hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

Abstract

Mutations in the HERG gene encoding the potassium ion channel HERG, represent one of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic mutation frequently presents different clinical phenotypes in the family. Our study aimed to model LQT2 and study functional differences between the mutation carriers of variable clinical phenotypes. We derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic HERG mutation carriers from the same family. When comparing asymptomatic and symptomatic single LQT2 hiPSC-CMs, results from allelic imbalance, potassium current density, and arrhythmicity on adrenaline exposure were similar, but a difference in Ca2+ transients was observed. The major differences were, however, observed at aggregate level with increased susceptibility to arrhythmias on exposure to adrenaline or potassium channel blockers on CM aggregates derived from the symptomatic individual. The effect of this mutation was modeled in-silico which indicated the reactivation of an inward calcium current as one of the main causes of arrhythmia. Our in-vitro hiPSC-CM model recapitulated major phenotype characteristics observed in LQT2 mutation carriers and strong phenotype differences between LQT2 asymptomatic vs. symptomatic were revealed at CM-aggregate level.

Long QT syndrome – Bench to bedside

“…The authors of the study suggested the importance of considering the clinical differences in phenotypes observed in single and aggregate hiPSC-CMs, particularly when conducting preclinical drug toxicity tests. 203 …”

Stem Cell-Based Disease Modeling and Cell Therapy

“…They also found that iPSC-CM aggregates from symptomatic patients, compared to asymptomatic patients, were more arrhythmic on rapid (IKr) and slow (IKs) delayed rectifier potassium channel blocks. This data suggests that this in-vitro human iPSC-CM model recapitulates major phenotype characteristics observed in LQT2 mutation carriers [ 27 ].…”

“…This Special Issue includes both research [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] and reviews articles [ 10 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ] which cover wide ranges of stem cell research: adult stem cells, cancer stem cells, pluripotent stem cells, and complex 3D organoid/cell aggregate models [ 26 , 27 , 33 ], with the focuses on stem cell biology/technology [ 10 , 23 , 24 , 25 , 26 , 31 , 32 , 34 ], and stem cell-based disease modeling [ 10 , 27 , 29 , 31 , 33 , 38 , 43 ] and cell therapy [ 24 , 28 , 30 , 32 , 35 , 36 , 37 , 39 , 40 , 41 ].…”

From Human Pluripotent Stem Cells to 3D Cardiac Microtissues: Progress, Applications and Challenges

“…The use of 3D cardiac models per se has also been proved to benefit cardiac disease modeling studies. EHT constructs [ 88 , 116 , 117 , 118 ] and 3D cultured hPSC-CMs [ 119 ] have been successfully used to recapitulate cardiac disease phenotypes, showing in some cases that the use of more complex cardiac models can benefit and improve the liability of the outcomes taken from disease modeling studies. Specifically, Goldfracht and colleagues, who studied catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) and long QT syndrome type 2 (LQTS2) disorders using patient-derived hPSC-CMs in an EHT model, showed that the arrhythmogenic potential of the generated CPVT2 and LQTS2 tissues was reduced in EHT constructs, compared with the same cells within single-cell models [ 88 ], being more similar to what occurs in vivo.…”

“…In the EHT-HCM model, it was possible to recapitulate several hallmarks of the disease including prolonged AP duration, increased contractility and hypertrophy. Also, upon modeling of LQTS2 cardiac disorder, Shah and co-workers revealed that clinical phenotypic differences observed in patients with this disease were also observed in hiPSC-CMs cultures as 3D aggregates but were not seen in homogenous cultures of hPSC-CMs, reinforcing the utility and necessity of more complex cardiac models in this field [ 119 ].…”