Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients

Zwi‐Dantsis, Limor; Huber, Irit; Habib, Manhal; Winterstern, Aaron; Gepstein, Amira; Arbel, Gil; Gepstein, Lior

doi:10.1093/eurheartj/ehs096

Cited by 69 publications

(51 citation statements)

References 31 publications

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“…This approach allows reprogramming of patient-specific somatic cells into pluripotent stem cells that can be coaxed to differentiate into several cell types including cardiomyocytes. 7,8 In the cardiac field, hiPSCs were established from healthy individuals and from patients inflicted with acquired 9 and several types of inherited cardiac disorders. 10,11 Patient-specific hiPSC-derived cardiomyocyte (hiPSC-CM) models of different inherited arrhythmogenic syndromes (including the long-QT, [12][13][14][15] Brugada, 16 and sodium channel overlap 17 syndromes; arrhythmogenic right ventricular cardiomyopathy 18,19 ; and both types of CPVT [20][21][22][23][24][25][26][27][28][29] ) were…”

Section: See Editorial By LI Et Almentioning

confidence: 99%

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Maizels

Huber

Arbel

et al. 2017

Circ: Arrhythmia and Electrophysiology

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Background-Catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) results from autosomal recessive CASQ2 mutations, causing abnormal Ca 2+ -handling and malignant ventricular arrhythmias. We aimed to establish a patient-specific human induced pluripotent stem cell (hiPSC) model of CPVT2 and to use the generated hiPSC-derived cardiomyocytes to gain insights into patient-specific disease mechanism and pharmacotherapy. Methods and Results-hiPSC cardiomyocytes were derived from a CPVT2 patient (D307H-CASQ2 mutation) and from healthy controls. Laser-confocal Ca 2+ and voltage imaging showed significant Ca 2+ -transient irregularities, marked arrhythmogenicity manifested by early afterdepolarizations and triggered arrhythmias, and reduced threshold for store overload-induced Ca 2+ -release events in the CPVT2-hiPSC cardiomyocytes when compared with healthy control cells. Pharmacological studies revealed the prevention of adrenergic-induced arrhythmias by β-blockers (propranolol and carvedilol), flecainide, and the neuronal sodium-channel blocker riluzole; a direct antiarrhythmic action of carvedilol (independent of its α/β-adrenergic blocking activity), flecainide, and riluzole; and suppression of abnormal Ca 2+ cycling by the ryanodine stabilizer JTV-519 and carvedilol. Mechanistic insights were gained on the different antiarrhythmic actions of the aforementioned drugs, with carvedilol and JTV-519 (but not flecainide or riluzole) acting primarily through sarcoplasmic reticulum stabilization. Finally, comparable outcomes were found between flecainide and labetalol antiarrhythmic effects in vitro and the clinical results in the same patient.Conclusions-These results demonstrate the ability of hiPSCs cardiomyocytes to recapitulate CPVT2 disease phenotype and drug response in the culture dish, to provide novel insights into disease and drug therapy mechanisms, and potentially to tailor patient-specific drug therapy. (Circ Arrhythm Electrophysiol. 2017;10:e004725.

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Section: See Editorial By LI Et Almentioning

confidence: 99%

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Maizels

Huber

Arbel

et al. 2017

Circ: Arrhythmia and Electrophysiology

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“…17 Briefly, undifferentiated hiPSCs were dispersed into small cell clumps using collagenase IV (300 U/mL for 45 minutes; Life Technologies) and cultivated in suspension for 10 days as EBs. The EBs were plated on 0.1% gelatin-coated culture dishes.…”

Section: Establishment and CM Differentiation Of The Arvc-hipscsmentioning

confidence: 99%

Modeling of Arrhythmogenic Right Ventricular Cardiomyopathy With Human Induced Pluripotent Stem Cells

