Cardiomyocytes Obtained From Induced Pluripotent Stem Cells With Long-QT Syndrome 3 Recapitulate Typical Disease-Specific Features In Vitro

Malan, Daniela; Friedrichs, Stephanie; Fleischmann, Bernd K.; Sasse, Philipp

doi:10.1161/circresaha.111.243139

Cited by 114 publications

(90 citation statements)

References 15 publications

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“…As others have reported, [21][22][23]32 we observed an increase in I Na in mPSC-CMs with prolonged culture, reaching a plateau at around day 17 of differentiation ( Figure IVA and IVB in the online-only Data Supplement). Therefore, only cardiomyocytes after 17 or 18 days of differentiation were analyzed further.…”

Section: Scn5a-het Mesc-cms and Mipsc-cms Displaysupporting

confidence: 84%

“…Several reports have already confirmed the ability of iPSC-CMs to model K ϩ , Ca 2ϩ , and Na ϩ gain-of-function mutations. 18,19,[32][33][34] Here, we demonstrate that cardiomyocytes derived from both ESCs and iPSCs can model a combined loss-and gain-offunction Na ϩ channel mutation that is conserved between humans and mice. 7 We chose to investigate this Scn5a mutation originally in mPSC-CMs for several reasons.…”

Section: Davis Et Al Disease Modeling With Psc Cardiomyocytes 3085mentioning

confidence: 75%

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Cardiomyocytes Derived From Pluripotent Stem Cells Recapitulate Electrophysiological Characteristics of an Overlap Syndrome of Cardiac Sodium Channel Disease

et al. 2012

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Background-Pluripotent stem cells (PSCs) offer a new paradigm for modeling genetic cardiac diseases, but it is unclear whether mouse and human PSCs can truly model both gain-and loss-of-function genetic disorders affecting the Na ϩ current (I Na ) because of the immaturity of the PSC-derived cardiomyocytes. To address this issue, we generated multiple PSC lines containing a Na ϩ channel mutation causing a cardiac Na ϩ channel overlap syndrome. Method and Results-Induced PSC (iPSC) lines were generated from mice carrying the Scn5a 1798insD/ϩ (Scn5a-het) mutation. These mouse iPSCs, along with wild-type mouse iPSCs, were compared with the targeted mouse embryonic stem cell line used to generate the mutant mice and with the wild-type mouse embryonic stem cell line. Patch-clamp experiments showed that the Scn5a-het cardiomyocytes had a significant decrease in I Na density and a larger persistent I Na compared with Scn5a-wt cardiomyocytes. Action potential measurements showed a reduced upstroke velocity and longer action potential duration in Scn5a-het myocytes. These characteristics recapitulated findings from primary cardiomyocytes isolated directly from adult Scn5a-het mice. Finally, iPSCs were generated from a patient with the equivalent SCN5A 1795insD/ϩ mutation. Patch-clamp measurements on the derivative cardiomyocytes revealed changes similar to those in the mouse PSC-derived cardiomyocytes. Conclusion-Here, we demonstrate that both embryonic stem cell-and iPSC-derived cardiomyocytes can recapitulate the characteristics of a combined gain-and loss-of-function Na ϩ channel mutation and that the electrophysiological immaturity of PSC-derived cardiomyocytes does not preclude their use as an accurate model for cardiac Na ϩ channel disease. (Circulation. 2012;125:3079-3091.) Key Words: cell differentiation Ⅲ disease models, animal Ⅲ electrophysiology Ⅲ sodium channels Ⅲ pluripotent stem cells M ultiple cardiac arrhythmia syndromes, including long-QT syndrome type 3 (LQT3), Brugada syndrome (BrS), progressive cardiac conduction disease, and sinus node dysfunction, have been linked to mutations in SCN5A, the gene encoding the ␣-subunit of the cardiac sodium (Na ϩ ) channel. 1,2 Most SCN5A mutations associated with LQT3 act by disrupting fast inactivation of the Na ϩ channel, resulting in a persistent inward Na ϩ current (I Na ) during the action potential (AP) plateau phase, subsequently delaying ventricular repolarization and prolonging the QT interval (gain-of-function mutations). 3 In contrast, SCN5A mutations underlying BrS and conduction disease are loss-of-function mutations and are believed to reduce the total amount of available I Na as a result of expression of nonfunctional channels, impaired intracellular trafficking, and decreased membrane surface channel expression or through altered channel gating properties. 1,2 Editorial see p 3055 Clinical Perspective on p 3091Initially, it was believed that these arrhythmia syndromes constituted separate clinical entities, with individual SCN5A Received September 9...

