Abstract
Adult zebrafish have the remarkable ability to regenerate their heart upon injury, a process that involves limited dedifferentiation and proliferation of spared cardiomyocytes (CMs), and migration of their progeny. During regeneration, proliferating CMs are detected throughout the myocardium, including areas distant to the injury site, but whether all of them are able to contribute to the regenerated tissue remains unknown. Here, we developed a CM-specific, photoinducible genetic labelling system, and show that CMs labelled in embryonic hearts survive and contribute to all three (primordial, trabecular and cortical) layers of the adult zebrafish heart. Next, using this system to investigate the fate of CMs from different parts of the myocardium during regeneration, we show that only CMs immediately adjacent to the injury site contributed to the regenerated tissue. Finally, our results show an extensive predetermination of CM fate during adult heart regeneration, with cells from each myocardial layer giving rise to cells that retain their layer identity in the regenerated myocardium. Overall, our results indicate that adult heart regeneration in the zebrafish is a rather static process governed by short-range signals, in contrast to the highly dynamic plasticity of CM fates that takes place during embryonic heart regeneration.
Highlights
The zebrafish has positioned itself as a valuable model for investigating heart regeneration due to its intrinsic capacity to restore large portions of this organ after amputation [1,2], cryoinjury [3,4,5] or genetic ablation [6]
Using this system to investigate the fate of CMs from different parts of the myocardium during regeneration, we show that only CMs immediately adjacent to the injury site contributed to the regenerated tissue
Our results indicate that adult heart regeneration in the zebrafish is a rather static process governed by short-range signals, in contrast to the highly dynamic plasticity of CM fates that takes place during embryonic heart regeneration
Summary
The zebrafish has positioned itself as a valuable model for investigating heart regeneration due to its intrinsic capacity to restore large portions of this organ after amputation [1,2], cryoinjury [3,4,5] or genetic ablation [6]. It should be noted that this type of cell proliferation assay provides information as to the location of BrdU- or EdU-labelled cells at the time of analysis, which may be different from their original position when they began proliferating and incorporated BrdU/EdU This raises the intriguing possibility that CMs could proliferate in specific, perhaps distant zones of the heart, and migrate towards the regenerating area where they would contribute to the newly formed myocardium. We sought to address these two outstanding questions: whether the CMs that proliferate at places distant to the injury site contribute to the regenerated myocardium, and if so, whether they are distributed randomly throughout the zebrafish heart, or they make up specific, regeneration-competent areas For this purpose, we have developed a genetic lineagetracing strategy based on the conditional expression of a fluorescent reporter transgene in few CMs by Cre/lox recombination. Our results show that CMs display a short-range migration, and only CMs immediately adjacent to the injury site contribute to the regenerating myocardium
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