Key result
Introduction of computationally modeled IK1 normalized immature action potential properties in human iPSC-derived cardiomyocytes, revealing that the functional effect of Ito,f is highly sensitive to the individual cell's plateau voltage.
The introduction of modeled IK1 via dynamic current clamp normalizes the immature action potential properties of human iPSC-CMs, enabling the functional assessment of Ito,f which demonstrates highly heterogeneous, cell-specific effects on plateau membrane potential.
May enhance iPSC-CM models for electrophysiology studies; leaves open clinical translation of IK1 modulation.
The transient outward potassium current ( I to ) plays a key, albeit incompletely defined, role in cardiomyocyte physiology and pathophysiology. In light of the technical challenges of studying adult human cardiomyocytes, this study examines the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a system which potentially preserves the native cellular milieu of human cardiomyocytes. ISPC-CMs express a robust I to with slow recovery kinetics and fail to express the rapidly recovering I to,f which is implicated in human disease. Overexpression of the accessory subunit KChIP2 (which is not expressed in iPSC-CMs) resulted in restoration of a rapid component of recovery. To define the functional role of I to , dynamic current clamp was used to introduce computationally modeled currents into iPSC-CMs while recording action potentials. However, iPSC-CMs exhibit action potentials with multiple immature physiological properties, including slow upstroke velocity, heterogeneous action potential waveforms, and the absence of a phase 1 notch, thus potentially limiting the utility of these cells as a model of adult cardiomyocytes. Importantly, the introduction of modeled inwardly rectified current ( I K1 ) ameliorated these immature properties by restoring a hyperpolarized resting membrane potential. In this context of normalized action potential morphologies, dynamic current clamp experiments introducing I to,f demonstrated that there is significant cell-to-cell heterogeneity and that the functional effect of I to,f is highly sensitive to the action potential plateau voltage in each cell.
No takes yet. Share an insight, caveat, or question.
Marrus et al. (2017) studied None (healthy iPSC-derived cardiomyocytes). Dynamic current clamp (modeled IK1 and Ito,f) and KChIP2 overexpression vs. Baseline (spontaneous action potentials without modeled currents) was evaluated on Action potential parameters (resting membrane potential, upstroke velocity, APD90). Introduction of computationally modeled IK1 normalized immature action potential properties in human iPSC-derived cardiomyocytes, revealing that the functional effect of Ito,f is highly sensitive to the individual cell's plateau voltage.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: