Abstract
We determined whether co-transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and mesenchymal stem cells (MSCs) had additive effects on left ventricular (LV) function and remodeling compared with hESC-CMs treatment alone in a rat myocardial infarction model. One week after myocardial infarction induced by left coronary ligation, nude rats received hESC-CMs (n=15), hESC-CMs + MSCs (n=16), hESC-CMs + MSCs transduced to over-express hemeoxygenase 1(HO-1) (n=14), or saline (n=19). At 4 weeks after treatment, LV function was assessed by left ventriculography, echocardiography and Millar catheter. Some hearts were processed for histology. The LV ejection fraction (LVEF) in sham noninfarcted hearts was 78.1±1.8% (n=5) in the nude rat model. LVEF in the 3 cell treated groups (hESC-CMs: 67.6±1.4%; hESC-CMs + MSCs: 67.2±1.6%; and hESC-CMs + MSCs with HO-1: 66.3±1.7%) were comparable, and significantly higher than in the saline group (60.6±1.2%, n=19; p=0.0022). There was a trend for less left ventricular akinesis and dyskinesis (expressed as % of LV circumference) assessed by left ventriculography at 8.96±1.9% in hESC-CMs group, 8.37±1.67% in hESC-CMs + MSCs group and 4.57±1% in hESC-CMs + MSCs with HO-1 group compared to 10.73±1.76% in the control group (p=0.056). There was a nonsignificant trend for LV fractional shortening assessed by echocardiography to be greater in the 3 cell groups (32.1±3.9% in hESC-CMs; 30.2±2% in hESC-CMs + MSCs; 31.0±1.9% in hESC-CMs + MSCs with HO-1) compared to 24.8±2.2% in the saline group (p=0.18). Expansion index reflecting thinning and dilatation of the infarct was significantly worse in the control group at 0.71±0.05 versus the other 3 groups at 0.32±0.05 (p=0.0039). Thus, cell therapy by hESC-CMs alone or combination transplantation of hESC-CMs and MSCs (with or without HO-1) significantly improved LV function assessed by left ventriculography and reduced expansion index. However, co-transplantation of hESC-CMs and MSCs did not provide better functional improvement compared with hESC-CMs treatment alone after left coronary artery occlusion in nude rats over a period of 4 weeks, suggesting that there may be a ceiling effect above which LV function can not further improve after cell therapy.
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