Studying cardiac diseases using human stem cell-derived cardiomyocytes

    Research output: ThesisThesis fully internal (DIV)

    546 Downloads (Pure)

    Abstract

    Heart failure is a complex syndrome characterized by the inability of the heart to pump enough blood to meet the needs of the body and can be caused by various cardiac diseases. Representative models are essential to understand the nature of these diseases. To that end, recapitulating cardiac diseases in vitro provides an accessible platform to study cell autonomous molecular mechanisms. We have employed human pluripotent stem cells to generate (patient-specific) cardiomyocytes. Consequently, we have demonstrated that cellular iron deficiency impairs both mitochondrial respiration and contractile function in human cardiomyocytes. Also, a specific signaling pathway in cardiac hypertrophy was identified, and inhibition of this pathway prevented hypertrophy altogether. In addition, we studied aspects of peripartum cardiomyopathy, a severe pregnancy-related cardiac disease. This intricate disease is believed to be the result of a complex interplay between genetic factors, cathepsin D, prolactin, multiple cell types and a specific microRNA. We established that increased levels of circulating cathepsin D are not only associated with peripartum cardiomyopathy, but also correlated with heart failure severity in large European population of heart failure patients. Moreover, we provide evidence that cathepsin D is protective for the heart during stress. Finally, through induced pluripotent stem cells, we generated peripartum cardiomyopathy patient-specific cardiomyocytes. Transcriptome sequencing revealed aberrant metabolic regulation in patient-specific cells. These studies signify in vitro cardiac disease models as a valuable tool to study afflictions of the heart in great detail to accelerate the progress of future treatment development.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • van der Meer, Peter, Supervisor
    • Bömer, Nils, Co-supervisor
    Award date20-Mar-2019
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-034-1405-8
    Electronic ISBNs978-94-034-1404-1
    Publication statusPublished - 2019

    Cite this