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Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes hPSC-CMs Using Multi-electrode Arrays MEAs
Published on: May 12, 2017
Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a
Kenichi Sasaki1, Takeru Makiyama1, Yoshinori Yoshida2
1Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Insights
This study developed a human induced pluripotent stem cell model for catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrical pacing successfully replicated CPVT
Area of Science:
- Cardiology
- Stem Cell Biology
- Genetics
Background:
- Human induced pluripotent stem cells (hiPSCs) are valuable for disease modeling.
- hiPSC-derived cardiomyocytes (hiPSC-CMs) often lack maturity, hindering accurate disease phenotype recapitulation.
- Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening arrhythmia triggered by adrenergic stimulation.
Purpose of the Study:
- To establish and analyze an iPSC-based model for CPVT.
- To investigate CPVT mechanisms using electrical pacing.
- To explore potential pharmacotherapies for CPVT.
Main Methods:
- Generated hiPSCs from a CPVT patient and differentiated them into cardiomyocytes.
- Utilized calcium (Ca2+) imaging and action potential recordings.
- Applied electrical field stimulation and isoproterenol challenge.
- Tested the efficacy of S107, a ryanodine receptor 2 stabilizer.
Main Results:
- Electrical pacing with isoproterenol induced abnormal diastolic Ca2+ increase and delayed afterdepolarizations (DADs) more frequently in CPVT-hiPSC-CMs than controls.
- Spontaneous beating conditions did not reveal significant differences.
- S107 significantly reduced the incidence of DADs in CPVT-hiPSC-CMs.
Conclusions:
- Electrical pacing successfully recapitulated CPVT's electrophysiological features in hiPSC-CMs.
- The developed model demonstrates the potential for studying CPVT mechanisms.
- S107 showed promise in suppressing CPVT-related DADs, indicating its therapeutic potential.
Introduction:
Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies.
Method And Results:
We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC-CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 μM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05).
Conclusions:
We recapitulated the electrophysiological features of CPVT-derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs.
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