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23 pages, 4112 KB

Open AccessArticle

Metabolic Culture Medium Enhances Maturation of Human iPSC-Derived Cardiomyocytes via Cardiac Troponin I Isoform Induction

by Daria V. Goliusova, Agnessa P. Bogomolova, Alina V. Davidenko, Kristina A. Lavrenteva, Margarita Y. Sharikova, Elena A. Zerkalenkova, Ekaterina M. Vassina, Alexandra N. Bogomazova, Maria A. Lagarkova, Ivan A. Katrukha and Olga S. Lebedeva

Int. J. Mol. Sci. 2025, 26(15), 7248; https://doi.org/10.3390/ijms26157248 - 26 Jul 2025

Cited by 2 | Viewed by 3289

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (iCMs) provide a powerful platform for investigating cardiac biology. However, structural, metabolic, and electrophysiological immaturity of iCMs limits their capacity to model adult cardiomyocytes. Currently, no universally accepted criteria or protocols for effective iCMs maturation exist. This study aimed to identify practical culture conditions that promote iCMs maturation, thereby generating more physiologically relevant in vitro cardiac models. We evaluated the effects of short- and long-term culture in media supplemented with various stimulatory compounds under 2D conditions, focusing on intracellular content and localization of slow skeletal troponin I (ssTnI) and cardiac troponin I (cTnI) isoforms. Our findings demonstrate that the multicomponent metabolic maturation medium (MM-1) effectively enhances the transition toward a more mature iCM phenotype, as evidenced by increased cTnI expression and formation of cross-striated myofibrils. iCMs cultured in MM-1 more closely resemble adult cardiomyocytes and are compatible with high-resolution single-cell techniques such as electron microscopy and patch-clamp electrophysiology. This work provides a practical and scalable approach for advancing the maturation of iPSC-derived cardiac models, with applications in disease modeling and drug screening. Full article

(This article belongs to the Special Issue Fundamental and Practical Perspectives in Regenerative Medicine: Proceedings of the VI National Congress of Regenerative Medicine (2024))

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17 pages, 13150 KB

Open AccessArticle

Rtf1 Transcriptionally Regulates Neonatal and Adult Cardiomyocyte Biology

by Adam D. Langenbacher, Fei Lu, Lauren Crisman, Zi Yi Stephanie Huang, Douglas J. Chapski, Thomas M. Vondriska, Yibin Wang, Chen Gao and Jau-Nian Chen

J. Cardiovasc. Dev. Dis. 2023, 10(5), 221; https://doi.org/10.3390/jcdd10050221 - 20 May 2023

Cited by 1 | Viewed by 3921

Abstract

The PAF1 complex component Rtf1 is an RNA Polymerase II-interacting transcription regulatory protein that promotes transcription elongation and the co-transcriptional monoubiquitination of histone 2B. Rtf1 plays an essential role in the specification of cardiac progenitors from the lateral plate mesoderm during early embryogenesis, but its requirement in mature cardiac cells is unknown. Here, we investigate the importance of Rtf1 in neonatal and adult cardiomyocytes using knockdown and knockout approaches. We demonstrate that loss of Rtf1 activity in neonatal cardiomyocytes disrupts cell morphology and results in a breakdown of sarcomeres. Similarly, Rtf1 ablation in mature cardiomyocytes of the adult mouse heart leads to myofibril disorganization, disrupted cell–cell junctions, fibrosis, and systolic dysfunction. Rtf1 knockout hearts eventually fail and exhibit structural and gene expression defects resembling dilated cardiomyopathy. Intriguingly, we observed that loss of Rtf1 activity causes a rapid change in the expression of key cardiac structural and functional genes in both neonatal and adult cardiomyocytes, suggesting that Rtf1 is continuously required to support expression of the cardiac gene program. Full article

(This article belongs to the Special Issue Epigenetic Regulation of Cardiac Development, Regeneration and Disease)

