Abstract
Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31− cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31− cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD) ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV) function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31− cells formed viable grafts and improved LV ejection fraction (EF) (Control, 54.5+/−2.4; MI, 17.6+/−3.1; Cell, 28.2+/−4.2, n = 9, P<0.01). IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/−2.2; n = 9, P<0.01) and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31− cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31− cells revealed that Sca-1+/CD31− cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.
Highlights
The left ventricular (LV) remodeling that occurs following myocardial infarction (MI) results, in part, from the abnormal LV wall stresses that develop in surviving myocardium
We found that IGF+hepatocyte growth factor (HGF) administration combined with cell transplantation significantly increased the rate of Sca-1+/CD312 cell engraftment, reduced infarct size, and further attenuated postacute MI LV structural and functional remodeling as compared to the results achieved by injection of Sca-1+/CD312 cells alone
LVEF was 19% in the untreated MI group, 28% in the cell treated MI group and 39% in the IGF+ HGF plus cell treated MI group (n = 9, P,0.01 vs untreated and cell treated MI groups). The dose of both IGF and HGF given to each heart ranged between,5 and 7 ng/heart and this dosage was comparable to that employed in several reports that showed significant cardiac regeneration from endogenous cardiac stem cells (CSCs) following growth factor administration [17,18]
Summary
The left ventricular (LV) remodeling that occurs following myocardial infarction (MI) results, in part, from the abnormal LV wall stresses that develop in surviving myocardium. The increased wall stress is thought to induce adverse molecular responses in the residual myocardium [1,2,3]. The limited ability of the heart to regenerate lost cardiomyocytes and vascular cells contributes to the severity of LV remodeling. Administration of various types of presumed cardiac regenerative cells including skeletal muscle myoblasts, marrow derived mesenchymal stem cells (MSCs), endogenous cardiac stem cells (CSCs), endothelial progenitor cells, induced pluripotent stem cells (iPSCs) and embryonic stem cells to hearts following acute infarction (acute MI) has been attempted in the hope of stimulating cardiac regeneration [4,5,6,7,8,9]. In most animal studies persistent engraftment of transplanted cells has been minimal and few of the transplanted cells appear to have proliferated and differentiated into new cardiomyocytes or vascular cells [10,11,12]
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