Abstract 1418: Modulation Of Beta-catenin Enhances Endogenous Myocardial Repair After Experimental Infarct
Transcription factors involved in cardiogenesis have been hypothesized to control differentiation of cardiac resident precursor cells in adult heart. Here, we analyzed αMHC-dependent, genetic β-catenin depletion upon loxP site recombination by the mifepristone-inducible CrePR1 fusion protein in adult mice. β-catenin depletion significantly improved four-week survival and left ventricular (LV) function (fractional shortening: control mice, 24±1.9%; β-catΔex3– 6: 30.2±1.6%, P<0.05) after experimental infarction. No significant changes in adult cardiomyocyte survival or hypertrophy were observed. Using a lacZ reporter gene, we found stem cell antigen (Sca-1)pos/cardiac troponin T (cTnT)neg precursor cells in endocardial, epicardial and intra-myocardial compartments to be primarily affected by αMHC-driven gene recombination. Associated with the functional improvement, LV scar cellularity was altered: β-catenin depleted mice showed a marked endocardial and epicardial layer of small cTnTpos cardiomyocytes associated with increased expression of cardiac developmental transcription factors Tbx5 and GATA4. Accordingly, isolated Sca1pos cardiac precursor cells from β-catenin depleted mice demonstrated increased differentiation towards α-actinpos cardiomyocytes in a co-culture assay after ten days (control: 38.0±1.0% α-actinpos; β-catΔex3– 6: 49.9±2.4% β-actinpos, p<0.001). In contrast, β-catenin stabilization induced opposite effects regarding post-infarct survival, Tbx5 and GATA4 gene expression as well as isolated Sca1pos precursor cell differentiation. We conclude that β-catenin depletion attenuates post-infarct LV remodeling through increased differentiation of endogenous Sca-1pos/cTnTneg cardiac-resident precursor cells.