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16 pages, 4244 KB

Open AccessArticle

Drosophila Nesprin-1 Isoforms Differentially Contribute to Muscle Function

by Alexandre Rey, Laurent Schaeffer, Bénédicte Durand and Véronique Morel

Cells 2021, 10(11), 3061; https://doi.org/10.3390/cells10113061 - 6 Nov 2021

Cited by 7 | Viewed by 3415

Abstract

Nesprin-1 is a large scaffold protein connecting nuclei to the actin cytoskeleton via its KASH and Calponin Homology domains, respectively. Nesprin-1 disconnection from nuclei results in altered muscle function and myonuclei mispositioning. Furthermore, Nesprin-1 mutations are associated with muscular pathologies such as Emery Dreifuss muscular dystrophy and arthrogryposis. Nesprin-1 was thus proposed to mainly contribute to muscle function by controlling nuclei position. However, Nesprin-1′s localisation at sarcomere’s Z-discs, its involvement in organelles’ subcellular localization, as well as the description of numerous isoforms presenting different combinations of Calponin Homology (CH) and KASH domains, suggest that the contribution of Nesprin-1 to muscle functions is more complex. Here, we investigate the roles of Nesprin-1/Msp300 isoforms in muscle function and subcellular organisation using Drosophila larvae as a model. Subsets of Msp300 isoform were down-regulated by muscle-specific RNAi expression and muscle global function and morphology were assessed. We show that nuclei anchoring in mature muscle and global muscle function are disconnected functions associated with different Msp300 isoforms. Our work further uncovers a new and unsuspected role of Msp300 in myofibril registration and nuclei peripheral displacement supported by Msp300 CH containing isoforms, a function performed by Desmin in mammals. Full article

(This article belongs to the Special Issue The Cytoskeleton: Structural, Functional, and Pathological Aspects)

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18 pages, 4814 KB

Open AccessReview

LncRNAs in Cardiomyocyte Maturation: New Window for Cardiac Regenerative Medicine

by Maryam Kay and Bahram M. Soltani

Non-Coding RNA 2021, 7(1), 20; https://doi.org/10.3390/ncrna7010020 - 10 Mar 2021

Cited by 9 | Viewed by 6457

Abstract

Cardiomyocyte (CM) maturation, which is characterized by structural, functional, and metabolic specializations, is the last phase of CM development that prepares the cells for efficient and forceful contraction throughout life. Over the past decades, CM maturation has gained increased attention due to the fact that pluripotent stem cell-derived CMs are structurally, transcriptionally, and functionally immature and embryonic-like, which causes a defect in cell replacement therapy. The current challenge is to discover and understand the molecular mechanisms, which control the CM maturation process. Currently, emerging shreds of evidence emphasize the role of long noncoding RNAs (lncRNAs) in regulating different aspects of CM maturation, including myofibril maturation, electrophysiology, and Ca²⁺ handling maturation, metabolic maturation and proliferation to hypertrophy transition. Here, we describe the structural and functional characteristics of mature CMs. Furthermore, this review highlights the lncRNAs as crucial regulators of different aspects in CM maturation, which have the potential to be used for mature CM production. With the current advances in oligonucleotide delivery; lncRNAs may serve as putative therapeutic targets to produce highly mature CMs for research and regenerative medicine. Full article

(This article belongs to the Section Long Non-Coding RNA)

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25 pages, 601 KB

Open AccessReview

Extracellular Matrix in Regulation of Contractile System in Cardiomyocytes

by Natalya Bildyug

Int. J. Mol. Sci. 2019, 20(20), 5054; https://doi.org/10.3390/ijms20205054 - 11 Oct 2019

Cited by 24 | Viewed by 7238

Abstract

The contractile apparatus of cardiomyocytes is considered to be a stable system. However, it undergoes strong rearrangements during heart development as cells progress from their non-muscle precursors. Long-term culturing of mature cardiomyocytes is also accompanied by the reorganization of their contractile apparatus with the conversion of typical myofibrils into structures of non-muscle type. Processes of heart development as well as cell adaptation to culture conditions in cardiomyocytes both involve extracellular matrix changes, which appear to be crucial for the maturation of contractile apparatus. The aim of this review is to analyze the role of extracellular matrix in the regulation of contractile system dynamics in cardiomyocytes. Here, the remodeling of actin contractile structures and the expression of actin isoforms in cardiomyocytes during differentiation and adaptation to the culture system are described along with the extracellular matrix alterations. The data supporting the regulation of actin dynamics by extracellular matrix are highlighted and the possible mechanisms of such regulation are discussed. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 2.0)

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