Applicability of human stem cell-derived cardiomyocytes for safety pharmacology

Abstract

In this thesis, we tested the hypothesis that human stem cell-derived cardiomyocytes can bridge the gap between the preclinical and the clinical phases of drug discovery by offering a new model system for cardiac safety pharmacology that is based on human cells. We show that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have many similarities with the adult CM (Chapters 4-5), but that they are electrically immature (Chapters 6 and 9), a feature that limits their general usability. Human cardiac progenitor cell (hCPC)-derived CMs, however, are more mature and therefore closer to an adult CM (Chapter 7), but are so far not being produced in a stable and reproducible manner. The ideal safety pharmacology model will I) be applicable to use with existing techniques and methodologies, and II) resemble the adult human CM in great detail. We have shown here that different techniques, ranging from in-depth patch clamp recordings of ion currents, to AP recordings using sharp microelectrodes, and medium-throughput beating frequency recordings using an impedance-based technique, can all be applied to SC-CM. These techniques are relevant tools currently in use by both small and large (pharmaceutical) companies. As for the resemblance to the adult CM, we have showed that even though human SC-CMs functionally express all major ion channels with the exception of IK1, the response to drugs affecting several ion channels was not as expected. The clearly immature phenotype of hESC-CM is currently the biggest obstacle for introducing them as a tool for broad safety pharmacology screening purposes, and thus strategies to improve their maturity through increased expression of IK1 must be developed. Still, based on the expression of most ion channel subunits, human SC-CM may be a useful tool to study ion channel kinetics and the effect of drugs thereof during voltage clamp experiments. With regards to AP recordings, the same cells can be used for hERG screening but testing multi-target drugs requires caution. The more mature CPC-CM may be a better tool considering its higher expression of IK1, but its use is limited due to production problems.