Approaches to Cardiac Regeneration

描述 摘要 在美国和发达国家，死亡的头号原因是由梗塞引起的心力衰竭。心脏修复的主要目标是替换心肌细胞，稳定新血管形成，并防止瘢痕形成。与哺乳动物心肌相反，斑马鱼心脏通过肌细胞替代、新血管生成和瘢痕组织的消退在损伤后再生。斑马鱼心脏的再生需要激活勾勒心脏的细胞，心外膜，但心外膜如何有助于再生尚不清楚。在小鼠心脏发育过程中，心外膜产生许多细胞类型，包括血管支持细胞和心肌细胞。尽管这些数据表明心外膜有潜力为心脏修复提供细胞，但成年心外膜细胞失去了成为心肌细胞的能力。心外膜谱系还产生心脏成纤维细胞/肌成纤维细胞，其有助于梗死后瘢痕形成。肝星状细胞（HSC）与心外膜成纤维细胞具有相同的胚胎起源，并且也有助于急性肝损伤后的纤维化。然而，HSC在肝再生期间经历衰老以促进瘢痕消退。这些发现表明我们的目标是通过促进心外膜细胞在损伤后接受心肌细胞的命运来实现心脏再生，以及心脏成纤维细胞经历衰老以解决瘢痕形成。为了实现这一目标，我们将产生心脏损伤的新模型和心外膜命运映射的新方法，以检查发育和成年小鼠心脏损伤后的心外膜行为。我们将确定胚胎心外膜细胞采用心肌细胞命运的能力的机制，并应用这些知识促进成年心外膜细胞在损伤后成为心肌细胞。我们将深入了解心脏成纤维细胞的衰老行为，在损伤环境中激活这些通路。如果成功，这些研究的结果将定义新的治疗方法，

DESCRIPTION Abstract The number one cause of death in the US and developed world is heart failure consequent to infarct. Primary goals for cardiac repair are to replace cardiomyocytes, stabilize neovascularization, and prevent scar formation. In contrast to mammalian myocardium, zebrafish heart regenerates post-injury by myocyte replacement, neoangiogenesis, and resolution of scar tissue. Regeneration of zebrafish heart requires activation of cells which outline the heart, the epicardium, but how epicardium contributes to regeneration is not known. During mouse heart development, epicardium gives rise to a number of cell types, including vascular support cells and cardiomyocytes. Although these data suggest the potential of epicardium to contribute cells for cardiac repair, adult epicardial cells lose the ability to become cardiomyocytes. Epicardial lineages also give rise to cardiac fibroblasts/myofibroblasts, which contribute to scarring post-infarct. Hepatic stellate cells (HSCs) share an embryonic origin with epicardial fibroblasts, and also contribute to fibrosis following acute liver injury. However, HSCs undergo senescence to promote scar resolution during liver regeneration. These findings suggest our goal, which is to achieve cardiac regeneration by promoting epicardial cells to adopt cardiomyocyte cell fates post-injury, and cardiac fibroblasts to undergo senescence to resolve scar formation. Toward this goal, we will generate new models of cardiac injury and new approaches for epicardial fate mapping to examine epicardial behavior post-injury in developing and adult mouse heart. We will identify mechanisms underlying the ability of embryonic epicardial cells to adopt cardiomyocyte cell fates, and apply this knowledge to promote adult epicardial cells becoming cardiomyocytes post-injury. We will gain insights into senescence behavior of cardiac fibroblasts, to activate these pathways in an injury setting. If successful, results of these studies will define new therapeuti