Leveraging zebrafish models to dissect and enhance heart regeneration

摘要 成年哺乳动物的心脏在损伤后很少或没有明显的心肌先天再生，并且 取而代之的是通过留下疤痕来治愈。这种再生缺陷具有重大的社会经济后果，因为 在美国，缺血性心肌梗死是发病率和死亡率的主要原因 数以百万计的美国人患有心力衰竭。许多年前，我们发现硬骨鱼斑马鱼表现出 心脏部分切除后强烈的再生反应，包括产生新的 心肌细胞很少或没有疤痕。这一发现开创了模型系统方法的先河 如今许多实验室都在使用再生技术。在过去的15年里，首席调查员 引入了新的工具和策略，揭示了许多核心概念和机制 斑马鱼的再生。在这里，我们描述一个综合方案，它以新的分辨率定义 先天心脏再生的分子成分，以及这些成分的作用机制 受监管的。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，包括通过因子传递刺激哺乳动物再生的尝试 以及使用病毒载体进行基因调控。我们的发现将继续为我们的基础知识 心脏再生的生物学，它们将直接关系到促进再生和 减少人类心力衰竭的发生率。它们也可能超出心血管生物学的范畴。 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.