scholarly journals Modelling Human Channelopathies Using Induced Pluripotent Stem Cells: A Comprehensive Review

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Martin Müller ◽  
Thomas Seufferlein ◽  
Anett Illing ◽  
Jörg Homann
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Ips Cells ◽  
Patient Specific ◽  
Long Qt ◽  
Qt Syndrome ◽  
Underlying Mechanisms ◽  
Induced Pluripotent

The generation of induced pluripotent stem cells (iPS cells) has pioneered the field of regenerative medicine and developmental biology. They can be generated by overexpression of a defined set of transcription factors in somatic cells derived from easily accessible tissues such as skin or plucked hair or even human urine. In case of applying this tool to patients who are classified into a disease group, it enables the generation of a disease- and patient-specific research platform. iPS cells have proven a significant tool to elucidate pathophysiological mechanisms in various diseases such as diabetes, blood disorders, defined neurological disorders, and genetic liver disease. One of the first successfully modelled human diseases was long QT syndrome, an inherited cardiac channelopathy which causes potentially fatal cardiac arrhythmia. This review summarizes the efforts of reprogramming various types of long QT syndrome and discusses the potential underlying mechanisms and their application.

scholarly journals From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2

2019 ◽  
Vol 40 (23) ◽  
pp. 1832-1836 ◽  
Author(s):  
Peter J Schwartz ◽  
Massimiliano Gnecchi ◽  
Federica Dagradi ◽  
Silvia Castelletti ◽  
Gianfranco Parati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Patient Specific ◽  
Syndrome Type ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent

scholarly journals Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

2012 ◽  
Vol 141 (1) ◽  
pp. 61-72 ◽  
Author(s):  
Cecile Terrenoire ◽  
Kai Wang ◽  
Kelvin W. Chan Tung ◽  
Wendy K. Chung ◽  
Robert H. Pass ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Na Channel ◽  
Long Qt ◽  
Complex Genetics ◽  
Drug Actions ◽  
Qt Syndrome ◽  
Induced Pluripotent

Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na+ channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism. The F1473C mutation occurs in the channel inactivation gate and enhances late Na+ channel current (INaL) that is carried by channels that fail to inactivate completely and conduct increased inward current during prolonged depolarization, resulting in delayed repolarization, a prolonged QT interval, and increased risk of fatal arrhythmia. We find a very pronounced rate dependence of INaL such that increasing the pacing rate markedly reduces INaL and, in addition, increases its inhibition by the Na+ channel blocker mexiletine. These rate-dependent properties and drug interactions, unique to the proband’s iPSC-CMs, correlate with improved management of arrhythmias in the patient and provide support for this approach in developing patient-specific clinical regimens.

Modelling the long QT syndrome with induced pluripotent stem cells

Nature ◽  
2011 ◽  
Vol 471 (7337) ◽  
pp. 225-229 ◽  
Author(s):  
Ilanit Itzhaki ◽  
Leonid Maizels ◽  
Irit Huber ◽  
Limor Zwi-Dantsis ◽  
Oren Caspi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent
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