Abstract
Myocardial infarction (MI) results in the loss of cardiac tissue which is rapidly replaced by a fibrotic scar, more rigid and incapable of generating any electrical activity or contraction. To compensate for this loss, pathological adaptations take place which in turn can lead to heart failure. In mammalian adults, the consequences of MI are irreversible. However, it has been shown that during embryonic or neonatal life, some mammalian species such as the mouse can regenerate a portion of their heart after injury. Unlike mammals, zebrafish are able to regenerate their hearts at all stages of life, representing a major interest for regenerative medicine. Understanding the mechanisms involved in this process would be the first step in the development of new therapies aimed at repairing the heart after MI in human.The objective of my thesis was to study different aspects of zebrafish cardiac physiology and regeneration. To this end, I first studied the regenerative response of cardiac endothelial cells. Using single cell RNA sequencing, we found that the expression of the transcription factor tal1 increases during regeneration. Using a zebrafish transgenic line expressing a dominant negative Tal1 isoform specifically in endothelial cells, we showed that Tal1 was essential for cardiac regeneration and that it contributed to the revascularisation of the wound.I then explored the electrical activity of the zebrafish heart and contributed to a project aiming to characterise the adult zebrafish electrocardiogram (ECG). Comparing different commonly used techniques to record zebrafish ECG, we showed that opening the pectoral muscles that cover the heart allowed for a better detection of all the characteristic ECG waves. Using this technique, we then described the zebrafish response to hypothermia and osmotic shock. In doing so, we observed that the ECG parameters were not impacted by osmotic shock while in contrast, hypothermia strongly affected several of these parameters such as heart rate or the duration of the QT interval, a parameter carefully looked at in cardiotoxicity assays.The electrical activity of cardiomyocytes is finely regulated by numerous cellular actors such as ion channels. During my thesis I studied the involvment of two of these channels in zebrafish cardiac physiology and regeneration: Trek-1 and Piezo1.Using a transgenic zebrafish line expressing a dominant-negative isoform of Trek-1 (DNTrek1) in cardiomyocytes, we showed that Trek-1 was essential for both cardiomyocyte maturation in juvenile fish and cardiomyocyte redifferentiation during cardiac regeneration. These two processes share common mechanisms such as the maturation of the cardiomyocyte contractile apparatus: the sarcomere. Using RNA sequencing, we found that DNTrek1 fish misexpressed many sarcomeric genes at the juvenile stage. Although we determined that Trek-1 channels regulate these processes, the pathways controled by Trek-1 remain to be determined.Finally, I studied the role of the Piezo1 channel in arrhythmia and found, using ECG, that an overactivation of this channel by its agonist Yoda1 leads to rhythm defects in the zebrafish isolated heart. This reveals the importance of studying the effects of Piezo1 variants on the channels activity as they could be related to arrhythmias in human.