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Abstract
Failure of proper ventricular trabeculation is often associated with congenital heart disease. Support from endocardial cells, including the secretion of extracellular matrix and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of extracellular matrix and growth factors is initiated and regulated by endocardial cells. We find that genetic knockout of histone deacetylase 3 in the endocardium in mice results in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identifies significant downregulation of extracellular matrix components in histone deacetylase 3 knockout endocardial cells. Secretome from cultured histone deacetylase 3 knockout mouse cardiac endothelial cells lacks transforming growth factor ß3 and shows significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which is remarkably rescued by transforming growth factor ß3 supplementation. Mechanistically, we identify that histone deacetylase 3 knockout induces transforming growth factor ß3 expression through repressing microRNA-129-5p. Our findings provide insights into the pathogenesis of congenital heart disease and conceptual strategies to promote myocardial regeneration.
Lack of trabeculation compromises heart structure and function. How myocardial trabeculation is regulated by nonmyocytes is poorly understood. Researchers found that histone deacetylase 3 in the developing endocardial cells guides myocardial trabeculation by inducing growth signals.
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1 Nationwide Children’s Hospital, Center for Cardiovascular Research, Abigail Wexner Research Institute, Columbus, USA (GRID:grid.240344.5) (ISNI:0000 0004 0392 3476); The Ohio State University College of Medicine, Department of Pediatrics, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943)
2 Max Planck Institute for Heart and Lung Research, Bioinformatics Core Unit (BCU), Bad Nauheim, Germany (GRID:grid.418032.c) (ISNI:0000 0004 0491 220X)
3 University of Maryland School of Medicine, Department of Surgery, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264)
4 Indiana University School of Medicine, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, USA (GRID:grid.261331.4) (ISNI:0000 0001 2296 1126)