Human Induced Pluripotent Stem Cell-Derived Cardiac Cell Sheets Expressing Genetically Encoded Voltage Indicator for Pharmacological and Arrhythmia Studies

Stem Cell Reports
Naim ShaheenLior Gepstein

Abstract

Fulfilling the potential of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes for studying conduction and arrhythmogenesis requires development of multicellular models and methods for long-term repeated tissue phenotyping. We generated confluent hiPSC-derived cardiac cell sheets (hiPSC-CCSs), expressing the genetically encoded voltage indicator ArcLight. ArcLight-based optical mapping allowed generation of activation and action-potential duration (APD) maps, which were validated by mapping the same hiPSC-CCSs with the voltage-sensitive dye, Di-4-ANBDQBS. ArcLight mapping allowed long-term assessment of electrical remodeling in the hiPSC-CCSs and evaluation of drug-induced conduction slowing (carbenoxolone, lidocaine, and quinidine) and APD prolongation (quinidine and dofetilide). The latter studies also enabled step-by-step depiction of drug-induced arrhythmogenesis ("torsades de pointes in the culture dish") and its prevention by MgSO4 and rapid pacing. Phase-mapping analysis allowed biophysical characterization of spiral waves induced in the hiPSC-CCSs and their termination by electrical cardioversion and overdrive pacing. In conclusion, ArcLight mapping of hiPSC-CCSs provides a powerful tool for drug testing...Continue Reading

Citations

May 23, 2019·Arrhythmia & Electrophysiology Review·Luca SalaPeter J Schwartz
Apr 17, 2020·Frontiers in Cardiovascular Medicine·Pim R R van GorpAntoine A F de Vries
Jun 25, 2020·Journal of Pharmacological and Toxicological Methods·Stéphane BedutJean-Marc D'Angelo
Jan 29, 2021·Circulation·Steven M DotzlerMichael J Ackerman
Aug 22, 2020·Regulatory Toxicology and Pharmacology : RTP·Gary GintantKsenia Blinova
Dec 31, 2020·International Journal of Molecular Sciences·Ekaterina S PotekhinaDmitry S Bilan
Dec 20, 2020·Nature Reviews. Cardiology·Emilia Entcheva, Matthew W Kay
Mar 10, 2021·European Heart Journal·Massimiliano GnecchiPeter J Schwartz
Apr 2, 2021·Circulation·Olga Shaihov-TeperJonathan Leor
Apr 4, 2021·International Journal of Molecular Sciences·Aleksandra NijakMaaike Alaerts
Jul 3, 2021·ELife·Parya AghasafariColleen E Clancy
Jul 25, 2021·International Journal of Molecular Sciences·Joseph AzarWassim Abou-Kheir
Jul 8, 2021·Biofabrication·Kenichi AraiKoichi Nakayama

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Methods Mentioned

BETA
transgenic
enzymatic dissociation
Fluorescence

Software Mentioned

MATLAB
OMProCCD
VSFP
CR
hiPSC
ArcLight
GEVIs
VSFP2
CCS
- CCS

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