Atrial-like Engineered Heart Tissue: An In Vitro Model of the Human Atrium

Lemme, Marta; Ulmer, Bärbel; Lemoine, Marc D.; Zech, Antonia T.L.; Flenner, Frederik; Ravens, Ursula; Reichenspurner, Hermann; Rol-Garcia, Miriam; Smith, Godfrey L.; Hansen, Arne; Christ, Torsten; Eschenhagen, Thomas

doi:10.1016/j.stemcr.2018.10.008

Cited by 122 publications

(134 citation statements)

References 67 publications

(104 reference statements)

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“…Furthermore, FHL1 knockdown promoted a shift toward larger values of AP amplitude and V max in the atrial-skewed clones, also consistent with the cells adopting more ventricular-like electrophysiology ( Supplementary Fig. S9) [11,13,40].…”

Section: Influence Of Fhl1 Expression On Atrial-associated Hipsc-cm Psupporting

confidence: 70%

Single-Cell RNA-Sequencing and Optical Electrophysiology of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Discordance Between Cardiac Subtype-Associated Gene Expression Patterns and Electrophysiological Phenotypes

Biendarra-Tiegs

et al. 2019

Stem Cells and Development

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The ability to accurately phenotype cells differentiated from human induced pluripotent stem cells (hiPSCs) is essential for their application in modeling developmental and disease processes, yet also poses a particular challenge without the context of anatomical location. Our specific objective was to determine if single-cell gene expression was sufficient to predict the electrophysiology of iPSC-derived cardiac lineages, to evaluate the concordance between molecular and functional surrogate markers. To this end, we used the genetically encoded voltage indicator ArcLight to profile hundreds of hiPSC-derived cardiomyocytes (hiPSC-CMs), thus identifying patterns of electrophysiological maturation and increased prevalence of cells with atrial-like action potentials (APs) between days 11 and 42 of differentiation. To profile expression patterns of cardiomyocyte subtypeassociated genes, single-cell RNA-seq was performed at days 12 and 40 after the populations were fully characterized with the high-throughput ArcLight platform. Although we could detect global gene expression changes supporting progressive differentiation, individual cellular expression patterns alone were not able to delineate the individual cardiomyocytes into atrial, ventricular, or nodal subtypes as functionally documented by electrophysiology measurements. Furthermore, our efforts to understand the distinct electrophysiological properties associated with day 12 versus day 40 hiPSC-CMs revealed that ion channel regulators SLMAP, FGF12, and FHL1 were the most significantly increased genes at day 40, categorized by electrophysiologyrelated gene functions. Notably, FHL1 knockdown during differentiation was sufficient to significantly modulate APs toward ventricular-like electrophysiology. Thus, our results establish the inability of subtypeassociated gene expression patterns to specifically categorize hiPSC-derived cells according to their functional electrophysiology, and yet, altered FHL1 expression is able to redirect electrophysiological maturation of these developing cells. Therefore, noncanonical gene expression patterns of cardiac maturation may be sufficient to direct functional maturation of cardiomyocytes, with canonical gene expression patterns being insufficient to temporally define cardiac subtypes of in vitro differentiation.

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Section: Influence Of Fhl1 Expression On Atrial-associated Hipsc-cm Psupporting

confidence: 70%

Single-Cell RNA-Sequencing and Optical Electrophysiology of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Discordance Between Cardiac Subtype-Associated Gene Expression Patterns and Electrophysiological Phenotypes

Biendarra-Tiegs

et al. 2019

Stem Cells and Development

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“…In some APs the notch was followed by a peculiar oscillation during plateau phase of the AP. This peculiarity of notch/oscillation was only observed in some of independent differentiation batches of the C25 cell line, but never in any other of three in-house cell lines or five commercial cell lines investigated with sharp microelectrodes as previously described [5,9,[27][28][29][30]. When the notch/oscillation was detected in one EHT, all impalements showed this peculiarity including all EHTs from this differentiation batch.…”

Section: Action Potentials With Strong Initial Repolarization and Oscsupporting

confidence: 50%

Case Report on: Very Early Afterdepolarizations in HiPSC-Cardiomyocytes—An Artifact by Big Conductance Calcium Activated Potassium Current (Ibk,Ca)

