Dynamic Clamp in Electrophysiological Studies on Stem Cell-Derived Cardiomyocytes-Why and How?

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are supposed to be a good human-based model, with virtually unlimited cell source, for studies on mechanisms underlying cardiac development and cardiac diseases, and for identification of drug targets. However, a major drawback of hPSC-CMs as a model system, especially for electrophysiological studies, is their depolarized state and associated spontaneous electrical activity. Various approaches are used to overcome this drawback, including the injection of "synthetic" inward rectifier potassium current (IK1), which is computed in real time, based on the recorded membrane potential ("dynamic clamp"). Such injection of an IK1-like current results in quiescent hPSC-CMs with a nondepolarized resting potential that show "adult-like" action potentials on stimulation, with functional availability of the most important ion channels involved in cardiac electrophysiology. These days, dynamic clamp has become a widely appreciated electrophysiological tool. However, setting up a dynamic clamp system can still be laborious and difficult, both because of the required hardware and the implementation of the dedicated software. In the present review, we first summarize the potential mechanisms underlying the depolarized state of hPSC-CMs and the functional consequences of this depolarized state. Next, we explain how an existing manual patch clamp setup can be extended with dynamic clamp. Finally, we shortly validate the extended setup with atrial-like and ventricular-like hPSC-CMs. We feel that dynamic clamp is a highly valuable tool in the field of cellular electrophysiological studies on hPSC-CMs and hope that our directions for setting up such dynamic clamp system may prove helpful.