Abstract
The transplantation of human cardiospheres derived cells (hCDCs) in clinical Phase I trials involving adult ischemic patients, results in reduction in scar formation. But this therapy faces three major issues: low survival rate (1-5%) of the transplanted cells and limited ventricular ejection fraction improvement. One of the major causes of decreased hCDCs engraftment is the prolonged and sustained pro-inflammatory response after acute myocardial infarct (MI). Pro-survival cocktail has been used to overcome this problem but it has major disadvantages for human use as a multi-component mixture, it may change the function of the stem cells and this method depends on anti-apoptotic molecules which may have side effects on the overall cellular turnover. A drug screen in our laboratory has discovered potent anti-inflammatory small molecules, Celastrol (CEL), a quinone triterpene. Oral administration of CEL significantly reduced the MI induced inflammatory cytokines release IL-1β by 2.6±0.4 fold (p<0.05, n=5), IL-6 by 2.1±0.2 fold, (p<0.01, n=5), TNF-α by 3.2±1.1 fold, (p<0.001, n=5) and MMP2 1.5±0.2, (p<0.05, n=5:) as analyzed in rat tissue by RT-PCR. This correlates with improved ventricular ejection fraction at day 7 and day 28 post MI (CEL 45.8 ± 2.4% vs. CNT, 34.8±3.3%, p=0.005 (7d), and 44.3 ± 2.8% vs 34.4 ± 4.1%, p=0.01 (28d). After 28 days post MI, MI+CEL group had a higher percentage of viable myocardial tissue as compared to MI group (MI+CEL, n=4: 70.2 ± 0.5%, vs MI, n=5: 56.38 ± 3.8%, n=4 p<0.05) as analyzed Masson’s Trichrome staining. We next combined Celastrol therapy with cardiac stem cell therapy (pretreatment of CDCs for 24 hours with Celastrol prior to their injection in infarcted myocardium) and evaluate the potential of CEL treated hCDCs to repair/preserve infarcted myocardium by ventricular ejection fraction. Echos performed after LAD ligation revealed a preserved ventricular ejection fraction in rats treated with CEL+hCDCs compared to controls (IMDM media) or CDCs by itself. (hCDCs+CEL, n=4: 62.9±1.0% vs IMDM, n=4: 32.95±2.7%, P<0.05; hCDCs, n=4: 53.28±4.0%, P<0.05 at 28 days). These initial studies suggests the effectiveness of combinatorial therapy of CEL and hCDCs. Oral delivery makes CEL a potentially clinically useful adjunct after MI.
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