Beta-Catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation.
We analyzed the effect of conditional, alphaMHC-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(Deltaex3-6): 24 +/- 1.9%; beta-cat(Deltaex3-6): 30.2 +/- 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(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 alphaMHC-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 (alphaMHC, GATA4, Tbx5) but not cardiac Troponin T (cTnT). The cell population overlaps in part with both the previously described c-kit(pos) and stem cell antigen-1 (Sca-1)(pos) precursor cell population but not with the Islet-1(pos) precursor cell pool. An in vitro coculture assay of highly enriched (>95%) Sca-1(pos) cardiac precursor cells from beta-catenin-depleted mice compared to cells isolated from control littermate demonstrated increased differentiation toward alpha-actin(pos) and cTnT(pos) cardiomyocytes after 10 days (CT(Deltaex3-6): 38.0 +/- 1.0% alpha-actin(pos); beta-cat(Deltaex3-6): 49.9 +/- 2.4% alpha-actin(pos), P < 0.001). We conclude that beta-catenin depletion attenuates postinfarct LV remodeling in part through increased differentiation of GATA4(pos)/Sca-1(pos) resident cardiac progenitor cells.
Zelarayán
Laura C
LC
Department of Cardiology, Campus-Buch and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Franz Volhard Klinik, Germany.
Noack
Claudia
C
Sekkali
Belaid
B
Kmecova
Jana
J
Gehrke
Christina
C
Renger
Anke
A
Zafiriou
Maria-Patapia
MP
van der Nagel
Roel
R
Dietz
Rainer
R
de Windt
Leon J
LJ
Balligand
Jean-Luc
JL
Bergmann
Martin W
MW
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation; D017930:Genes, Reporter; D051379:Mice; D008822:Mice, Transgenic; D032386:Myoblasts, Cardiac / Q000473:pathology / Q000502:physiology*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012038:Regeneration / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D001616:beta-Galactosidase / Q000235:genetics
D051176:beta Catenin; D001616:beta-Galactosidase