Fu-Li Xiang1, Yin Liu1, Xiangru Lu1, Douglas L Jones1, Qingping Feng2. 1. From the Departments of Physiology and Pharmacology (F.-L.X., Y.L., X.L., D.L.J., Q.F.) and Medicine (D.L.J., Q.F.), and Lawson Health Research Institute (D.L.J., Q.F.), Western University, London, Ontario, Canada. 2. From the Departments of Physiology and Pharmacology (F.-L.X., Y.L., X.L., D.L.J., Q.F.) and Medicine (D.L.J., Q.F.), and Lawson Health Research Institute (D.L.J., Q.F.), Western University, London, Ontario, Canada. qfeng@uwo.ca.
Abstract
BACKGROUND: The adult epicardium is a potential source of cardiac progenitors after myocardial infarction (MI). We tested the hypothesis that cardiomyocyte-specific overexpression of membrane-associated human stem cell factor (hSCF) enhances epicardial activation, epicardium-derived cells (EPDCs) production, and myocardial arteriogenesis post MI. METHODS AND RESULTS: Wild-type and the inducible cardiac-specific hSCF transgenic (hSCF/tetracycline transactivator) mice were subjected to MI. Wilms tumor-1 (Wt1)-positive epicardial cells were higher in hSCF/tetracycline transactivator compared with wild-type mice 3 days post MI. Arteriole density was significantly higher in the peri-infarct area of hSCF/tetracycline transactivator mice compared with wild-type mice 5 days post MI. In cultured EPDCs, adenoviral hSCF treatment significantly increased cell proliferation and growth factor expression. Furthermore, adenoviral hSCF treatment in wild-type cardiomyocytes significantly increased EPDC migration. These effects of hSCF overexpression on EPDC proliferation and growth factor expression were all abrogated by ACK2, a neutralizing antibody against c-kit. Finally, lineage tracing using ROSA(mTmG);Wt1(CreER) mice showed that adenoviral hSCF treatment increased Wt1(+) lineage-derived EPDC migration into the infarcted myocardium 5 days post MI, which was inhibited by ACK2. CONCLUSIONS: Cardiomyocyte-specific overexpression of hSCF promotes epicardial activation and myocardial arteriogenesis post MI.
BACKGROUND: The adult epicardium is a potential source of cardiac progenitors after myocardial infarction (MI). We tested the hypothesis that cardiomyocyte-specific overexpression of membrane-associated humanstem cell factor (hSCF) enhances epicardial activation, epicardium-derived cells (EPDCs) production, and myocardial arteriogenesis post MI. METHODS AND RESULTS: Wild-type and the inducible cardiac-specific hSCF transgenic (hSCF/tetracycline transactivator) mice were subjected to MI. Wilms tumor-1 (Wt1)-positive epicardial cells were higher in hSCF/tetracycline transactivator compared with wild-type mice 3 days post MI. Arteriole density was significantly higher in the peri-infarct area of hSCF/tetracycline transactivator mice compared with wild-type mice 5 days post MI. In cultured EPDCs, adenoviral hSCF treatment significantly increased cell proliferation and growth factor expression. Furthermore, adenoviral hSCF treatment in wild-type cardiomyocytes significantly increased EPDC migration. These effects of hSCF overexpression on EPDC proliferation and growth factor expression were all abrogated by ACK2, a neutralizing antibody against c-kit. Finally, lineage tracing using ROSA(mTmG);Wt1(CreER) mice showed that adenoviral hSCF treatment increased Wt1(+) lineage-derived EPDC migration into the infarcted myocardium 5 days post MI, which was inhibited by ACK2. CONCLUSIONS: Cardiomyocyte-specific overexpression of hSCF promotes epicardial activation and myocardial arteriogenesis post MI.
Authors: Liam A Ridge; Karen Mitchell; Ali Al-Anbaki; Wasay Mohiuddin Shaikh Qureshi; Louise A Stephen; Gennadiy Tenin; Yinhui Lu; Irina-Elena Lupu; Christopher Clowes; Abigail Robertson; Emma Barnes; Jayne A Wright; Bernard Keavney; Elisabeth Ehler; Simon C Lovell; Karl E Kadler; Kathryn E Hentges Journal: PLoS Genet Date: 2017-10-30 Impact factor: 5.917