Horváth

Christ

Koivumäki

et al. 2020

Cells

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Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent an unlimited source of human CMs that could be a standard tool in drug research. However, there is concern whether hiPSC-CMs express all cardiac ion channels at physiological level and whether they might express non-cardiac ion channels. In a control hiPSC line, we found large, “noisy” outward K+ currents, when we measured outward potassium currents in isolated hiPSC-CMs. Currents were sensitive to iberiotoxin, the selective blocker of big conductance Ca2+-activated K+ current (IBK,Ca). Seven of 16 individual differentiation batches showed a strong initial repolarization in the action potentials (AP) recorded from engineered heart tissue (EHT) followed by very early afterdepolarizations, sometimes even with consecutive oscillations. Iberiotoxin stopped oscillations and normalized AP shape, but had no effect in other EHTs without oscillations or in human left ventricular tissue (LV). Expression levels of the alpha-subunit (KCa1.1) of the BKCa correlated with the presence of oscillations in hiPSC-CMs and was not detectable in LV. Taken together, individual batches of hiPSC-CMs can express sarcolemmal ion channels that are otherwise not found in the human heart, resulting in oscillating afterdepolarizations in the AP. HiPSC-CMs should be screened for expression of non-cardiac ion channels before being applied to drug research.

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“…Human PSCs also remain a highly attractive cells source for personalized medicine applications due to the ease with which their genomes can be modified using state-of-the art genome editing technologies (167)(168)(169) allowing (i) the introduction of disease-associated genetic variants in PSCs of a healthy individual and (ii) 'genetic curing' of patient-derived PSCs (154,170,171). Of the various approaches to improve PSCbased arrhythmia models, the engineering of 3D cardiac tissue constructs including heart-on-a-chip devices is of particular interest as this will allow assessment of cardiac electrical activity in a more realistic setting than can be provided by 2D CM monocultures (165,(172)(173)(174). This is nicely illustrated by a recent study of Goldfracht et al, who generated ring-shaped atrial and ventricular EHTs from hESCs showing heart chamber-specific differences in gene expression, electrophysiology, contractile properties and pharmacology (175).…”

Section: (Human) Psc-derived Atrial(-like) Cmsmentioning

confidence: 99%

Multicellular In vitro Models of Cardiac Arrhythmias: Focus on Atrial Fibrillation

Gorp

Trines

Pijnappels

et al. 2020

Front. Cardiovasc. Med.

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Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice with a large socioeconomic impact due to its associated morbidity, mortality, reduction in quality of life and health care costs. Currently, antiarrhythmic drug therapy is the first line of treatment for most symptomatic AF patients, despite its limited efficacy, the risk of inducing potentially life-threating ventricular tachyarrhythmias as well as other side effects. Alternative, in-hospital treatment modalities consisting of electrical cardioversion and invasive catheter ablation improve patients' symptoms, but often have to be repeated and are still associated with serious complications and only suitable for specific subgroups of AF patients. The development and progression of AF generally results from the interplay of multiple disease pathways and is accompanied by structural and functional (e.g., electrical) tissue remodeling. Rational development of novel treatment modalities for AF, with its many different etiologies, requires a comprehensive insight into the complex pathophysiological mechanisms. Monolayers of atrial cells represent a simplified surrogate of atrial tissue well-suited to investigate atrial arrhythmia mechanisms, since they can easily be used in a standardized, systematic and controllable manner to study the role of specific pathways and processes in the genesis, perpetuation and termination of atrial arrhythmias. In this review, we provide an overview of the currently available two-and three-dimensional multicellular in vitro systems for investigating the initiation, maintenance and termination of atrial arrhythmias and AF. This encompasses cultures of primary (animal-derived) atrial cardiomyocytes (CMs), pluripotent stem cell-derived atrial-like CMs and (conditionally) immortalized atrial CMs. The strengths and weaknesses of each of these model systems for studying atrial arrhythmias will be discussed as well as their implications for future studies.

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Atrial-like Engineered Heart Tissue: An In Vitro Model of the Human Atrium

Cited by 122 publications

References 67 publications

Single-Cell RNA-Sequencing and Optical Electrophysiology of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Discordance Between Cardiac Subtype-Associated Gene Expression Patterns and Electrophysiological Phenotypes

Single-Cell RNA-Sequencing and Optical Electrophysiology of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Discordance Between Cardiac Subtype-Associated Gene Expression Patterns and Electrophysiological Phenotypes

Case Report on: Very Early Afterdepolarizations in HiPSC-Cardiomyocytes—An Artifact by Big Conductance Calcium Activated Potassium Current (Ibk,Ca)

Multicellular In vitro Models of Cardiac Arrhythmias: Focus on Atrial Fibrillation

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