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The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes
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The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 23577

Special Issue Editor

Prof. Dr. Ofer Binah

E-Mail Website
Guest Editor
Department of Physiology, Biophysics and System Biology, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Interests: modeling inherited cardiac pathologies by means of patients’ iPSC-derived cardiomyocyte
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Until the late 2000s, researchers worldwide utilized freshly isolated or cultured animal-derived cardiomyocytes to investigate a broad range of topics, such as excitation–contraction coupling (ECC) machinery, effects of stress conditions (e.g., hypertrophy, hypoxia), bioenergetics and metabolism, and drug toxicity. Inasmuch as these numerous studies yielded comprehensive understanding of cardiac cellular function, due to major differences between human and animal cardiomyocytes, the latter do not faithfully recapitulate human cardiac features, such as electrophysiology and drug responsiveness.

The area of the cardiac research (as well as other areas) was revolutionized by the novel discovery in 1998 by Thomson, Itskovitz and co-workers, that pluripotent embryonic stem cells (ESCs) can be derived from the inner cell mass of human blastocytes. Shortly thereafter, in 2006–2007, the scientific world was astounded by a second revolution led by Takahashi and Yamanaka, who discovered that induced pluripotent stem cells (iPSC) can be generated by introducing four transcription factors into fully differentiated somatic cells. Like ESC, iPSC can give rise to all three germ layers and thus can be differentiated to a variety of cell types such as neurons, skeletal muscle cells, and cardiomyocytes (iPSC-CMs).

The issue entitled “The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes” will include both review and original research papers covering key topics related to iPSC-CMs, such as: (1) excitation–contraction coupling (ECC) machinery of immature iPSC-CM; (2) the means to cause maturation of immature iPSC-CM; (3) modeling acquired and inherited cardiac diseases; (4) developing novel drugs for cardiac diseases; (5) investigating mechanisms of automaticity, propagation and activation; (6) testing potential toxicity of approved drugs and new chemical entities (NCE); and (7) using iPSC-CM for cardiac muscle regeneration. We are hopeful that our readers coming from diverse disciplines will benefit from this issue, serving as the gate to the amazing world of induced pluripotent stem cells.

Prof. Dr. Ofer Binah
Guest Editor

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Keywords

  • Reprogramming somatic cells
  • Induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CM)
  • Cardiomyocytes
  • Excitation-contraction-coupling (ECC)
  • Maturation of iPSC-CM
  • Modeling acquired and inherited cardiac diseases
  • Testing drug toxicity
  • Developing novel drugs for cardiac diseases
  • iPSC-CM for cardiac regeneration

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Published Papers (7 papers)

