Membrane remodelling triggers maturation of excitation–contraction coupling in 3D-shaped human-induced pluripotent stem cell-derived cardiomyocytes

Kermani, Fatemeh; Mosqueira, Matías; Peters, Kyra; Lemma, Enrico Domenico; Rapti, Kleopatra; Grimm, Dirk; Bastmeyer, Martin; Laugsch, Magdalena; Hecker, Markus; Ullrich, Nina D.

doi:10.1007/s00395-023-00984-5

Cited by 4 publications

(2 citation statements)

References 64 publications

(80 reference statements)

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“…The capacity for Ca 2+ handling and storage in immature hiPSC-CMs is present but relatively incomplete, owing to the absence of well-developed T-tubule networks and lower expression of important Ca 2+ -related proteins such as RyR2, SERCA, and calsequestrin (CASQ2) ( Kermani et al, 2023 ). This aspect is important to consider when investigating SK currents, which are present in hiPSC-CMs ( Zhao et al, 2018 ), given their spatiotemporal relationship with Ca 2+ sources for activation.…”

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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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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“…Cell culture has been used for decades to study cellular functions in a defined and reproducible setting. More recently, more complex approaches for assessing heterocellular interactions ex vivo have been developed, ranging from multi-cell type and spatially structured co-cultures and 3D organoids to printed cell and ECM scaffolds or ‘heart-on-a-chip’ systems [ 31 , 87 , 119 , 124 ]. While 3D organoids largely rely on the self-assembly of stem cells into spheroids, 3D printed cell assemblies are typically built from defined mixtures of cardiac cell types and exogenous extracellular matrix [ 124 ].…”

Section: Implications…mentioning

confidence: 99%

The heterocellular heart: identities, interactions, and implications for cardiology

Lother¹,

Kohl²

2023

Basic Res Cardiol

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The heterocellular nature of the heart has been receiving increasing attention in recent years. In addition to cardiomyocytes as the prototypical cell type of the heart, non-myocytes such as endothelial cells, fibroblasts, or immune cells are coming more into focus. The rise of single-cell sequencing technologies enables identification of ever more subtle differences and has reignited the question of what defines a cell’s identity. Here we provide an overview of the major cardiac cell types, describe their roles in homeostasis, and outline recent findings on non-canonical functions that may be of relevance for cardiology. We highlight modes of biochemical and biophysical interactions between different cardiac cell types and discuss the potential implications of the heterocellular nature of the heart for basic research and therapeutic interventions.

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Printed Electronic Devices and Systems for Interfacing with Single Cells up to Organoids

Saghafi,

Vasantham,

Hussain

et al. 2023

Adv Funct Materials

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The field of bioelectronics with the aim to contact cells, cell clusters, biological tissues and organoids has become a vast enterprise. Currently, it is mainly relying on classical micro‐ and nanofabrication methods to build devices and systems. Very recently the field is highly pushed by the development of novel printable organic, inorganic and biomaterials as well as advanced digital printing technologies such as laser and inkjet printing employed in this endeavor. Recent advantages in alternative additive manufacturing and 3D printing methods enable interesting new routes, in particular for applications requiring the incorporation of delicate biomaterials or creation of 3D scaffold structures that show a high potential for bioelectronics and building of hybrid bio‐/inorganic devices. Here the current state of printed 2D and 3D electronic structures and related lithography techniques for the interfacing of electronic devices with biological systems are reviewed. The focus lies on in vitro applications for interfacing single cell, cell clusters, and organoids. Challenges and future prospects are discussed for all‐printed hybrid bio/electronic systems targeting biomedical research, diagnostics, and health monitoring.

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Membrane remodelling triggers maturation of excitation–contraction coupling in 3D-shaped human-induced pluripotent stem cell-derived cardiomyocytes

Cited by 4 publications

References 64 publications

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

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

The heterocellular heart: identities, interactions, and implications for cardiology

Printed Electronic Devices and Systems for Interfacing with Single Cells up to Organoids

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