CAREFISH · Cardiac fibrosis versus regeneration: lessons learned from the zebrafish

Myocardial infarction (MI) leading to ischemic heart disease is the most common cause of death worldwide. In mammals, MI results in the in the replacement of the damaged myocardium with a scar. However, other animals, such as teleost fish have a remarkable capacity to regenerate damaged tissue replacing it with newly formed tissue. Recently, a zebrafish model of MI has been established. Cryoinjury (CI) of 25% of the ventricle leads to massive cell death and the deposition of fibrotic tissue. While in mammals cardiac fibrosis is irreversible, in the zebrafish the scar regresses and the injured area is replaced by new cardiomyocytes. Although the regenerative capacity of the zebrafish heart was described a decade ago, little is known about its molecular mechanisms.The aim of this project is to analyse the fate of myofibroblast during cardiac regeneration in the zebrafish. Only few apoptotic myofibroblasts are detected after CI leaving several questions unanswered as to what happens to these cells.Another important aspect is to understand the molecular mechanisms behind cardiac regeneration in a MI-model in zebrafish. We will test if cardiac regeneration is accomplished by the re-expression of developmentally active genes. We will study the role of the transcription factor tbx1 (involved in cardiac development in zebrafish as well as in humans), which has been identified in a recent screen performed in the host group. We will also analyse the function of molecules secreted from the epicardium. This mesothelial layer has been recently shown to play a pivotal role during cardiac repair and, given its accessibility, poses an attractive target for therapeutic intervention.In sum, this project will characterize how in zebrafish mechanisms driving cardiomyocyte proliferation and scar formation are outbalanced to allow cardiac regeneration and propose that the findings may ultimately contribute to future therapies for the improvement of human cardiovascular health.