Current status of drug screening and disease modelling in human pluripotent stem cells

Rajamohan, Divya; Matsa, Elena; Kalra, Spandan; Crutchley, James; Patel, Asha K.; George, Vinoj; Denning, Chris

doi:10.1002/bies.201200053

Cited by 88 publications

(81 citation statements)

References 164 publications

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“…3 B and C show typical APs and average AP properties, respectively, measured at 1 Hz. AP duration at 20, 50, and 90% repolarization (APD 20 , APD 50 , and APD 90 , respectively) in JLNS 478-2T/T -CMs were significantly increased compared with wt1 and heterozygous controls. In addition, AP amplitude (APA) and plateau amplitude (PlaA) were significantly increased in JLNS 478-2T/T -CMs.…”

Section: Resultsmentioning

confidence: 90%

Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: Disease mechanisms and pharmacological rescue

Zhang

D’Aniello²,

Verkerk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

163

161

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Jervell and Lange-Nielsen syndrome (JLNS) is one of the most severe life-threatening cardiac arrhythmias. Patients display delayed cardiac repolarization, associated high risk of sudden death due to ventricular tachycardia, and congenital bilateral deafness. In contrast to the autosomal dominant forms of long QT syndrome, JLNS is a recessive trait, resulting from homozygous (or compound heterozygous) mutations in KCNQ1 or KCNE1. These genes encode the α and β subunits, respectively, of the ion channel conducting the slow component of the delayed rectifier K + current, I Ks . We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1. Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of I Ks . We show that this phenotype had distinct underlying molecular mechanisms in the two sets of cell lines: the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane. Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS-CMs. Furthermore, sensitivity to proarrhythmic drugs was strongly enhanced in JLNSCMs but could be pharmacologically corrected. Our data provide mechanistic insight into distinct classes of JLNS-causing mutations and demonstrate the potential of hiPSC-CMs in drug evaluation.Jervell and Lange-Nielsen syndrome | long QT syndrome | human induced pluripotent stem cells | disease modeling | KCNQ1

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Section: Resultsmentioning

confidence: 90%

Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: Disease mechanisms and pharmacological rescue

Zhang

D’Aniello²,

Verkerk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

163

161

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“…Obviously, experiments in human cells and in 3D do not solve all problems of cell culture work, including dependence on numerous and only partially controlled culture conditions, reproducibility, and robustness. 70 However, good evidence suggests that cardiac myocytes in a 3D cardiac tissue reach a higher degree of maturation so that 3D tissues are more stable than 2D cultures and allow higher content readouts and automation. The upcoming chapter discusses the current state and direction of further development.…”

Section: Heart Tissue As An Advanced In Vitro Model Promisesmentioning

confidence: 99%

Cardiac Tissue Engineering

Hirt

Hansen

Eschenhagen

2014

Circulation Research

358

294

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Abstract:The engineering of 3-dimensional (3D) heart muscles has undergone exciting progress for the past decade.Profound advances in human stem cell biology and technology, tissue engineering and material sciences, as well as prevascularization and in vitro assay technologies make the first clinical application of engineered cardiac tissues a realistic option and predict that cardiac tissue engineering techniques will find widespread use in the preclinical research and drug development in the near future. Tasks that need to be solved for this purpose include standardization of human myocyte production protocols, establishment of simple methods for the in vitro vascularization of 3D constructs and better maturation of myocytes, and, finally, thorough definition of the predictive value of these methods for preclinical safety pharmacology. The present article gives an overview of the present state of the art, bottlenecks, and perspectives of cardiac tissue engineering for cardiac repair and in vitro testing. ( Jeffrey Robbins, EditorOriginal received May 24, 2013; revision received July 12, 2013; accepted July 15, 2013. In November 2013, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.6 days.From the Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.Correspondence to Thomas Eschenhagen, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. E-mail t.eschenhagen@uke.de by guest on May 9, 2018 http://circres.ahajournals.org/ Downloaded from Hirt et al Cardiac Tissue Engineering 355gyratory shaking of embryonic chicken cardiac myocytes in an Erlenmeyer flask induced the formation of spontaneously beating spheroids with improved functionality when compared with standard 2D-cultured myocytes. This selfassembly is still used in variations to generate cardiac microspheres. 5 Current cardiac tissue engineering methods embark on this endogenous capacity and use engineering techniques to make 3D constructs of the desired size, geometry, and orientation (Table). Hydrogel TechniqueThe hydrogel method has been pioneered in the 1980s as an advanced culture method for fibroblasts and skeletal muscle cells 6 and gave rise to the first successful cardiac tissue.7 It needs 3 factors: solutions of gelling natural products, such as collagen I, matrigel, fibrin, or mixtures of them; casting molds; and anchoring constructs. The hydrogel entraps cells in a 3D space during gelling, the mold gives the 3D form, and the anchors allow the growing tissue to fix and to develop mechanical tension between ≥2 anchor points. Important aspects of this technique are that the naturally occurring hydrogels stimulate cells to spread and form intercellular connections and that the cells compress the gel, reduce the w...

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“…The concept of in vitro replication of human disease phenotypes in specialized cells derived from patientspecific iPS cells already has gained at least partial validation for a number of neurologic, hematopoietic, cardiovascular, and metabolic disorders (Unternaehrer and Daley, 2011;Ebert et al, 2012;Maury et al, 2012;Rajamohan et al, 2013). Examples of specific conditions for which patient-specific iPS cells have been obtained and differentiated into disease-relevant cell types include Parkinson's disease (Byers et al, 2012;Jang et al, 2012) and other neurodegenerative disorders Jung et al, 2012), Wilson's disease (Yi et al, 2012), lysosomal storage disorders (Huang et al, 2012b), and diabetes (Fujikura et al, 2012).…”

Section: Disease Models From Patient-specific Reprogrammed Cellsmentioning

confidence: 99%