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Triiodothyronine and dexamethasone alter potassium channel expression and promote electrophysiological maturation of human-induced pluripotent stem cell-derived cardiomyocytes.
- Source :
-
Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2021 Dec; Vol. 161, pp. 130-138. Date of Electronic Publication: 2021 Aug 13. - Publication Year :
- 2021
-
Abstract
- Background: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising tool for disease modeling and drug development. However, hiPSC-CMs remain functionally immature, which hinders their utility as a model of human cardiomyocytes.<br />Objective: To improve the electrophysiological maturation of hiPSC-CMs.<br />Methods and Results: On day 16 of cardiac differentiation, hiPSC-CMs were treated with 100 nmol/L triiodothyronine (T3) and 1 μmol/L Dexamethasone (Dex) or vehicle for 14 days. On day 30, vehicle- and T3 + Dex-treated hiPSC-CMs were dissociated and replated either as cell sheets or single cells. Optical mapping and patch-clamp technique were used to examine the electrophysiological properties of vehicle- and T3 + Dex-treated hiPSC-CMs. Compared to vehicle, T3 + Dex-treated hiPSC-CMs had a slower spontaneous beating rate, more hyperpolarized resting membrane potential, faster maximal upstroke velocity, and shorter action potential duration. Changes in spontaneous activity and action potential were mediated by decreased hyperpolarization-activated current (I <subscript>f</subscript> ) and increased inward rectifier potassium currents (I <subscript>K1</subscript> ), sodium currents (I <subscript>Na</subscript> ), and the rapidly and slowly activating delayed rectifier potassium currents (I <subscript>Kr</subscript> and I <subscript>Ks</subscript> , respectively). Furthermore, T3 + Dex-treated hiPSC-CM cell sheets (hiPSC-CCSs) exhibited a faster conduction velocity and shorter action potential duration than the vehicle. Inhibition of I <subscript>K1</subscript> by 100 μM BaCl <subscript>2</subscript> significantly slowed conduction velocity and prolonged action potential duration in T3 + Dex-treated hiPSC-CCSs but had no effect in the vehicle group, demonstrating the importance of I <subscript>K1</subscript> for conduction velocity and action potential duration.<br />Conclusion: T3 + Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Action Potentials drug effects
Cells, Cultured
Gene Expression Regulation drug effects
Humans
Myocytes, Cardiac drug effects
Potassium Channels metabolism
Single-Cell Analysis
Dexamethasone pharmacology
Induced Pluripotent Stem Cells cytology
Myocytes, Cardiac physiology
Potassium Channels genetics
Triiodothyronine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-8584
- Volume :
- 161
- Database :
- MEDLINE
- Journal :
- Journal of molecular and cellular cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 34400182
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2021.08.005