Texas Heart Institute, Cardiomyocyte Renewal Lab, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Dev Cell. 2018 Apr 23;45(2):153-169.e6. doi: 10.1016/j.devcel.2018.03.019.
During development, progenitors progress through transition states. The cardiac epicardium contains progenitors of essential non-cardiomyocytes. The Hippo pathway, a kinase cascade that inhibits the Yap transcriptional co-factor, controls organ size in developing hearts. Here, we investigated Hippo kinases Lats1 and Lats2 in epicardial diversification. Epicardial-specific deletion of Lats1/2 was embryonic lethal, and mutant embryos had defective coronary vasculature remodeling. Single-cell RNA sequencing revealed that Lats1/2 mutant cells failed to activate fibroblast differentiation but remained in an intermediate cell state with both epicardial and fibroblast characteristics. Lats1/2 mutant cells displayed an arrested developmental trajectory with persistence of epicardial markers and expanded expression of Yap targets Dhrs3, an inhibitor of retinoic acid synthesis, and Dpp4, a protease that modulates extracellular matrix (ECM) composition. Genetic and pharmacologic manipulation revealed that Yap inhibits fibroblast differentiation, prolonging a subepicardial-like cell state, and promotes expression of matricellular factors, such as Dpp4, that define ECM characteristics.
在发育过程中，祖细胞经历过渡状态。心脏外胚层包含重要的非心肌细胞的祖细胞。Hippo 通路是一种激酶级联反应，可抑制 Yap 转录共因子，控制发育心脏的器官大小。在这里，我们研究了 Hippo 激酶 Lats1 和 Lats2 在心脏外胚层多样化中的作用。心脏外胚层特异性敲除 Lats1/2 是胚胎致死的，突变胚胎的冠状动脉血管重塑有缺陷。单细胞 RNA 测序显示，Lats1/2 突变细胞未能激活成纤维细胞分化，但仍处于具有心脏外胚层和成纤维细胞特征的中间细胞状态。Lats1/2 突变细胞显示出发育轨迹停滞，心脏外胚层标志物持续存在，Yap 靶标 Dhrs3（一种抑制视黄酸合成的抑制剂）和 Dpp4（一种调节细胞外基质 (ECM) 组成的蛋白酶）的表达扩大。遗传和药理学操作表明，Yap 抑制成纤维细胞分化，延长类似心脏外胚层的细胞状态，并促进细胞外基质特征定义的细胞基质因子，如 Dpp4 的表达。
