iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development

Simons, Eline; Loeys, Bart; Alaerts, Maaike

doi:10.3390/biomedicines11020334

Cited by 4 publications

(2 citation statements)

References 129 publications

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“…These hiPSCs can be differentiated into cardiomyocytes (hiPSC-CMs), which can be examined within microphysiological systems, often referred to as organs on a chips 52 , 53 . Specifically, these systems hold considerable potential for detecting undesirable side effects of emerging drug compounds 54 – 56 .…”

Section: Discussionmentioning

confidence: 99%

The simplified Kirchhoff network model (SKNM): a cell-based reaction–diffusion model of excitable tissue

Jæger,

Tveito

2023

Sci Rep

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Cell-based models of excitable tissues offer the advantage of cell-level precision, which cannot be achieved using traditional homogenized electrophysiological models. However, this enhanced accuracy comes at the cost of increased computational demands, necessitating the development of efficient cell-based models. The widely-accepted bidomain model serves as the standard in computational cardiac electrophysiology, and under certain anisotropy ratio conditions, it is well known that it can be reduced to the simpler monodomain model. Recently, the Kirchhoff Network Model (KNM) was developed as a cell-based counterpart to the bidomain model. In this paper, we aim to demonstrate that KNM can be simplified using the same steps employed to derive the monodomain model from the bidomain model. We present the cell-based Simplified Kirchhoff Network Model (SKNM), which produces results closely aligned with those of KNM while requiring significantly less computational resources.

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Section: Discussionmentioning

confidence: 99%

The simplified Kirchhoff network model (SKNM): a cell-based reaction–diffusion model of excitable tissue

Jæger,

Tveito

2023

Sci Rep

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“…In addition, electrophysiological and transcriptomic studies have demonstrated that hiPSC-CMs express SK channels ( Zhao et al, 2018 ; Simons et al, 2023 ). However, the expression of SK channels in hiPSC-aCMs has not been studied.…”

Section: Hipsc-cms As a Model For The Study Of Sk Channel Risk Variantsmentioning

confidence: 99%

hiPSC-derived cardiomyocytes as a model to study the role of small-conductance Ca2+-activated K+ (SK) ion channel variants associated with atrial fibrillation

Babini,

Jiménez-Sábado,

Stogova

et al. 2024

Front. Cell Dev. Biol.

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Atrial fibrillation (AF), the most common arrhythmia, has been associated with different electrophysiological, molecular, and structural alterations in atrial cardiomyocytes. Therefore, more studies are required to elucidate the genetic and molecular basis of AF. Various genome-wide association studies (GWAS) have strongly associated different single nucleotide polymorphisms (SNPs) with AF. One of these GWAS identified the rs13376333 risk SNP as the most significant one from the 1q21 chromosomal region. The rs13376333 risk SNP is intronic to the KCNN3 gene that encodes for small conductance calcium-activated potassium channels type 3 (SK3). However, the functional electrophysiological effects of this variant are not known. SK channels represent a unique family of K+ channels, primarily regulated by cytosolic Ca2+ concentration, and different studies support their critical role in the regulation of atrial excitability and consequently in the development of arrhythmias like AF. Since different studies have shown that both upregulation and downregulation of SK3 channels can lead to arrhythmias by different mechanisms, an important goal is to elucidate whether the rs13376333 risk SNP is a gain-of-function (GoF) or a loss-of-function (LoF) variant. A better understanding of the functional consequences associated with these SNPs could influence clinical practice guidelines by improving genotype-based risk stratification and personalized treatment. Although research using native human atrial cardiomyocytes and animal models has provided useful insights, each model has its limitations. Therefore, there is a critical need to develop a human-derived model that represents human physiology more accurately than existing animal models. In this context, research with human induced pluripotent stem cells (hiPSC) and subsequent generation of cardiomyocytes derived from hiPSC (hiPSC-CMs) has revealed the underlying causes of various cardiovascular diseases and identified treatment opportunities that were not possible using in vitro or in vivo studies with animal models. Thus, the ability to generate atrial cardiomyocytes and atrial tissue derived from hiPSCs from human/patients with specific genetic diseases, incorporating novel genetic editing tools to generate isogenic controls and organelle-specific reporters, and 3D bioprinting of atrial tissue could be essential to study AF pathophysiological mechanisms. In this review, we will first give an overview of SK-channel function, its role in atrial fibrillation and outline pathophysiological mechanisms of KCNN3 risk SNPs. We will then highlight the advantages of using the hiPSC-CM model to investigate SNPs associated with AF, while addressing limitations and best practices for rigorous hiPSC studies.

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Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) for modeling cardiac arrhythmias: strengths, challenges and potential solutions

Joshi,

Albers,

Smole

et al. 2024

Front. Physiol.

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Ion channels and cytoskeletal proteins in the cardiac dyad play a critical role in maintaining excitation-contraction (E-C) coupling and provide cardiac homeostasis. Functional changes in these dyad proteins, whether induced by genetic, epigenetic, metabolic, therapeutic, or environmental factors, can disrupt normal cardiac electrophysiology, leading to abnormal E-C coupling and arrhythmias. Animal models and heterologous cell cultures provide platforms to elucidate the pathogenesis of arrhythmias for basic cardiac research; however, these traditional systems do not truly reflect human cardiac electro-pathophysiology. Notably, patients with the same genetic variants of inherited channelopathies (ICC) often exhibit incomplete penetrance and variable expressivity which underscores the need to establish patient-specific disease models to comprehend the mechanistic pathways of arrhythmias and determine personalized therapies. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) inherit the genetic background of the patient and reflect the electrophysiological characteristics of the native cardiomyocytes. Thus, iPSC-CMs provide an innovative and translational pivotal platform in cardiac disease modeling and therapeutic screening. In this review, we will examine how patient-specific iPSC-CMs historically evolved to model arrhythmia syndromes in a dish, and their utility in understanding the role of specific ion channels and their functional characteristics in causing arrhythmias. We will also examine how CRISPR/Cas9 have enabled the establishment of patient-independent and variant-induced iPSC-CMs-based arrhythmia models. Next, we will examine the limitations of using human iPSC-CMs with respect to in vitro arrhythmia modeling that stems from variations in iPSCs or toxicity due to gene editing on iPSC or iPSC-CMs and explore how such hurdles are being addressed. Importantly, we will also discuss how novel 3D iPSC-CM models can better capture in vitro characteristics and how all-optical platforms provide non-invasive and high- throughput electrophysiological data that is useful for stratification of emerging arrhythmogenic variants and drug discovery. Finally, we will examine strategies to improve iPSC-CM maturity, including powerful gene editing and optogenetic tools that can introduce/modify specific ion channels in iPSC-CMs and tailor cellular and functional characteristics. We anticipate that an elegant synergy of iPSCs, novel gene editing, 3D- culture models, and all-optical platforms will offer a high-throughput template to faithfully recapitulate in vitro arrhythmogenic events necessary for personalized arrhythmia monitoring and drug screening process.

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iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development

Cited by 4 publications

References 129 publications

The simplified Kirchhoff network model (SKNM): a cell-based reaction–diffusion model of excitable tissue

The simplified Kirchhoff network model (SKNM): a cell-based reaction–diffusion model of excitable tissue

hiPSC-derived cardiomyocytes as a model to study the role of small-conductance Ca2+-activated K+ (SK) ion channel variants associated with atrial fibrillation

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) for modeling cardiac arrhythmias: strengths, challenges and potential solutions

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