Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome

Moretti, Alessandra; Bellin, Milena; Welling, Andrea; Jung, Christian B.; Lam, Jason T.; Bott-Flügel, Lorenz; Dorn, Tatjana; Goedel, Alexander; Höhnke, Christian; Hofmann, Franz; Seyfarth, Melchior; Sinnecker, Daniel; Schömig, Albert; Laugwitz, Karl‐Ludwig

doi:10.1056/nejmoa0908679

Cited by 1,132 publications

(954 citation statements)

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“…Patient-specific iPSderived cardiomyocytes (iPS-CMs) have been used to investigate inherited arrhythmia syndromes such as long QT syndrome (LQTS) and catecholeminergic polymorphic ventricular tachycardia (9,21,31,34). These proof of concept studies have recapitulated some characteristic features of human disease (8, 23).…”

Section: Ik1-enhanced Induced Pluripotent Stem Cell-derived Cardiomyomentioning

confidence: 99%

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

Vaidyanathan

Markandeya

Kamp

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Vaidyanathan R, Markandeya YS, Kamp TJ, Makielski JC, January CT, Eckhardt LL. IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes. Am J Physiol Heart Circ Physiol 310: H1611-H1621, 2016. First published April 8, 2016; doi:10.1152/ajpheart.00481.2015.-Currently available induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) do not ideally model cellular mechanisms of human arrhythmic disease due to lack of a mature action potential (AP) phenotype. In this study, we create and characterize iPS-CMs with an electrically mature AP induced by potassium inward rectifier (IK1) enhancement. The advantages of IK1-enhanced iPS-CMs include the absence of spontaneous beating, stable resting membrane potentials at approximately Ϫ80 mV and capability for electrical pacing. Compared with unenhanced, IK1-enhanced iPS-CMs calcium transient amplitudes were larger (P Ͻ 0.05) with a typical staircase pattern. IK1-enhanced iPS-CMs demonstrated a twofold increase in cell size and membrane capacitance and increased DNA synthesis compared with control iPS-CMs (P Ͻ 0.05). Furthermore, IK1-enhanced iPS-CMs expressing the F97C-CAV3 long QT9 mutation compared with wild-type CAV3 demonstrated an increase in AP duration and late sodium current. I K1-enhanced iPSCMs represent a more mature cardiomyocyte model to study arrhythmia mechanisms. arrhythmia; potassium ion channel; LQTS; iPS-CM NEW & NOTEWORTHY Ik1-enhanced induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) more closely represent the cell size, structure, multinucleation, electrophysiology, and calcium handling properties of adult human cardiomyocytes. These I K1-enhanced iPS-CMs will permit advanced studies of arrhythmia mechanisms such as rotor and reentry generation in plated iPS-CMs or drug safety testing due to the mature cellular phenotype.INDUCED PLURIPOTENT STEM (iPS) cells have opened new avenues to investigate many human diseases (33). Patient-specific iPSderived cardiomyocytes (iPS-CMs) have been used to investigate inherited arrhythmia syndromes such as long QT syndrome (LQTS) and catecholeminergic polymorphic ventricular tachycardia (9,21,31,34). These proof of concept studies have recapitulated some characteristic features of human disease (8, 23). However, despite advances in differentiation and culturing techniques, currently available iPS-CMs have several features of immature cardiomyocytes, which limit their application for modeling cellular arrhythmia mechanisms and inherited arrhythmic disease. The electrophysiological limitations occur predominately due to action potential (AP) diastolic properties including a relatively depolarized resting membrane potential and spontaneous automaticity due to a small inward rectifier (I K1 ) density and unopposed pacemaker current (I f ) (5, 18). In turn, this results in partial inactivation of ion channels such as the cardiac sodium channel to reduce current (I Na ) amplitude. Automaticity also interferes w...

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Section: Ik1-enhanced Induced Pluripotent Stem Cell-derived Cardiomyomentioning

confidence: 99%

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

Vaidyanathan

Markandeya

Kamp

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…[57][58][59] These reports confirmed that patient-specific iPS cells can give rise to differentiated CMCs that possess the main functional and morphological aberration typical of the disease in vivo.…”

Section: Reprogramming Strategies: a Peek At Disease Mechanisms Whilementioning

confidence: 56%

Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function

et al. 2012

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Engineered recombinant viral vectors are a powerful tool for vehiculating genetic information into mammalian cells. Because of their ability to infect both dividing and non-dividing cells with high efficiency, lentiviral vectors have gained particular interest for basic research and preclinical studies in the cardiovascular field. We review here the major applications for lentiviral-vector technology in the cardiovascular field: we will discuss their use in trailing gene expression during the induction of differentiation, in protocols for the isolation of cardiac cells and in the tracking of cardiac cells after transplantation in vivo; we will also describe lentivirally-mediated gene delivery uses, such as the induction of a phenotype of interest in a target cell or the treatment of cardiovascular diseases. In addition, a section of the review will be dedicated to reprogramming approaches, focusing attention on the generation of pluripotent stem cells and on transdifferentiation, two emerging strategies for the production of cardiac myocytes from human cells and for the investigation of human diseases. Finally, in order to give a perspective on their future clinical use we will critically discuss advantages and disadvantages of lentivirus-based strategies for the treatment of cardiovascular diseases.

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“…the slow I Ks , and the rapid I Kr components of the delayed rectifier potassium currents, the sodium current I Na , and the L‐type calcium current I CaL ) varying widely even among wild‐type control hiPSC‐CMs 55, 56. Most notably, very different levels of I Ks have been described (ranging from ~ 0.3 to ~ 2.5 pA/pF 5, 57), variable observation leading to controversial conclusions: on the one hand, I Ks recapitulates physiological behaviour in playing a major role when repolarisation reserve is attenuated 58, 59; on the other, it seems to contribute to repolarisation in hiPSC‐CMs even in the absence of sympathetic stimulation 5, 36, 60, 61. The immature phenotype of all stem cell derivatives including hiPSC‐CMs is probably the reason for this variability but, independent of the cause, it is a limitation to extrapolating results obtained using hiPSC‐CMs to native – healthy and diseased – adult human CMs as discussed below.…”

Section: Pathological Phenotypes and New Mechanistic Insightsmentioning

confidence: 99%

“…Inherited cardiovascular disorders and in particular channelopathies have been among the first human diseases studied using iPSCs 5, 6, 7, 8. Indeed, although animal models have been and continue to be essential in advancing the understanding of cardiovascular disease 9, 10, 11, interspecies differences hamper translation of many results directly to humans.…”

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confidence: 99%

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

Bellin

Mummery

2016

FEBS Letters

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Induced pluripotent stem cells (iPSCs) were first generated 10 years ago. Their ability to differentiate into any somatic cell type of the body including cardiomyocytes has already made them a valuable resource for modelling cardiac disease and drug screening. Initially human iPSCs were used mostly to model known disease phenotypes; more recently, and despite a number of recognised shortcomings, they have proven valuable in providing fundamental insights into the mechanisms of inherited heart disease with unknown genetic cause using surprisingly small cohorts. In this review, we summarise the progress made with human iPSCs as cardiac disease models with special focus on the latest mechanistic insights and related challenges. Furthermore, we suggest emerging solutions that will likely move the field forward.

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Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome

Cited by 1,132 publications

References 40 publications

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

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