PDF(Pubmed)
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.
摘要：
正常心室小梁形成的失败通常与先天性心脏病有关。来自心内膜细胞的支持，包括细胞外基质和生长因子的分泌是小梁形成的关键。然而,人们对心内膜细胞如何启动和调节细胞外基质和生长因子的分泌知之甚少。我们发现，小鼠心内膜中组蛋白去乙酰化酶3的基因敲除会导致早期胚胎致死率和心室过少。单细胞RNA测序鉴定了组蛋白去乙酰化酶3敲除心内膜细胞中细胞外基质成分的显著下调。来自培养的组蛋白去乙酰化酶3敲除小鼠心脏内皮细胞的分泌体缺乏转化生长因子β3，并且显示出刺激培养的心肌细胞增殖的能力显着降低，这是通过补充转化生长因子β3来显著拯救的。机械上,我们发现组蛋白去乙酰化酶3敲除通过抑制microRNA-129-5p诱导转化生长因子β3的表达。我们的发现为先天性心脏病的发病机制和促进心肌再生的概念策略提供了见解。
