Regeneration of Cryoinjury Induced Necrotic Heart Lesions in Zebrafish Is Associated with Epicardial Activation and Cardiomyocyte Proliferation

In mammals, myocardial cell death due to infarction results in scar formation and little regenerative response. In contrast, zebrafish have a high capacity to regenerate the heart after surgical resection of myocardial tissue. However, whether zebrafish can also regenerate lesions caused by cell death has not been tested. Here, we present a simple method for induction of necrotic lesions in the adult zebrafish heart based on cryoinjury. Despite widespread tissue death and loss of cardiomyocytes caused by these lesions, zebrafish display a robust regenerative response, which results in substantial clearing of the necrotic tissue and little scar formation. The cellular mechanisms underlying regeneration appear to be similar to those activated in response to ventricular resection. In particular, the epicardium activates a developmental gene program, proliferates and covers the lesion. Concomitantly, mature uninjured cardiomyocytes become proliferative and invade the lesion. Our injury model will be a useful tool to study the molecular mechanisms of natural heart regeneration in response to necrotic cell death.在哺乳动物体内，因心肌梗死引发的心肌细胞死亡会导致瘢痕形成，且再生反应极为微弱。相较之下，斑马鱼在心肌组织经外科切除后，具备极强的心脏再生能力。然而，斑马鱼是否能够修复由细胞死亡引发的损伤，这一问题尚未得到实验验证。本研究开发了一种基于冷冻损伤的简便方法，可在成年斑马鱼心脏中诱导坏死性损伤。尽管此类损伤会造成广泛的组织死亡与心肌细胞丢失，斑马鱼仍会启动强劲的再生反应，可有效清除坏死组织且几乎不形成瘢痕。其再生背后的细胞机制，似乎与心室切除后激活的机制高度相似。具体而言，心外膜会激活发育相关的基因程序，发生增殖并覆盖损伤区域。与此同时，成熟的未损伤心肌细胞会进入增殖状态并侵入损伤部位。本损伤模型将成为研究坏死性细胞死亡引发的天然心脏再生分子机制的实用工具。