Endocardial HDAC3 is required for myocardial trabeculation

Failure of proper ventricular trabeculation is often associated with congenital heart disease (CHD). Support from endocardial cells, including the secretion of extracellular matrix (ECM) and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of ECM and growth factors is initiated and regulated by endocardial cells. We found that genetic knockout (KO) of histone deacetylase 3 ( Hdac3 ) in the endocardium in mice resulted in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identified significant downregulation of ECM components in Hdac3 KO endocardial cells. Secretome from cultured Hdac3 KO mouse cardiac endothelial cells lacked transforming growth factor ß3 (TGFß3) and showed significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which was remarkably rescued by TGFß3 supplementation. Mechanistically, we identified that HDAC3 induced Tgfß3 expression through repressing microRNA (miR)-129-5p. Our findings provide novel insights into the pathogenesis of CHD and conceptual strategies to promote myocardial regeneration.