Caspi

Huber

Gepstein

et al. 2013

Circ Cardiovasc Genet

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dilated and hypertrophic cardiomyopathies, 13,14 and cathecolaminergic polymorphic ventricular tachycardia. 15 In the current study, we aimed to use the emerging hiPSC technology to establish an in vitro model of ARVC. We Background-Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder resulting from desmosomal protein mutations. ARVC is characterized pathologically by fibrofatty infiltration and clinically by arrhythmias and sudden cardiac death. We aimed to establish a patient-/disease-specific human induced pluripotent stem cell (hiPSC) model of ARVC. Methods and Results-Dermal fibroblasts were obtained from 2 patients with ARVC with plakophilin-2 (PKP2) mutations, reprogrammed to generate hiPSCs, coaxed to differentiate into cardiomyocytes (CMs), and then compared with healthy control hiPSC-derived CMs (hiPSC-CMs). Real-time polymerase chain reaction showed a significant decrease in the expression of PKP2 in the ARVC-hiPSC-CMs. Immunostainings revealed reduced densities of PKP2, the associated desmosomal protein plakoglobin, and the gap-junction protein connexin-43. Electrophysiological assessment demonstrated prolonged field potential rise time in the ARVC-hiPSC-CMs. Transmission electron microscopy identified widened and distorted desmosomes in the ARVC-hiPSC-CMs. Clusters of lipid droplets were identified in the ARVC-CMs that displayed the more severe desmosomal pathology. This finding was associated with upregulation of the proadipogenic transcription factor peroxisome proliferator-activated receptor-γ. Exposure of the cells to apidogenic stimuli augmented desmosomal distortion and lipid accumulation. The latter phenomenon was prevented by application of a specific inhibitor of glycogen synthase kinase 3β (6-bromoindirubin-3'-oxime). Conclusions-This study highlights the unique potential of the hiPSC technology for modeling inherited cardiac disorders in general and ARVC specifically. The hiPSC-CMs were demonstrated to recapitulate the ARVC phenotype in the dish, provide mechanistic insights into early disease pathogenesis, and provide a unique platform for drug discovery and testing in this disorder.

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“…Zwi-Dantsis et al 2012 created iPSC lines from the dermal fibroblasts of two male (51 and 61 y/o) ischemic cardiomyopathy patients with advanced heart failure 43 . Authors found that these heart failure iPSC lines differentiated in EBs to form cardiomyocytes that coupled electrically and mechanically with rat ventricular myocytes in vitro and in vivo .…”

Section: Application Of Ipsc Technology For Cardiac Repairmentioning

confidence: 99%

“…Importantly, authors report no significant difference between iPSCs derived from these heart failure patients and control iPSCs derived from a healthy individual’s foreskin fibroblasts. Authors reason that patient-specific iPSCs could serve as a source of cardiomyocytes for cell-replacement therapy because the patients’ heart failure was acquired and does not aversely affect the genotypic qualities of the iPSCs 43 . It is important to note, however, that higher propensities for heart disease associated with family history will still translate to these patient-specific iPSCs.…”

Section: Application Of Ipsc Technology For Cardiac Repairmentioning

confidence: 99%

Advancements in Induced Pluripotent Stem Cell Technology for Cardiac Regenerative Medicine

Suh

Wang

Bartulos

et al. 2014

J Cardiovasc Pharmacol Ther

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Cardiovascular diseases remain the leading causes of morbidity and mortality in the developed world. Cellular based cardiac regenerative therapy serves as a potential approach to treating cardiovascular diseases. Although various cellular types have been tested, induced pluripotent stem cells are regarded as a promising cell source for therapy. In this review, we will highlight some of the advances in generating induced pluripotent stem cells and differentiation to cardiac cells. We will also discuss the progress in modeling cardiovascular diseases using induced pluripotent stem cell derived cardiac cells. As we continue to make progress in induced pluripotent stem cell and cardiac differentiation technology, we will become closer to application of cardiac regenerative medicine.

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Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients

Cited by 69 publications

References 31 publications

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

Modeling of Arrhythmogenic Right Ventricular Cardiomyopathy With Human Induced Pluripotent Stem Cells

Advancements in Induced Pluripotent Stem Cell Technology for Cardiac Regenerative Medicine

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