Stem Cell R&D - Cardiomyocytes

Human pluripotent stem cells have the capacity to differentiate into spontaneously contracting cells with cardiomyocyte-like properties and they represent a potential unlimited source for human cardiomyocytes.

No robust immortalised human cardiomyocyte cell line exists today and viable cardiac tissue samples from patients are rare and variable. However, the successful derivation of cardiomyocytes from human pluripotent stem cells is likely to lead to significant advances in development of in vitro applications for cardiac drug discovery and cardiac safety assessment of novel compounds. For target identification, validation, and evaluation studies, the use of representative human cells will improve the precision of the assays.

The possibilities to evaluate new targets in a close to physiologic environment are clearly advantageous to the use of animal cell based models or transfected abnormal cell lines. In addition, investigations of the cardiovascular risk profile of novel drug candidates at an early stage of development are essential in order to determine any unacceptable safety profile. In particular, the number one safety issue in the development of new drugs is QT interval prolongation which can lead to fatal ventricular arrhythmia (Torsade de Points). Unanticipated QT interval prolongation is the primary cause of drug withdrawal from the market over the last ten years. Novel improved in vitro models based on physiologically relevant human cells will result in more cost-effective assays ultimately leading to lower attrition rates and safer new drugs.

The cardiomyocytes derived from human pluripotent stem cells are spontaneously contracting cells and they can be cultured for extended time in vitro without loss of basic functionality.

The cells exhibit specific markers and functional properties similar to their adult counterparts. For example, structural proteins, ion-channels, tight junction proteins, transcription factors, and hormones typical for cardiomyocytes are expressed by the cells. Electrophysiological analyses have demonstrated that cardiomyocytes derived from hES cells may display ventricular, atrial, and nodal action potentials. In addition, they respond to α/β-adrenergic- and muscarinic stimuli indicating that the cells express specific surface membrane receptors coupled to a signalling pathway that activate ion channels, membrane transporters and myofilament proteins. The expression of hERG-channels has also been verified on a molecular and functional level. The cardiomyocytes derived from human pluripotent stem cells will provide the basis for cardiac safety pharmacology assays and the discovery of novel cardiac drug targets.