Leveraging zebrafish models to dissect and enhance heart regeneration

摘要 成年哺乳动物心脏在损伤后显示很少或没有显著的心肌先天再生， 而是通过疤痕愈合这种再生不足具有重大的社会经济后果，因为 缺血性心肌梗塞是美国发病率和死亡率的主要原因， 100万美国人患有心力衰竭。很多年前，我们发现硬骨鱼斑马鱼 心室再生：心室部分切除后产生的强有力的再生反应，包括产生新的 几乎没有或没有疤痕的心肌细胞。这一发现开创了心脏模型系统方法 再生，这是今天许多实验室采用。在过去的15年里，首席研究员 介绍了新的工具和策略，以揭示心脏的许多关键概念和机制 斑马鱼的再生在这里，我们描述了一个综合计划，定义在新的决议， 先天性心脏再生的分子成分，以及这些成分被 监管.我们将利用这些信息来创新控制心脏功效的新方法。 跨物种再生，包括尝试通过因子传递刺激哺乳动物再生 和使用病毒载体的基因调控。我们的发现将继续为人类的基本 心脏再生的生物学，他们将直接涉及到思想和方法，以加强再生， 降低人类心力衰竭的发病率。它们也可能延伸到心血管生物学之外 并与其他组织的修复有关。

ABSTRACT The adult mammalian heart shows little or no significant innate regeneration of cardiac muscle after injury, and instead heals by scarring. This regenerative deficiency has major socioeconomic consequences, given that ischemic myocardial infarction is a leading cause of morbidity and mortality in the United States and over 5 million Americans suffer from heart failure. Many years ago, we found that the teleost zebrafish displays a vigorous regenerative response after partial resection of the cardiac ventricle, involving creation of new cardiomyocytes with little or no scarring. This discovery pioneered the model system approach to heart regeneration that is employed by many laboratories today. For the past 15 years, the principal investigator has introduced new tools and strategies to reveal many key concepts and mechanisms underlying heart regeneration in zebrafish. Here, we describe an integrative program that defines at new resolution the molecular components of innate heart regeneration, as well as mechanisms by which these components are regulated. We will harness this information to innovate new methods for controlling the efficacy of heart regeneration across species, including attempts to stimulate regeneration in mammals through factor delivery and gene regulation using viral vectors. The discoveries we make will continue to inform the fundamental biology of heart regeneration, and they will directly relate to ideas and methods to enhance regeneration and reduce the incidence of heart failure in humans. They are also likely to extend beyond cardiovascular biology and have relevance to the repair of other tissues.