Final Report Summary - STEMCARDIOVASC (Human Pluripotent Stem Cells: the new heart patient?)
Our aim in the project was to build human “mini-hearts” from pluripotent stem cells and to use these to understand how the human heart develops, what can go wrong, which cells are affected in heart disease and how we might discover new drugs to treat these ailments. We first found ways to derive all cells of the heart from stem cells: these included contractile cardiomyocytes, cardiac endothelial cells that form the blood vessels and cardiac fibroblasts that contribute to the connective tissues and provide the heart with structure. As we expected though, these cells were immature and could recapitulate some but not all disease states which often occur only in adults. Crucial to moving forward was finding ways to make these mini-hearts transit from a fetal-like to adult state. For this purpose, we generated a series of transgenic pluripotent stem cell lines in which fluorescent dyes indicated each of the individual cells types: green fluorescence for cardiomyocytes, red for endothelial cells, blue for atrial cells. These colors allowed us to monitor how each cell type behaved over time in the cardiac micro-tissues and which cardiac cell types were affected by drugs or disease. We found that in some cases endothelial cells were the target and not cardiomyocytes as expected. We also found that cardiac fibroblasts were essential for cardiomyocyte maturation, solving a longstanding problem in the field. We identified potential new drug targets for one cardiac “channelopathy” (abnormal heart rate) and a vascular disease in which patients are prone to hemorrhage due to weak blood vessels.