Human pluripotent stem cells in understanding genetic cardiovascular disease and effects of drugs
Derivation of many different cell types from human pluripotent stem cells (embryonic stem cells or HESCs and induced pluripotent stem cells or hiPS cells) is an area of growing interest both for potential cell therapy and as a platform for drug discovery and toxicity. Most particularly, the recent availability of methods to introduce specific disease mutations into human pluripotent stem cells and/or to derive these cells as hiPS cells by reprogramming from any patient of choice, are creating unprecedented opportunities to create disease models “in a dish” and study ways to treat it or slow down its rate of development. We produce isogenic pairs of hiPSC lines to compare diseased and corresponding healthy cardiomyocytes and vascular endothelial cells and identify disease related phenotypes and mechanisms. We have shown in hiPSC-cardiomyocytes that mutations in ion channel genes can accurately predict changes in cardiac electrical properties and reveal drug sensitivities observed in patients. Similar studies will be described using vascular endothelial cells from hPSC. Relevant in all cases is the development of appropriate bioassays in which to measure disease phenotypes which may be highly cell type specific dependent. For heart cells, this might be electrical activity or contractions force; for vascular cells, responses to fluid flow flow and inflammation. Various approaches to this will be presented.
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