Wang Jinhu, Cao Jingli, Dickson Amy L, Poss Kenneth D
Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Nature. 2015 Jun 11;522(7555):226-230. doi: 10.1038/nature14325. Epub 2015 May 4.
In response to cardiac damage, a mesothelial tissue layer enveloping the heart called the epicardium is activated to proliferate and accumulate at the injury site. Recent studies have implicated the epicardium in multiple aspects of cardiac repair: as a source of paracrine signals for cardiomyocyte survival or proliferation; a supply of perivascular cells and possibly other cell types such as cardiomyocytes; and as a mediator of inflammation. However, the biology and dynamism of the adult epicardium is poorly understood. To investigate this, we created a transgenic line to ablate the epicardial cell population in adult zebrafish. Here we find that genetic depletion of the epicardium after myocardial loss inhibits cardiomyocyte proliferation and delays muscle regeneration. The epicardium vigorously regenerates after its ablation, through proliferation and migration of spared epicardial cells as a sheet to cover the exposed ventricular surface in a wave from the chamber base towards its apex. By reconstituting epicardial regeneration ex vivo, we show that extirpation of the bulbous arteriosus-a distinct, smooth-muscle-rich tissue structure that distributes outflow from the ventricle-prevents epicardial regeneration. Conversely, experimental repositioning of the bulbous arteriosus by tissue recombination initiates epicardial regeneration and can govern its direction. Hedgehog (Hh) ligand is expressed in the bulbous arteriosus, and treatment with a Hh signalling antagonist arrests epicardial regeneration and blunts the epicardial response to muscle injury. Transplantation of Sonic hedgehog (Shh)-soaked beads at the ventricular base stimulates epicardial regeneration after bulbous arteriosus removal, indicating that Hh signalling can substitute for the influence of the outflow tract. Thus, the ventricular epicardium has pronounced regenerative capacity, regulated by the neighbouring cardiac outflow tract and Hh signalling. These findings extend our understanding of tissue interactions during regeneration and have implications for mobilizing epicardial cells for therapeutic heart repair.
为响应心脏损伤，包裹心脏的间皮组织层（称为心外膜）被激活，在损伤部位增殖并聚集。最近的研究表明，心外膜在心脏修复的多个方面发挥作用：作为旁分泌信号的来源，促进心肌细胞存活或增殖；提供血管周围细胞以及可能的其他细胞类型，如心肌细胞；并作为炎症的介质。然而，成人心外膜的生物学特性和动态变化仍知之甚少。为了研究这一点，我们创建了一个转基因品系，用于在成年斑马鱼中消融心外膜细胞群。在此我们发现，心肌损失后心外膜的基因缺失会抑制心肌细胞增殖并延迟肌肉再生。心外膜在消融后能有力地再生，通过留存的心外膜细胞作为一个整体进行增殖和迁移，以波浪形式从心室基部向心尖覆盖暴露的心室表面。通过在体外重建心外膜再生，我们发现摘除球囊动脉（一种独特的、富含平滑肌的组织结构，负责分配心室流出的血液）会阻止心外膜再生。相反，通过组织重组对球囊动脉进行实验性重新定位可启动心外膜再生并控制其方向。刺猬（Hh）配体在球囊动脉中表达，用Hh信号拮抗剂处理会阻止心外膜再生，并减弱心外膜对肌肉损伤的反应。在心室基部移植浸泡过音猬因子（Shh）的珠子可刺激球囊动脉摘除后的心外膜再生，表明Hh信号可替代流出道的影响。因此，心室心外膜具有显著的再生能力，受邻近的心脏流出道和Hh信号调控。这些发现扩展了我们对再生过程中组织相互作用的理解，并对动员心外膜细胞进行治疗性心脏修复具有启示意义。
