Abstract 21629: Cell Therapy Stimulates Endogenous Cardiomyocyte Progenitors
Background: Progenitor cell therapy can improve cardiac function in animals and humans after injury, but the mechanism of this improvement is unclear.
Hypothesis: We hypothesized that cell therapy with bone-marrow derived progenitors after myocardial infarction (MI) activates endogenous cardiac progenitors.
Methods: We performed randomized, blinded cell therapy experiments in genetically-engineered lineage-mapping mice, cross-bred from the MerCreMer mouse and ZEG reporter. After 4-OH-tamoxifen, these mice undergo a permanent cardiomyocyte-specific switch from B-galactosidase to green fluorescent protein (GFP) expression.
Results: MI resulted in dilution of the GFP+ cardiomyocyte pool at the infarct borderzone compared to sham operated mice(68.8+/−1.5% vs 82.6+/−1.2% p<0.001), indicating cardiomyocyte refreshment by non-GFP+ progenitors. Intramyocardial delivery of wild-type bone marrow-derived c-kit cells further diluted the GFP+ pool (56.6+/−1.7% vs 68.8+/−1.5% p<0.001), consistent with c-kit cell-mediated augmentation of cardiomyocyte progenitor activity. This effect was not observed after therapy with bone marrow derived mesenchymal stem cells (MSC). We then transplanted c-kit+ cells and MSCs from MerCreMer/ZEG male mice into wild-type females after MI. After 6 wks, 4-OH-tamoxifen was administered to induce GFP expression in exogenously delivered cells having undergone transdifferentiation into cardiomyocytes. Although we demonstrated successful cell delivery and survival at 5 min and 1 wk by identification of Y-chromosome+ cells, we found no GFP+ or Y-chromosome+ cells 8 wks after MI suggesting that the c-kit mediated effect could not be explained by cardiomyocyte transdifferentiation of exogenously delivered cells(>7.5x105 borderzone cardiomyocytes screened, Chi-square p<0.0001). C-kit cell therapy was associated with an improvement in cardiac function as measured by invasive hemodynamic studies 8 wks after MI(EF=35.1+/−3.0% vs 22.8+/−2.8% p<0.05); MSC cell therapy did not improve function.
Conclusions: These data reveal stimulation of endogenous cardiogenic progenitor activity as a potentially critical mechanism of cardiac cell therapy.
- © 2010 by American Heart Association, Inc.