Derivation of heart cells from human pluripotent stem cells (hPSC) is an area of growing interest as a way of modelling disease phenotypes and as a platform for drug discovery and toxicity. Applying the underlying developmental mechanisms that control cardiac differentiation to hPSCs through the use of defined culture conditions in vitro is rapidly moving the field forward: cardiomyocyte differentiation is now a fairly efficient and reproducible process. Genetically marked hESCs have been produced in which expression of the green fluorescent protein marker is driven by specific lineage markers like Nkx2.5. We are now using these tagged lines in which GFP to select the progenitors of cardiomyocytes, endothelial cells and smooth muscle cells. Applications of hESC- and hiPSC-derived cardiomyocytes in drug discovery and disease are thus now close to implementation. Results of these studies, in particular drug responses of hPSC- cardiomyocytes to a variety of drugs will be shown. There is an urgent unmet need for reliable cardiac safety pharmacology assays to identify potential risks early in drug development and reduce time and cost to market. The field potential of hPSC-CM can be measured using commercially available multi electrode arrays. Systematic generation of dose response curves for cardiac and non-cardiac drugs show that hPSC-CM accurately predict reported drug effects on the human heart. These include blocking the hERG ion channel, resulting in QT-prolongation; this is associated with life-threatening arrhythmias. Dose responses of a wide range of compounds have been compared and the outcome shown to predict clinical effects.
Induced pluripotent stem cells (hiPSC) from patients with genetic disease are source of somatic cells that can carry disease mutations and show disease phenotypes. However, stem cell derivatives are usually immature and whether they represent phenotypes observed in the adult patient and what are appropriate controls, is still a matter of discussion. Data generated using isogenic pairs of hPSC bearing the same cardiac disease mutation as well as a comparison of (mouse) iPSC and ESC-derived cardiomyocytes with adult heart cells will be shown.