2. Academic Validation
  3. Triiodothyronine and dexamethasone alter potassium channel expression and promote electrophysiological maturation of human-induced pluripotent stem cell-derived cardiomyocytes

Triiodothyronine and dexamethasone alter potassium channel expression and promote electrophysiological maturation of human-induced pluripotent stem cell-derived cardiomyocytes

  • J Mol Cell Cardiol. 2021 Dec;161:130-138. doi: 10.1016/j.yjmcc.2021.08.005.
Lili Wang 1,  Yuko Wada 2,  Nimer Ballan 3,  Jeffrey Schmeckpeper 2,  Jijun Huang 4,  Christoph Daniel Rau 4,  Yibin Wang 4,  Lior Gepstein 5,  Bjorn C Knollmann 6
Affiliations

Affiliations

  • 1 Department of Medicine, Vanderbilt University Medical Center, Medical Research Building IV, Rm.1275, 2215B Garland Ave, Nashville, TN 37232, USA. Electronic address: lili.wang@vumc.org.
  • 2 Department of Medicine, Vanderbilt University Medical Center, Medical Research Building IV, Rm.1275, 2215B Garland Ave, Nashville, TN 37232, USA.
  • 3 Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 3109601, Israel.
  • 4 Department of Anesthesiology, Medicine and Physiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
  • 5 Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 3109601, Israel; Cardiology Department, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 2 Efron St., POB 9649, Haifa, 3109601, Israel.
  • 6 Department of Medicine, Vanderbilt University Medical Center, Medical Research Building IV, Rm.1275, 2215B Garland Ave, Nashville, TN 37232, USA. Electronic address: bjorn.knollmann@vanderbilt.edu.
PMID: 34400182 DOI: 10.1016/j.yjmcc.2021.08.005
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.

Objective: To improve the electrophysiological maturation of hiPSC-CMs.

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 (If) and increased inward rectifier potassium currents (IK1), sodium currents (INa), and the rapidly and slowly activating delayed rectifier potassium currents (IKr and IKs, 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 IK1 by 100 μM BaCl2 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 IK1 for conduction velocity and action potential duration.

Conclusion: T3 + Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.

Keywords

Action potential; Conduction velocity; Electrophysiological maturation; HiPSC-CMs; Potassium currents; T3 + Dex treatment.

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