Abstract

A Novel Optical Dynamic Clamp Platform For iPSC-derived Cardiomyocytes

Bonnie Quach, Researcher, Weill Cornell Graduate School

iPSC-derived cardiomyocytes (iPSC-CMs) are a potentially viable platform for drug screening since they provide a renewable source of human cardiomyocytes that can be derived from a target patient population. However, one major obstacle to using iPSC-CMs for drug development is their fetal-like electrophysiology. Artificial addition of the missing inward rectifier potassium current, IK1, via dynamic clamp has been shown to produce an adult-like electrical phenotype. However, dynamic clamp is low throughput and limited to a single cell format because it requires a whole-cell patch. Optogenetic tools have been shown to stimulate neural and cardiac cells to fire action potentials using depolarizing opsins and inhibit electrical activity with hyperpolarizing opsins. We present a proof-of-concept of using optogenetics to dynamically generate a target current instead of an electrode. ArchT was used to mimic IK1, resulting in a more adult-like action potential morphology, similar to using traditional dynamic clamp methods. An in silico ArchT model was used to calculate the light intensity needed to activate ArchT in vivo and generate the target current (IK1). This is the first step towards the overarching goal of establishing a novel optical dynamic-clamp platform using iPSC-CMs for drug screening based on the principles of dynamic clamp. This method aims to be fully optically controlled, allowing for the use of iPSC-CM beating clusters and is more high throughput.