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Research

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25 pages, 3786 KiB  
Article
Electrophysiological Properties of Tetraploid Cardiomyocytes Derived from Murine Pluripotent Stem Cells Generated by Fusion of Adult Somatic Cells with Embryonic Stem Cells
by Guoxing Xu, Azra Fatima, Martin Breitbach, Alexey Kuzmenkin, Christopher J. Fügemann, Dina Ivanyuk, Kee Pyo Kim, Tobias Cantz, Kurt Pfannkuche, Hans R. Schöler, Bernd K. Fleischmann, Jürgen Hescheler and Tomo Šarić
Int. J. Mol. Sci. 2023, 24(7), 6546; https://doi.org/10.3390/ijms24076546 - 31 Mar 2023
Cited by 1 | Viewed by 2035
Abstract
Most cardiomyocytes (CMs) in the adult mammalian heart are either binucleated or contain a single polyploid nucleus. Recent studies have shown that polyploidy in CMs plays an important role as an adaptive response to physiological demands and environmental stress and correlates with poor [...] Read more.
Most cardiomyocytes (CMs) in the adult mammalian heart are either binucleated or contain a single polyploid nucleus. Recent studies have shown that polyploidy in CMs plays an important role as an adaptive response to physiological demands and environmental stress and correlates with poor cardiac regenerative ability after injury. However, knowledge about the functional properties of polyploid CMs is limited. In this study, we generated tetraploid pluripotent stem cells (PSCs) by fusion of murine embryonic stem cells (ESCs) and somatic cells isolated from bone marrow or spleen and performed a comparative analysis of the electrophysiological properties of tetraploid fusion-derived PSCs and diploid ESC-derived CMs. Fusion-derived PSCs exhibited characteristics of genuine ESCs and contained a near-tetraploid genome. Ploidy features and marker expression were also retained during the differentiation of fusion-derived cells. Fusion-derived PSCs gave rise to CMs, which were similar to their diploid ESC counterparts in terms of their expression of typical cardiospecific markers, sarcomeric organization, action potential parameters, response to pharmacologic stimulation with various drugs, and expression of functional ion channels. These results suggest that the state of ploidy does not significantly affect the structural and electrophysiological properties of murine PSC-derived CMs. These results extend our knowledge of the functional properties of polyploid CMs and contribute to a better understanding of their biological role in the adult heart. Full article
(This article belongs to the Special Issue The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes)
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20 pages, 1923 KiB  
Article
shRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele
by Lucía Cócera-Ortega, Ronald Wilders, Selina C. Kamps, Benedetta Fabrizi, Irit Huber, Ingeborg van der Made, Anouk van den Bout, Dylan K. de Vries, Lior Gepstein, Arie O. Verkerk, Yigal M. Pinto and Anke J. Tijsen
Int. J. Mol. Sci. 2022, 23(7), 4053; https://doi.org/10.3390/ijms23074053 - 6 Apr 2022
Cited by 2 | Viewed by 3531
Abstract
Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1. Patients heterozygous for such a mutation co-assemble both mutant and wild-type KCNQ1-encoded subunits into tetrameric Kv7.1 potassium channels. Here, we investigated whether allele-specific inhibition of mutant KCNQ1 by targeting a [...] Read more.
Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1. Patients heterozygous for such a mutation co-assemble both mutant and wild-type KCNQ1-encoded subunits into tetrameric Kv7.1 potassium channels. Here, we investigated whether allele-specific inhibition of mutant KCNQ1 by targeting a common variant can shift the balance towards increased incorporation of the wild-type allele to alleviate the disease in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We identified the single nucleotide polymorphisms (SNP) rs1057128 (G/A) in KCNQ1, with a heterozygosity of 27% in the European population. Next, we determined allele-specificity of short-hairpin RNAs (shRNAs) targeting either allele of this SNP in hiPSC-CMs that carry an LQT1 mutation. Our shRNAs downregulated 60% of the A allele and 40% of the G allele without affecting the non-targeted allele. Suppression of the mutant KCNQ1 allele by 60% decreased the occurrence of arrhythmic events in hiPSC-CMs measured by a voltage-sensitive reporter, while suppression of the wild-type allele increased the occurrence of arrhythmic events. Furthermore, computer simulations based on another LQT1 mutation revealed that 60% suppression of the mutant KCNQ1 allele shortens the prolonged action potential in an adult cardiomyocyte model. We conclude that allele-specific inhibition of a mutant KCNQ1 allele by targeting a common variant may alleviate the disease. This novel approach avoids the need to design shRNAs to target every single mutation and opens up the exciting possibility of treating multiple LQT1-causing mutations with only two shRNAs. Full article
(This article belongs to the Special Issue The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes)
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13 pages, 2491 KiB  
Article
The Effect of Sera from Children with Obstructive Sleep Apnea Syndrome (OSAS) on Human Cardiomyocytes Differentiated from Human Embryonic Stem Cells
by Hen Haddad, Sharon Etzion, Tatiana Rabinski, Rivka Ofir, Danielle Regev, Yoram Etzion, Jacob Gopas and Aviv Goldbart
Int. J. Mol. Sci. 2021, 22(21), 11418; https://doi.org/10.3390/ijms222111418 - 22 Oct 2021
Cited by 1 | Viewed by 1987
Abstract
Obstructive sleep apnea syndrome (OSAS) patients suffer from cardiovascular morbidity, which is the leading cause of death in this disease. Based on our previous work with transformed cell lines and primary rat cardiomyocytes, we determined that upon incubation with sera from pediatric OSAS [...] Read more.
Obstructive sleep apnea syndrome (OSAS) patients suffer from cardiovascular morbidity, which is the leading cause of death in this disease. Based on our previous work with transformed cell lines and primary rat cardiomyocytes, we determined that upon incubation with sera from pediatric OSAS patients, the cell’s morphology changes, NF-κB pathway is activated, and their beating rate and viability decreases. These results suggest an important link between OSAS, systemic inflammatory signals and end-organ cardiovascular diseases. In this work, we confirmed and expanded these observations on a new in vitro system of beating human cardiomyocytes (CM) differentiated from human embryonic stem cells (hES). Our results show that incubation with pediatric OSAS sera, in contrast to sera from healthy children, induces over-expression of NF-κB p50 and p65 subunits, marked reduction in CMs beating rate, contraction amplitude and a strong reduction in intracellular calcium signal. The use of human CM cells derived from embryonic stem cells has not been previously reported in OSAS research. The results further support the hypothesis that NF-κB dependent inflammatory pathways play an important role in the evolution of cardiovascular morbidity in OSAS. This study uncovers a new model to investigate molecular and functional aspects of cardiovascular pathology in OSAS. Full article
(This article belongs to the Special Issue The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes)
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24 pages, 4676 KiB  
Article
Investigating LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
by Yuval Shemer, Lucy N. Mekies, Ronen Ben Jehuda, Polina Baskin, Rita Shulman, Binyamin Eisen, Danielle Regev, Eloisa Arbustini, Brenda Gerull, Mihaela Gherghiceanu, Eyal Gottlieb, Michael Arad and Ofer Binah
Int. J. Mol. Sci. 2021, 22(15), 7874; https://doi.org/10.3390/ijms22157874 - 23 Jul 2021
Cited by 9 | Viewed by 3962
Abstract
LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA [...] Read more.
LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients’ induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (If) density; (2) prolonged action potential duration and increased L-type Ca2+ current (ICa,L) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na+/Ca2+ exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy. Full article
(This article belongs to the Special Issue The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes)
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17 pages, 3864 KiB  
Article
Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
by Jacqueline A. Treat, Ryan Pfeiffer, Hector Barajas-Martinez, Robert J. Goodrow, Corina Bot, Rodolfo J. Haedo, Ronald Knox and Jonathan M. Cordeiro
Int. J. Mol. Sci. 2021, 22(13), 7108; https://doi.org/10.3390/ijms22137108 - 1 Jul 2021
Cited by 5 | Viewed by 3153
Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found [...] Read more.
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a “pseudo” QRS complex suggesting reduced inward current(s). Voltage clamp analysis of ICa showed no difference in the magnitude of current. Measurements of INa reveal a 60% reduction in INa density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of INa was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of INa due to a mutation in PKP2 coupled with and a gain of function in IK,ATP due to a mutation in ABCC9. Full article
(This article belongs to the Special Issue The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes)
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Review

