Cardiac-Specific Overexpression of Human Stem Cell Factor Promotes Epicardial Activation and Arteriogenesis after Myocardial Infarction
Background—The adult epicardium is a potential source of cardiac progenitors following 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 (WT) and the inducible cardiac-specific hSCF transgenic (hSCF/tTA) mice were subjected to MI. Wilm's tumor-1 (Wt1) positive epicardial cells were higher in hSCF/tTA compared to WT mice 3 days post-MI. Arteriole density was significantly higher in the peri-infarct area of hSCF/tTA mice compared to WT 5 days post-MI. In cultured EPDCs, adenoviral (Ad) hSCF treatment significantly increased cell proliferation and growth factor expression. Furthermore, Ad-hSCF treatment in WT 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 ROSAmTmG;Wt1CreER mice showed that Ad-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.
- Received May 2, 2014.
- Accepted August 7, 2014.