[beta]-Catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation

We analyzed the effect of conditional, [alpha]MHC-dependent genetic [beta]-catenin depletion and stabilization on cardiac remodeling following experimental infarct. [beta]-Catenin depletion significantly improved 4-week survival and left ventricular (LV) function (fractional shortening: [CT.sup.[delta]ex3-6]: 24 [+ or -] 1.9%; [beta]-[cat.sup.[delta]ex3-6]; 30.2 [+ or -] 1.6%, P < 0.001). [beta]-Catenin stabilization had opposite effects. No significant changes in adult cardiomyocyte survival or hypertrophy were observed in either transgenic line. Associated with the functional improvement, LV scar cellularity was altered: [beta]-catenin-depleted mice showed a marked subendocardial and subepicardial layer of small [cTnT.sup.pos] cardiomyocytes associated with increased expression of cardiac lineage markers Tbx5 and GATA4. Using a Cre-dependent lacZ reporter gene, we identified a noncardiomyocyte cell population affected by [alpha]MHC-driven gene recombination localized to these tissue compartments at baseline. These cells were found to be cardiac progenitor cells since they coexpressed markers of proliferation (Ki67) and the cardiomyocyte lineage ([alpha]MHC, GATA4, Tbx5) but not cardiac Troponin T (cTnT). The cell population overlaps in part with both the previously described c-[kit.sup.pos] and stem cell antigen-1 [(Sca-1).sup.pos] precursor cell population but not with the Islet-[1.sup.pos] precursor cell pool. An in vitro coculture assay of highly enriched (>95%) Sca-[1.sup.pos] cardiac precursor cells from [beta]-catenin-depleted mice compared to cells isolated from control littermate demonstrated increased differentiation toward [alpha]-[actin.sup.pos] and [cTnT.sup.pos] cardiomyocytes after 10 days ([CT.sup.[delta]ex3-6]: 38.0 [+ or -] 1.0% [alpha]-[actin.sup.pos] [beta]-[cat.sup.[delta]ex3-6]: 49.9 [+ or -] 2.4% [alpha]-[actin.sup.pos], P < 0.001). We conclude that [beta]-catenin depletion attenuates postinfarct LV remodeling in part through increased differentiation of [GATA4.sup.pos]/Sca-[1.sup.pos] resident cardiac progenitor cells.