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BackgroundTrabeculation, a key process in early heart development, is the formation of myocardial trabecular meshwork. The failure of trabeculation often leads to embryonic lethality. Support from endocardial cells, including the secretion of extracellular matrix (ECM) and growth factors is critical for trabeculation; however, it is unknown how the secretion of ECM and growth factors is initiated and regulated by endocardial cells.MethodsVarious cellular and mouse models in conjunction with biochemical and molecular tools were employed to study the role of histone deacetylase 3 (HDAC3) in the developing endocardium.ResultsWe found that genetic deletion ofHdac3in endocardial cells in mice resulted in early embryo lethality presenting as a hypotrabeculation cardiac phenotype. Single cell RNA sequencing identified several ECM components including collagens that were significantly downregulated inHdac3knockout (KO) endocardial cells. When cultured with supernatant fromHdac3KO mouse cardiac endothelial cells (MCECs), wild-type mouse embryonic cardiomyocytes showed decreased proliferation, suggesting that growth signaling fromHdac3KO MCECs is disrupted. Subsequent transcriptomic analysis revealed that transforming growth factor ß3 (TGFß3) was significantly downregulated inHdac3KO MCECs andHdac3cardiac endothelial KO hearts. Mechanistically, we identified that microRNA (miR)-129-5p was significantly upregulated inHdac3KO MCECs andHdac3cardiac endothelial KO hearts. Overexpression of miR-129-5p repressedTgfß3expression in wild-type MCECs, whereas knockdown of miR-129-5p restoredTgfß3expression inHdac3KO MCECs.ConclusionOur findings reveal a critical signaling pathway in which endocardial HDAC3 promotes trabecular myocardium growth by stimulating TGFß signaling through repressing miR-129-5p, providing novel insights into the etiology of congenital heart disease and conceptual strategies to promote myocardial regeneration. |
