title: Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish.
abstract: The zebrafish heart has the capacity to regenerate after ventricular resection. Although this regeneration model has proved useful for the elucidation of certain regeneration mechanisms, it is based on the removal of heart tissue rather than its damage. Here, we characterize the cellular response and regenerative capacity of the zebrafish heart after cryoinjury, an alternative procedure that more closely models the pathophysiological process undergone by the human heart after myocardial infarction (MI). Localized damage was induced in 25% of the ventricle by cryocauterization (CC). During the first 24 hours post-injury, CC leads to cardiomyocyte death within the injured area and the near coronary vasculature. Cell death is followed by a rapid proliferative response in endocardium, epicardium and myocardium. During the first 3 weeks post-injury cell debris was cleared and the injured area replaced by a massive scar. The fibrotic tissue was subsequently degraded and replaced by cardiac tissue. Although animals survived CC, their hearts showed nonhomogeneous ventricular contraction and had a thickened ventricular wall, suggesting that regeneration is associated with processes resembling mammalian ventricular remodeling after acute MI. Our results provide the first evidence that, like mammalian hearts, teleost hearts undergo massive fibrosis after cardiac damage. Unlike mammals, however, the fish heart can progressively eliminate the scar and regenerate the lost myocardium, indicating that scar formation is compatible with myocardial regeneration and the existence of endogenous mechanisms of scar regression. This finding suggests that CC-induced damage in zebrafish could provide a valuable model for the study of the mechanisms of scar removal post-MI.
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares CNIC, Calle Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: González-Rosa
authors.forename: Víctor
authors.initials: V
authors.lastname: Martín
authors.forename: Marina
authors.initials: M
authors.lastname: Peralta
authors.forename: Miguel
authors.initials: M
authors.lastname: Torres
authors.forename: Nadia
authors.initials: N
authors.lastname: Mercader
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D002921:Cicatrix / Q000209:etiology / Q000473:pathology* / Q000534:rehabilitation; D003452:Cryosurgery / Q000009:adverse effects / Q000534:rehabilitation; D004719:Endomyocardial Fibrosis / Q000473:pathology / Q000534:rehabilitation; D005615:Freezing / Q000009:adverse effects*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006335:Heart Injuries / Q000473:pathology* / Q000534:rehabilitation; D009206:Myocardium / Q000473:pathology; D012038:Regeneration / Q000502:physiology*; D054928:Validation Studies as Topic; D020257:Ventricular Remodeling / Q000502:physiology; D015027:Zebrafish / Q000502:physiology*
chemical_list: D049452:Green Fluorescent Proteins