These presumably represent CMs that have only recently started to redifferentiate and reactivated the transgene and thus have not yet accumulated high levels of DsRed. At the same time, proliferation of both old and newly formed CMs can be detected. Thus, zebrafish heart regeneration involves replacement of the resected myocardium with newly forming cardiomyocytes. Recent genetic lineage tracing data using the Cre-Lox system has indicated that the entire regenerated myocardium is derived from existing, differentiated CMs. In particular, a subepicardial population of CMs that upregulate a gata4 promoter fragment after ventricular resection appears to produce the bulk of the regenerated myocardial tissue. Thus, a model emerges in which CMs in the subepicardial space dedifferentiate in response to injury, re-enter the cell cycle and proliferate to replace the missing tissue. At 60 dpa, most of the wound has been resolved, the missing myocardium has been replaced and no scar tissue has formed. Thus, zebrafish completely regenerate surgically removed myocardium. Although the regenerative capacity of the zebrafish heart is impressive, it has remained untested whether it is associated with the type of injury that has so far been used, tissue removal. Clinically relevant NBD 556 models of heart injuries in mammals involve tissue death, typically due to ischemia. It is conceivable that necrotic tissue represents an obstacle to regeneration that also the zebrafish cannot overcome. To address this, we have established a cryoinjury model of the adult zebrafish heart. We find that zebrafish robustly regenerate ventricular necrotic lesions and that the regenerative response involves early activation of the epicardium and induction of cardiomyocyte proliferation. Thus, our results show that the regenerative abilities of the zebrafish heart are not restricted to damage by tissue removal and that similar cellular mechanisms underlie regeneration after resection and cryoinjury. Our injury model will be of great use for studies of the molecular mechanisms of heart repair. The epicardial epithelium surrounding the myocardium was evident as a single cell layer. The intra-trabecular space was filled with erythrocytes. One day after cryoinjury, the external myocardial layer was reduced in width and devoid of cells Nicergoline displaying cardiomyocyte morphology. Likewise, most myocardial cells in the affected trabecular area had lost their typical striated morphology and characteristic nuclei, and displayed vacuolar structures indicative of cell death. Furthermore, erythrocytes were strongly enriched in the lesioned area. The wounded area was found to be infiltrated with leukocytes, most of which displayed the characteristic nuclear morphology of neutrophil granulocytes. This indicates an induction of an inflammatory response to clear cellular debris from the affected area.