Electronic Expression of IK1 in Human Induced Pluripotent Stem Cell Derived Cardiocytes Reveals Atrial vs Ventricular Specific Properties

Abstract

Cardiomyocytes derived from human induced pluripotent stem cells (hIPSC-CMs) provide a promising platform for understanding human cardiac pathology and physiology. HIPSC-CMs differentiate into a mixed population of cells composed of ventricular, atrial, and nodal cell types; cellular phenotype is generally distinguished by morphology of the action potential (APs). However, in hIPSC-CMs a very small inward rectifying potassium channel (IK1) relative to native cardiac cells causes a depolarized membrane potential which contributes to inconsistent AP properties and misidentification of cellular phenotype.We used Electronic expression of IK1 via dynamic clamp to restore the AP and resting membrane potential back to a physiological levels. This allowed for improved discrimination of atrial and ventricular cells based on AP morphology. Using standard patch clamp techniques, we compared the inward sodium currents (INa) of cells with atrial and ventricular AP morphologies. INa current densities in cells with atrial like APs were larger than ventricular-like APs (at −30 mV, in pA/pF: −71.22 ± 6.96 (n=5) vs. −46.25 ±5.03 (n=14), p < 0.05). Analysis of steady-state inactivation parameters of INa showed that cells with an atrial like AP had a more negative steady-state inactivation (V1/2: −81.84 ± 2.75 (n=5) vs. −74.72 ±0.8 (n=14), p<0.05). Cells with atrial APs had a larger Kv1.5-like component at +50 mV than ventricular APs (in pA/pF: 3.71 ± 0.55 (n=5) vs 1.00 ± 0.10 (n=16),P<0.05) but similar peak currents: (6.89 ± 0.50 (n=5) vs. 6.58 ± 0.67 (n=14),P=N.S). IK1 current density was more than 3x smaller in cells with atrial-like APs at −120 mV (in pA/pF: −0.71 ± 0.08 (n=5) vs. −3.45 ± 0.61 (n=14), p<0.05). These data suggest that differential AP morphology in hIPSC-CM has a similar electrophysiological basis to native cells.