Approaches to Cardiac Regeneration

描述 摘要 美国和发达国家的头号死因是心肌梗塞导致的心力衰竭。心脏修复的主要目标是替换心肌细胞，稳定新生血管，防止瘢痕形成。与哺乳动物心肌不同，斑马鱼心脏在损伤后通过肌细胞替代、新生血管生成和疤痕组织的溶解而再生。斑马鱼心脏的再生需要激活概述心脏的细胞，即心外膜，但心外膜如何促进再生尚不清楚。在小鼠心脏发育过程中，心外膜产生多种类型的细胞，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可能为心脏修复提供细胞，但成人心外膜细胞失去了成为心肌细胞的能力。心外膜血统也可产生心脏成纤维细胞/肌成纤维细胞，这有助于梗死后的瘢痕形成。肝星状细胞(HSCs)与心外膜成纤维细胞具有共同的胚胎起源，也参与了急性肝损伤后的纤维化。然而，在肝再生过程中，肝干细胞经历衰老以促进瘢痕的消退。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采用心肌细胞命运，以及心脏成纤维细胞经历衰老来解决瘢痕形成来实现心脏再生。为了实现这一目标，我们将建立新的心脏损伤模型和新的心外膜命运标测方法，以检查发育中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适应心肌细胞命运的潜在机制，并应用这一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，以便在损伤环境中激活这些途径。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