic><topic>Bone marrow</topic><topic>Cardiomyocytes</topic><topic>Cell cycle</topic><topic>Cell Proliferation - 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drug therapy</topic><topic>Myocardial Infarction - metabolism</topic><topic>Myocardium - metabolism</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Physiological aspects</topic><topic>Precursors</topic><topic>Protein kinase</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Regeneration</topic><topic>Regeneration - drug effects</topic><topic>Research and analysis methods</topic><topic>Risk factors</topic><topic>Rodents</topic><topic>STAT Transcription Factors - metabolism</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Stem Cells - metabolism</topic><topic>Tamoxifen</topic><topic>Transcription</topic><topic>Transgenic animals</topic><topic>University graduates</topic><topic>Ventricle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kanda, Masato</creatorcontrib><creatorcontrib>Nagai, Toshio</creatorcontrib><creatorcontrib>Takahashi, Toshinao</creatorcontrib><creatorcontrib>Liu, Mei Lan</creatorcontrib><creatorcontrib>Kondou, Naomichi</creatorcontrib><creatorcontrib>Naito, Atsuhiko T</creatorcontrib><creatorcontrib>Akazawa, Hiroshi</creatorcontrib><creatorcontrib>Sashida, Goro</creatorcontrib><creatorcontrib>Iwama, Atsushi</creatorcontrib><creatorcontrib>Komuro, Issei</creatorcontrib><creatorcontrib>Kobayashi, Yoshio</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kanda, Masato</au><au>Nagai, Toshio</au><au>Takahashi, Toshinao</au><au>Liu, Mei Lan</au><au>Kondou, Naomichi</au><au>Naito, Atsuhiko T</au><au>Akazawa, Hiroshi</au><au>Sashida, Goro</au><au>Iwama, Atsushi</au><au>Komuro, Issei</au><au>Kobayashi, Yoshio</au><au>Limana, Federica</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-05-26</date><risdate>2016</risdate><volume>11</volume><issue>5</issue><spage>e0156562</spage><epage>e0156562</epage><pages>e0156562-e0156562</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27227407</pmid><doi>10.1371/journal.pone.0156562</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-05, Vol.11 (5), p.e0156562-e0156562 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1791862542 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Animals Biology and Life Sciences Bone marrow Cardiomyocytes Cell cycle Cell Proliferation - drug effects Cellular signal transduction Cytokines Diagnosis Disease Models, Animal Extracellular signal-regulated kinase Fibroblasts Fluorescence Green fluorescent protein Green fluorescent proteins Heart Heart attack Heart attacks Heart cells Heart diseases Heart failure Janus kinase Janus Kinases - metabolism Laboratory animals Leukemia Leukemia inhibitory factor Leukemia Inhibitory Factor - pharmacology MAP kinase MAP Kinase Kinase Kinases - metabolism MAP Kinase Signaling System - drug effects Medicine Medicine and Health Sciences Mice Mice, Transgenic Myocardial infarction Myocardial Infarction - drug therapy Myocardial Infarction - metabolism Myocardium - metabolism Myocytes, Cardiac - metabolism Phosphatidylinositol 3-Kinases - metabolism Physiological aspects Precursors Protein kinase Proto-Oncogene Proteins c-akt - metabolism Regeneration Regeneration - drug effects Research and analysis methods Risk factors Rodents STAT Transcription Factors - metabolism Stem cell transplantation Stem cells Stem Cells - metabolism Tamoxifen Transcription Transgenic animals University graduates Ventricle |
| title | Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction |
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