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Section: Scn5a-het Mesc-cms and Mipsc-cms Displaysupporting

confidence: 84%

Section: Davis Et Al Disease Modeling With Psc Cardiomyocytes 3085mentioning

confidence: 75%

Cardiomyocytes Derived From Pluripotent Stem Cells Recapitulate Electrophysiological Characteristics of an Overlap Syndrome of Cardiac Sodium Channel Disease

et al. 2012

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“…Differentiation protocols may also account for the development of cells at variable stage of maturation. Malan et al circumvent the problem of APD variability by studying the effect of pacing or drugs within a single cell in iPS-derived myocytes from genetically modified mice (26); this longitudinal approach could also be tested in human studies.…”

Section: Action Potential Morphologies In Ips-derived Myocytesmentioning

confidence: 99%

Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias

et al. 2013

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The discovery of the genetic basis of inherited arrhythmias has paved the way for an improved understanding of arrhythmogenesis in a wide spectrum of life-threatening conditions. In vitro expression of mutations and transgenic animal models have been instrumental in enhancing this understanding, but the applicability of results to the human heart remains unknown. The ability to differentiate induced pluripotent stem cells (iPSs) into cardiomyocytes enables the potential to generate patient-specific myocytes, which could be used to recapitulate the features of inherited arrhythmias in the context of the patient's genetic background. Few studies have been reported on iPS-derived myocytes obtained from patients with heritable arrhythmias, but they have demonstrated the applicability of this innovative approach to the study of inherited arrhythmias. Here we review the results achieved by iPS investigations in arrhythmogenic syndromes and discuss the existing challenges to be addressed before the use of iPS-derived myocytes can become a part of personalized management of inherited arrhythmias.

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“…using patient-specific iPS cells, refined methods of differentiating and isolating cells for target tissue is indispensable. Although recently there has been a great deal of research into patient-specific iPS cells [39][40][41][42][43][44][45][46][47][48][49][50][51][52], research into their use in the vasculature and endocrine organs is still rare [53]. We are now investigating the pathogenesis of several inherited vascular disorders with collaborators.…”

Section: Acknowledgementmentioning

confidence: 99%

Vascular research using human pluripotent stem cells and humoral factors [Review]

Sone

Nakao

2013

Endocr J

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Abstract. Embryonic stem (ES) cells are pluripotent cells collected from the inner cell mass of blastocysts. Induced pluripotent stem cells exhibit characteristics and pluripotency similar to ES cells, even though they were generated from adult somatic cells. We have been investigating the vascular differentiation kinetics of human pluripotent stem cells (PSCs) and their application to human vascular research and clinical medicine. In this review, we present an overview of recent vascular research using human PSCs, focusing on the role of humoral factors and their receptors. We also discuss possible future application of human PSCs to translational research on human vascular disorders.

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Cardiomyocytes Obtained From Induced Pluripotent Stem Cells With Long-QT Syndrome 3 Recapitulate Typical Disease-Specific Features In Vitro

Cited by 114 publications

References 15 publications

Cardiomyocytes Derived From Pluripotent Stem Cells Recapitulate Electrophysiological Characteristics of an Overlap Syndrome of Cardiac Sodium Channel Disease

Cardiomyocytes Derived From Pluripotent Stem Cells Recapitulate Electrophysiological Characteristics of an Overlap Syndrome of Cardiac Sodium Channel Disease

Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias

Vascular research using human pluripotent stem cells and humoral factors [Review]

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