Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129.
Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1403-8. doi: 10.1073/pnas.1311705111. Epub 2014 Jan 13.
The human heart's failure to replace ischemia-damaged myocardium with regenerated muscle contributes significantly to the worldwide morbidity and mortality associated with coronary artery disease. Remarkably, certain vertebrate species, including the zebrafish, achieve complete regeneration of amputated or injured myocardium through the proliferation of spared cardiomyocytes. Nonetheless, the genetic and cellular determinants of natural cardiac regeneration remain incompletely characterized. Here, we report that cardiac regeneration in zebrafish relies on Notch signaling. Following amputation of the zebrafish ventricular apex, Notch receptor expression becomes activated specifically in the endocardium and epicardium, but not the myocardium. Using a dominant negative approach, we discovered that suppression of Notch signaling profoundly impairs cardiac regeneration and induces scar formation at the amputation site. We ruled out defects in endocardial activation, epicardial activation, and dedifferentiation of compact myocardial cells as causative for the regenerative failure. Furthermore, coronary endothelial tubes, which we lineage traced from preexisting endothelium in wild-type hearts, formed in the wound despite the myocardial regenerative failure. Quantification of myocardial proliferation in Notch-suppressed hearts revealed a significant decrease in cycling cardiomyocytes, an observation consistent with a noncell autonomous requirement for Notch signaling in cardiomyocyte proliferation. Unexpectedly, hyperactivation of Notch signaling also suppressed cardiomyocyte proliferation and heart regeneration. Taken together, our data uncover the exquisite sensitivity of regenerative cardiomyocyte proliferation to perturbations in Notch signaling.
人类心脏无法用再生肌肉替代缺血性损伤的心肌，这是导致与冠状动脉疾病相关的全球发病率和死亡率的重要原因。值得注意的是，某些脊椎动物物种，包括斑马鱼，通过保留的心肌细胞增殖来实现断肢或受伤心肌的完全再生。然而，自然心脏再生的遗传和细胞决定因素仍未完全描述。在这里，我们报告称，斑马鱼的心脏再生依赖于 Notch 信号。在斑马鱼心室顶点切除后，Notch 受体表达在心脏内膜和心外膜中特异性激活，但不在心肌中激活。通过使用显性负性方法，我们发现抑制 Notch 信号会严重损害心脏再生，并在断肢部位诱导瘢痕形成。我们排除了心内膜激活、心外膜激活和致密心肌细胞去分化缺陷是再生失败的原因。此外，尽管心肌再生失败，但我们从野生型心脏中原生内皮追踪的冠状动脉内皮管在伤口处形成。在 Notch 受抑制的心脏中，心肌细胞增殖的定量分析显示，有丝分裂的心肌细胞数量显著减少，这一观察结果与 Notch 信号在心肌细胞增殖中的非细胞自主需求一致。出乎意料的是，Notch 信号的过度激活也抑制了心肌细胞增殖和心脏再生。总之，我们的数据揭示了再生心肌细胞增殖对 Notch 信号扰动的敏感性。
