A novel medium-throughput platform for target validation of regulators of cardiac regeneration in zebrafish larvae

Kateřina Apolínová1,4*, Sylvia Dyballa1, Benedetta Coppe3, Carole Jung2, Nadia Mercader Huber3, Vincenzo Di Donato1†, Javier Terriente1,2† 1ZeClinics SL, Badalona, Spain. 2ZeCardio SL, Badalona, Spain. 3Department of Developmental Biology and Regeneration, Faculty of Medicine, University of Bern, Bern, Switzerland. 4University Pompeu Fabra, Barcelona, Spain. *Email: katerina.apolinova@zeclinics.com †These authors contributed equally to the work.

ABSTRACT

Cardiovascular diseases remain the leading cause of death worldwide, and few effective treatment options are available. Myocardial injury, such as myocardial infarction, causes irreversible damage of the heart muscle and its replacement by scar, leading to a chronic decrease in heart function. In contrast to humans, the injured zebrafish heart muscle regenerates efficiently through robust proliferation of myocardial cells. Thus, the zebrafish presents a beneficial vertebrate model for studying genetic programs behind cardiac regeneration, which may be present, albeit dormant, in the adult human heart.

To this end, we established a novel platform for studying heart regeneration after cardiomyocyte ablation in zebrafish larvae. The specific ablation of cardiomyocytes is achieved through a transgenic construct inducing the expression of nitroreductase, a bacterial enzyme, in a pool of ventricular cardiomyocytes. Subsequent treatment with antibiotics induces cell death specifically in nitroreductase-expressing cells. In combination with automated 3D heart imaging, this platform can be used for medium-throughput screening of genes and compounds with presumed effects on regeneration. Our results confirm that we induce a robust loss of the targeted cardiomyocytes, which are replaced through the proliferation of remaining cardiomyocytes within 4 days post injury. Our results further show that treatment with known anti-regenerative molecules causes a significant delay in regeneration kinetics, providing a proof of principle for this platform in identifying anti-regenerative effects of genes and drugs. Using this platform, we aim to discover therapeutic targets and drugs that will allow us to activate the dormant regenerative potential of the human heart.

A novel medium-throughput platform for target validation of regulators of cardiac regeneration in zebrafish larvae

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