Myocardial infarction causes cardiac cell death and contractile dysfunction leading to adverse patient outcomes – yet effective therapies remain lacking. Patients with heart failure suffer from major impairments in quality of life and poor long-term prognosis. Loss of cardiomyocytes is a major hallmark of heart failure and is linked to an approximate 25% decrease in cardiomyocytes due to cell death. However, unlike other tissues that can compensate cell death through proliferative induction, cardiomyocytes are post-mitotic and have very limited capacity for proliferation, regeneration or repair to restore damaged tissue to overcome remodeling and fibrotic processes leading to heart failure and death. Thus, there remains a high unmet need for novel therapeutics to reduce heart failure morbidity and mortality. This course will provide the experimental background to study cardiac regeneration ex vivo, in a state-of-the-art self-organised human cardiac organoid system that we have established.
iPSC-derived human cardiac organoids have been shown to recapitulate heart tissue function and pathophysiologic responses – providing a powerful in vitro system to study cardiogenesis, genetic cardiomyopathies, stress-induced disease, and as a platform to identify and validate novel drugs. Our lab has established the generation of adult self-organizing cardiac organoids (SCOs), which spontaneously organize into epicardial, myocardial and endocardial layers, and contain all cell types of the native human myocardium including cardiomyocytes, endothelial cells, cardiac fibroblasts, pericytes, smooth muscle cells, macrophages and neurons. Further, the SCOs reveal a distinct cardiac lumen, contain mature 3D vascular networks, and mimicked mature human myocardial responses to stress and benchmark compound stimulation.
In this setting, we will study the differential effects of drugs on proliferative responses in cardiomyocytes, endothelial cells and pericytes/smooth muscle cells. This Elective will run over 2 consecutive days, comprising of a Teaching/Seminar component (2-3hrs) and a Practical component (8-12hrs). The Practical component will involve observation, handling and staining of 3D cardiac cultures with proliferation and cell lineage markers, followed by confocal microscopic imaging and quantitative analysis of lineage-specific cell proliferation.
Depending on student interest, there would be the opportunity to tailor the course towards a greater focus and emphasis on metabolic or contractile/functional adaptations of drugs on proliferative responses. The language of the course is English