PDF(Pubmed)
Abstract：
The heart develops in a synchronized sequence of proliferation and differentiation of cardiac progenitor cells (CPCs) from two anatomically distinct pools of cells, the first heart field (FHF) and second heart field (SHF). Congenital heart defects arise upon dysregulation of these processes, many of which are restricted to derivatives of the FHF or SHF. Of the conserved set of signaling pathways that regulate development, the Wnt signaling pathway has long been known for its importance in SHF development. The source of such Wnts has remained elusive, though it has been postulated that these Wnts are secreted from ectodermal or endodermal sources. The central question remains unanswered: Where do these Wnts come from? Here, we show that CPCs autoregulate SHF development via Wnt through genetic manipulation of a key Wnt export protein (Wls), scRNA-seq analysis of CPCs, and use of our precardiac organoid system. Through this, we identify dysregulated developmental trajectories of anterior SHF cell fate, leading to a striking single ventricle phenotype in knockout embryos. We then applied our findings to our precardiac organoid model and found that Wnt2 is sufficient to restore SHF cell fate in our model of disrupted endogenous Wnt signaling. In this study, we provide a basis for SHF cell fate decision-proliferation vs. differentiation-autoregulated by CPCs through Wnt.
摘要：
心脏从两个解剖学上不同的细胞池中以心脏祖细胞（CPCs）的增殖和分化的同步顺序发展，第一心场(FHF)和第二心场(SHF)。这些过程失调会导致先天性心脏缺陷，其中许多仅限于FHF或SHF的衍生物。在调节发育的一组保守的信号通路中，Wnt信号通路在SHF发育中的重要性早已为人所知。这种Wnts的来源仍然难以捉摸，尽管据推测这些Wnt是从外胚层或内胚层来源分泌的。核心问题仍然没有答案:这些Wnts来自哪里？这里，我们表明，CPC通过关键的Wnt输出蛋白（Wls）的遗传操作通过Wnt自动调节SHF发育，CPC的scRNA-seq分析，和使用我们的心前器官系统。通过这个,我们确定了前SHF细胞命运失调的发育轨迹，导致敲除胚胎中惊人的单心室表型。然后，我们将我们的发现应用于我们的心前类器官模型，发现Wnt2足以恢复我们的内源性Wnt信号模型中的SHF细胞命运。在这项研究中,我们为SHF细胞命运决定增殖与增殖提供了基础CPCs通过Wnt自动调节分化。
