Uncovering the road towards cardiomyocyte proliferation: Temporal and spatial analysis of heart regeneration in zebrafish

Abstract

Myocardial infarctions are a major cause of death in the Western world. During such an event the heart loses millions of cardiomyocytes resulting from a lack of oxygen and nutrients. Since adult human cardiomyocytes are considered post-mitotic and replace lost tissue, the damaged tissue is replaced by a permanent scar. This scar does not contribute to contractions and as, a consequence, myocardial infarction patients frequently suffer from heart failure. To combat this, there is a need for new ways to replace the lost cardiac tissue.

Opposite to humans, the zebrafish holds the unique capacity to replace the lost cardiomyocytes after cardiac damage. To achieve this the zebrafish makes use of a layer of surviving cardiomyocytes directly adjacent to the injury. We will call this region the border zone from now. The cardiomyocytes in this border zone start to proliferate after injury and produce new myocardial tissue that will eventually repopulate the injury area and restore cardiac function. In this thesis we used to zebrafish to study this special population of proliferating cardiomyocytes based on the premise that knowledge obtained from this cell population holds the potential to boost human cardiomyocyte proliferation as well. For this, we made use of microscopy and sequencing techniques to study the changes these cells undergo leading to proliferation at a single cell level. Doing so, we were the first to describe changes in sarcomeres and metabolism during the process of adult cardiomyocyte proliferation. Moreover, we generated a transcriptomic roadmap towards cardiomyocyte proliferation and identified novel targets that hold the potential to boost this process. For one of these factors we additionally confirmed its importance for successful heart regeneration.

In conclusion, we used a live imaging and transcriptomic techniques at the single cell level to study border zone cardiomyocytes prior to and during proliferation. The knowledge we obtain in this thesis on these cells holds promise to stimulate cardiomyocyte proliferation in humans as well and boost heart regeneration after myocardial damage.