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14 pages, 8625 KiB  
Review
The Structural and the Functional Aspects of Intercellular Communication in iPSC-Cardiomyocytes
by Eva Kiss, Carolin Fischer, Jan-Mischa Sauter, Jinmeng Sun and Nina D. Ullrich
Int. J. Mol. Sci. 2022, 23(8), 4460; https://doi.org/10.3390/ijms23084460 - 18 Apr 2022
Cited by 4 | Viewed by 3320
Abstract
Recent advances in the technology of producing novel cardiomyocytes from induced pluripotent stem cells (iPSC-cardiomyocytes) fuel new hope for future clinical applications. The use of iPSC-cardiomyocytes is particularly promising for the therapy of cardiac diseases such as myocardial infarction, where these cells could [...] Read more.
Recent advances in the technology of producing novel cardiomyocytes from induced pluripotent stem cells (iPSC-cardiomyocytes) fuel new hope for future clinical applications. The use of iPSC-cardiomyocytes is particularly promising for the therapy of cardiac diseases such as myocardial infarction, where these cells could replace scar tissue and restore the functionality of the heart. Despite successful cardiogenic differentiation, medical applications of iPSC-cardiomyocytes are currently limited by their pronounced immature structural and functional phenotype. This review focuses on gap junction function in iPSC-cardiomyocytes and portrays our current understanding around the structural and the functional limitations of intercellular coupling and viable cardiac graft formation involving these novel cardiac muscle cells. We further highlight the role of the gap junction protein connexin 43 as a potential target for improving cell–cell communication and electrical signal propagation across cardiac tissue engineered from iPSC-cardiomyocytes. Better insight into the mechanisms that promote functional intercellular coupling is the foundation that will allow the development of novel strategies to combat the immaturity of iPSC-cardiomyocytes and pave the way toward cardiac tissue regeneration. Full article
(This article belongs to the Special Issue The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes)
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23 pages, 3362 KiB  
Review
Application of Patient-Specific iPSCs for Modelling and Treatment of X-Linked Cardiomyopathies
by Jennifer Zhang, Oscar Hou-In Chou, Yiu-Lam Tse, Kwong-Man Ng and Hung-Fat Tse
Int. J. Mol. Sci. 2021, 22(15), 8132; https://doi.org/10.3390/ijms22158132 - 29 Jul 2021
Cited by 4 | Viewed by 3437
Abstract
Inherited cardiomyopathies are among the major causes of heart failure and associated with significant mortality and morbidity. Currently, over 70 genes have been linked to the etiology of various forms of cardiomyopathy, some of which are X-linked. Due to the lack of appropriate [...] Read more.
Inherited cardiomyopathies are among the major causes of heart failure and associated with significant mortality and morbidity. Currently, over 70 genes have been linked to the etiology of various forms of cardiomyopathy, some of which are X-linked. Due to the lack of appropriate cell and animal models, it has been difficult to model these X-linked cardiomyopathies. With the advancement of induced pluripotent stem cell (iPSC) technology, the ability to generate iPSC lines from patients with X-linked cardiomyopathy has facilitated in vitro modelling and drug testing for the condition. Nonetheless, due to the mosaicism of the X-chromosome inactivation, disease phenotypes of X-linked cardiomyopathy in heterozygous females are also usually more heterogeneous, with a broad spectrum of presentation. Recent advancements in iPSC procedures have enabled the isolation of cells with different lyonisation to generate isogenic disease and control cell lines. In this review, we will summarise the current strategies and examples of using an iPSC-based model to study different types of X-linked cardiomyopathy. The potential application of isogenic iPSC lines derived from a female patient with heterozygous Danon disease and drug screening will be demonstrated by our preliminary data. The limitations of an iPSC-derived cardiomyocyte-based platform will also be addressed. Full article
(This article belongs to the Special Issue The Magnificent World of Induced Pluripotent Stem Cell-Derived Cardiomyocytes)
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