Centres for Microvascular Research and for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Cardiac Regeneration and Therapeutics, Graduate School of Medicine, Osaka University, Osaka, Japan.
Sci Rep. 2019 Aug 16;9(1):11953. doi: 10.1038/s41598-019-48321-y.
The endocardium is the endothelial component of the vertebrate heart and plays a key role in heart development. Where, when, and how the endocardium segregates during embryogenesis have remained largely unknown, however. We now show that Nkx2-5 cardiac progenitor cells (CPCs) that express the Sry-type HMG box gene Sox17 from embryonic day (E) 7.5 to E8.5 specifically differentiate into the endocardium in mouse embryos. Although Sox17 is not essential or sufficient for endocardium fate, it can bias the fate of CPCs toward the endocardium. On the other hand, Sox17 expression in the endocardium is required for heart development. Deletion of Sox17 specifically in the mesoderm markedly impaired endocardium development with regard to cell proliferation and behavior. The proliferation of cardiomyocytes, ventricular trabeculation, and myocardium thickening were also impaired in a non-cell-autonomous manner in the Sox17 mutant, likely as a consequence of down-regulation of NOTCH signaling. An unknown signal, regulated by Sox17 and required for nurturing of the myocardium, is responsible for the reduction in NOTCH-related genes in the mutant embryos. Our results thus provide insight into differentiation of the endocardium and its role in heart development.
心内膜是脊椎动物心脏的内皮成分，在心脏发育中起着关键作用。然而，心内膜在胚胎发生过程中是如何分离的，在何处、何时以及如何分离，仍然知之甚少。我们现在表明，从胚胎第 7.5 天到第 8.5 天表达 Sry 型 HMG 盒基因 Sox17 的 Nkx2-5 心脏祖细胞 (CPC) 特异性分化为小鼠胚胎中的心内膜。尽管 Sox17 对于心内膜命运不是必需的或充分的，但它可以使 CPC 的命运偏向于心内膜。另一方面，心内膜中 Sox17 的表达对于心脏发育是必需的。Sox17 在中胚层中的特异性缺失明显损害了心内膜的发育，包括细胞增殖和行为。Sox17 突变体中心肌细胞的增殖、心室小梁化和心肌增厚也以非细胞自主的方式受损，可能是由于 NOTCH 信号的下调。一种未知的信号，由 Sox17 调节并需要滋养心肌，负责减少突变体胚胎中与 NOTCH 相关的基因。因此，我们的研究结果为心内膜的分化及其在心脏发育中的作用提供了深入的了解。
