Open AccessToward Personalized Medicine: Using Cardiomyocytes Differentiated From Urine‐Derived Pluripotent Stem Cells to Recapitulate Electrophysiological Characteristics of Type 2 Long QT Syndrome
Author(s) -
Jouni Mariam,
SiTayeb Karim,
EsSalahLamoureux Zeineb,
Latypova Xenia,
Champon Benoite,
Caillaud Amandine,
Rungoat Anais,
Charpentier Flavien,
Loussouarn Gildas,
Baró Isabelle,
Zibara Kazem,
Lemarchand Patricia,
Gaborit Nathalie
Publication year - 2015
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.115.002159
Subject(s) - herg , induced pluripotent stem cell , long qt syndrome , medicine , cardiac action potential , phenotype , myocyte , microbiology and biotechnology , bioinformatics , embryonic stem cell , qt interval , electrophysiology , potassium channel , biology , genetics , repolarization , gene
Background Human genetically inherited cardiac diseases have been studied mainly in heterologous systems or animal models, independent of patients' genetic backgrounds. Because sources of human cardiomyocytes ( CM s) are extremely limited, the use of urine samples to generate induced pluripotent stem cell–derived CM s would be a noninvasive method to identify cardiac dysfunctions that lead to pathologies within patients' specific genetic backgrounds. The objective was to validate the use of CMs differentiated from urine‐derived human induced pluripotent stem (UhiPS) cells as a new cellular model for studying patients' specific arrhythmia mechanisms. Methods and Results Cells obtained from urine samples of a patient with long QT syndrome who harbored the HERG A561P gene mutation and his asymptomatic noncarrier mother were reprogrammed using the episomal‐based method. Uhi PS cells were then differentiated into CM s using the matrix sandwich method. Uhi PS ‐ CM s showed proper expression of atrial and ventricular myofilament proteins and ion channels. They were electrically functional, with nodal‐, atrial‐ and ventricular‐like action potentials recorded using high‐throughput optical and patch‐clamp techniques. Comparison of HERG expression from the patient's Uhi PS ‐ CM s to the mother's Uhi PS ‐ CM s showed that the mutation led to a trafficking defect that resulted in reduced delayed rectifier K + current (I Kr ). This phenotype gave rise to action potential prolongation and arrhythmias. Conclusions UhiPS cells from patients carrying ion channel mutations can be used as novel tools to differentiate functional CMs that recapitulate cardiac arrhythmia phenotypes.