Potentials of Stem Cell derived cardiomyocytes
Authors:   , Maas Renée Goverdina Catharina 
Published: February 2024

Cardiomyopathies are disorders of the heart caused by a wide variety of factors, leading to cardiac dysfunction, aggravated by arrhythmias, heart failure, and sudden cardiac death. Many people suffer from cardiomyopathies caused by a genetic defect. Genetic cardiomyopathies unfortunately have low predictability when it comes to the onset of disease, progression and treatment. The understanding of the pathophysiological and molecular mechanisms that cause these genetic cardiomyopathies is crucial to developing novel therapies to prevent heart failure. Cardiomyocytes (heartcells) differentiated from human derived induced pluripotent stem cells (hiPSCs-CMs) are powerful experimental tools for studying genetic cardiomyopathies in the lab. This so called; ‘’In vitro disease modeling’’ can help to model the onset of the first variable phenotypic presentations and, therefore, forms a scalable platform for human disease modeling, drug discovery, and the clinical validation of novel therapeutic developments.

The general aim of this thesis was to investigate the potentials of stem cell-derived cardiomyocytes to answer the question ’’Can we use stem cell-derived cardiomyocytes to find a cure for genetic cardiomyopathies?’’. This question was answered using two main thesis parts. In part I of this thesis, we investigated the human heart development to make the best possible stem-cell derived cardiomyocytes in the laboratory. This lead to the identification of particular mechanisms involved in cardiomyocyte proliferation and very efficient strategies for the massive production and biobanking of cardiomyocytes. Moreover, cardiomyocyte division, gene manipulation, cardiomyocyte maturation and ischemic disease modeling of stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro are described in various chapters.

In part II of this thesis, the aforementioned hiPSC-CM findings are placed into methodological, mechanistic, and clinical perspective. This research was mainly focused on one specific genetics cardiomyopathy; the deletion of arginine 14 in the Phospholamban gene (PLN-R14del). In the Netherlands, PLN-R14del is remarkably responsible for 10% of all patients with dilated cardiomyopathy, 15% with arrhythmogenic cardiomyopathy and represents 25% of the annual heart transplants, underlining its significant impact on cardiac health. Three chapters addressed various unanswered questions about which triggers underlie the onset of pathological features in PLN-R14del cardiomyopathy. Additionally, two chapter described the generation and use of cardiac spheroids as three-dimensional ‘mini-hearts’ for functional disease modeling and high throughput screening of novel therapeutic strategies for genetic cardiomyopathies. This thesis showcases that patient hiPSC-CMs can be conducted with scientifically sound methods using pragmatic in vitro disease models and innovative disease pathway analysis. Considering the output from more than five years of translational hiPSC-CM research summarized in this thesis, Renée Maas concludes to have—hopefully—not only added data that will improve these ‘mini-hearts’ to predict but also prevent and cure the burden of cardiomyopathies in people we try to help so hard – the patients.