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Utilizing Induced Pluripotent Stem Cells and Cardiomyocytes: From Basic Research to Disease Modeling

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 330

Special Issue Editor


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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
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Special Issue Information

Dear Colleagues,

At the molecular level, stem cell research has unlocked new avenues for understanding and manipulating the intricate networks within the heart.

The advent of human induced pluripotent stem cells (iPSCs) and their derivative cardiomyocytes (iPSC-CMs) has allowed for the detailed investigation and manipulation of cardiomyocytes at the molecular level.

At the molecular level, iPSCs undergo a reprogramming process that involves alterations in gene expression patterns, the activation of signaling pathways and epigenetic modifications. This reprogramming converts mature somatic cells into pluripotent stem cells, which can then differentiate into the three germ layers, and consequently to any cell type in the body. The molecular mechanisms underlying this reprogramming process are actively being investigated, with the aim of improving its efficiency and safety for therapeutic applications.

iPSC-CMs behave like native cardiomyocytes, respecting molecular and functional aspects such as the excitation–contraction–coupling machinery and responsiveness to autonomic hormones and neurotransmitters and to a variety of pharmacological agents. Further, iPSC-CMs can be employed to model both acquired and inherited cardiac diseases, as well as screen for novel potential therapeutic modalities. Further, by manipulating the genetic makeup of iPSC-CMs, researchers can gain insights into the molecular basis of inherited cardiac disorders. Additionally, iPSC-CMs can be exposed to various pathological conditions, such as hypoxia or oxidative stress, and to study the molecular responses that occur during heart disease development.

This Special Issue dedicated to iPSC-CMs highlights the latest advancements in basic research, disease modeling and drug development at the molecular level. This Special Issue features technological innovations such as genome editing tools, high-throughput sequencing methods, and single-cell sequencing techniques that have enabled researchers to delve deeper into the molecular mechanisms underlying cardiac diseases. Experimental methods optimized for the study of iPSC-CMs are also discussed, along with their translational potential in clinical settings.

By providing a platform for sharing cutting-edge research and fostering collaborations among the global community of scientists and researchers, we aim to accelerate the development of innovative therapies for cardiovascular diseases. Through collective efforts and the cross-fertilization of ideas, we hope to overcome the challenges in stem cell research and translate the molecular insights gained into effective treatments for patients with cardiac disorders.

Prof. Dr. Ofer Binah
Guest Editor

Manuscript Submission Information

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Keywords

  • induced pluripotent stem cells
  • cardiomyocytes
  • disease modeling
  • basic research
  • translational applications

Published Papers (1 paper)

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Research

24 pages, 1787 KiB  
Article
Stress-Induced Proteasome Sub-Cellular Translocation in Cardiomyocytes Causes Altered Intracellular Calcium Handling and Arrhythmias
by Shunit Neeman-Egozi, Ido Livneh, Irit Dolgopyat, Udi Nussinovitch, Helena Milman, Nadav Cohen, Binyamin Eisen, Aaron Ciechanover and Ofer Binah
Int. J. Mol. Sci. 2024, 25(9), 4932; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25094932 - 30 Apr 2024
Viewed by 177
Abstract
The ubiquitin–proteasome system (UPS) is an essential mechanism responsible for the selective degradation of substrate proteins via their conjugation with ubiquitin. Since cardiomyocytes have very limited self-renewal capacity, as they are prone to protein damage due to constant mechanical and metabolic stress, the [...] Read more.
The ubiquitin–proteasome system (UPS) is an essential mechanism responsible for the selective degradation of substrate proteins via their conjugation with ubiquitin. Since cardiomyocytes have very limited self-renewal capacity, as they are prone to protein damage due to constant mechanical and metabolic stress, the UPS has a key role in cardiac physiology and pathophysiology. While altered proteasomal activity contributes to a variety of cardiac pathologies, such as heart failure and ischemia/reperfusion injury (IRI), the environmental cues affecting its activity are still unknown, and they are the focus of this work. Following a recent study by Ciechanover’s group showing that amino acid (AA) starvation in cultured cancer cell lines modulates proteasome intracellular localization and activity, we tested two hypotheses in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs, CMs): (i) AA starvation causes proteasome translocation in CMs, similarly to the observation in cultured cancer cell lines; (ii) manipulation of subcellular proteasomal compartmentalization is associated with electrophysiological abnormalities in the form of arrhythmias, mediated via altered intracellular Ca2+ handling. The major findings are: (i) starving CMs to AAs results in proteasome translocation from the nucleus to the cytoplasm, while supplementation with the aromatic amino acids tyrosine (Y), tryptophan (W) and phenylalanine (F) (YWF) inhibits the proteasome recruitment; (ii) AA-deficient treatments cause arrhythmias; (iii) the arrhythmias observed upon nuclear proteasome sequestration(-AA+YWF) are blocked by KB-R7943, an inhibitor of the reverse mode of the sodium–calcium exchanger NCX; (iv) the retrograde perfusion of isolated rat hearts with AA starvation media is associated with arrhythmias. Collectively, our novel findings describe a newly identified mechanism linking the UPS to arrhythmia generation in CMs and whole hearts. Full article
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