Stem Cell–Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy

Kamdar, Forum; Das, Satyabrata; Gong, Wuming; Kamdar, Andre Klaassen; Meyers, Tatyana A.; Shah, Pruthvi; Ervasti, James M.; Townsend, De Wayne; Kamp, Timothy J.; Wu, Joseph C.; Garry, Mary G.; Zhang, Jianyi; Garry, Daniel J.

doi:10.1016/j.jacc.2019.12.066

Cited by 51 publications

(46 citation statements)

References 25 publications

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“…From a clinical point of view, analyzing the transcriptional activity of the myonuclei of the respiratory muscle fibers of the diaphragm (58) could provide insights into respiratory insufficiency in DMD patients. In addition, future snRNA-seq analysis on DMD hearts could identify the physiological changes leading to dystrophic heart failure (59).…”

Section: Discussionmentioning

confidence: 99%

Degenerative and regenerative pathways underlying Duchenne muscular dystrophy revealed by single-nucleus RNA sequencing

Chemello

Wang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

106

132

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Duchenne muscular dystrophy (DMD) is a fatal muscle disorder characterized by cycles of degeneration and regeneration of multinucleated myofibers and pathological activation of a variety of other muscle-associated cell types. The extent to which different nuclei within the shared cytoplasm of a myofiber may display transcriptional diversity and whether individual nuclei within a multinucleated myofiber might respond differentially to DMD pathogenesis is unknown. Similarly, the potential transcriptional diversity among nonmuscle cell types within dystrophic muscle has not been explored. Here, we describe the creation of a mouse model of DMD caused by deletion of exon 51 of the dystrophin gene, which represents a prevalent disease-causing mutation in humans. To understand the transcriptional abnormalities and heterogeneity associated with myofiber nuclei, as well as other mononucleated cell types that contribute to the muscle pathology associated with DMD, we performed single-nucleus transcriptomics of skeletal muscle of mice with dystrophin exon 51 deletion. Our results reveal distinctive and previously unrecognized myonuclear subtypes within dystrophic myofibers and uncover degenerative and regenerative transcriptional pathways underlying DMD pathogenesis. Our findings provide insights into the molecular underpinnings of DMD, controlled by the transcriptional activity of different types of muscle and nonmuscle nuclei.

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Section: Discussionmentioning

confidence: 99%

Degenerative and regenerative pathways underlying Duchenne muscular dystrophy revealed by single-nucleus RNA sequencing

Chemello

Wang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

106

132

View full text Add to dashboard Cite

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“…Experiments concerning Duchenne muscular dystrophy (DMD), rare genetic disorder caused by the mutations in DMD gene and total lack of dystrophin protein, manifested by progressive muscle weakness and accompanying cardiomyopathy (for a review, see Loboda and Dulak [ 111 ]), demonstrated increased arrhythmic events rate in DMD hiPSC-CMs in comparison to isogenic control [ 83 ]. Stimulation with propranolol, known beta-blocker, alleviates those effects (also in vivo), suggesting it as a potential clinical treatment for patients developing DMD-associated cardiomyopathy.…”

Section: Hipsc-derived Cardiomyocytes Application For Drug Researchmentioning

confidence: 99%

Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research

Andrysiak

Stępniewski

Dulak

2021

Pflugers Arch - Eur J Physiol

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Development of new drugs is of high interest for the field of cardiac and cardiovascular diseases, which are a dominant cause of death worldwide. Before being allowed to be used and distributed, every new potentially therapeutic compound must be strictly validated during preclinical and clinical trials. The preclinical studies usually involve the in vitro and in vivo evaluation. Due to the increasing reporting of discrepancy in drug effects in animal and humans and the requirement to reduce the number of animals used in research, improvement of in vitro models based on human cells is indispensable. Primary cardiac cells are difficult to access and maintain in cell culture for extensive experiments; therefore, the human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) became an excellent alternative. This technology enables a production of high number of patient- and disease-specific cardiomyocytes and other cardiac cell types for a large-scale research. The drug effects can be extensively evaluated in the context of electrophysiological responses with a use of well-established tools, such as multielectrode array (MEA), patch clamp, or calcium ion oscillation measurements. Cardiotoxicity, which is a common reason for withdrawing drugs from marketing or rejection at final stages of clinical trials, can be easily verified with a use of hiPSC-CM model providing a prediction of human-specific responses and higher safety of clinical trials involving patient cohort. Abovementioned studies can be performed using two-dimensional cell culture providing a high-throughput and relatively lower costs. On the other hand, more complex structures, such as engineered heart tissue, organoids, or spheroids, frequently applied as co-culture systems, represent more physiological conditions and higher maturation rate of hiPSC-derived cells. Furthermore, heart-on-a-chip technology has recently become an increasingly popular tool, as it implements controllable culture conditions, application of various stimulations and continuous parameters read-out. This paper is an overview of possible use of cardiomyocytes and other cardiac cell types derived from hiPSC as in vitro models of heart in drug research area prepared on the basis of latest scientific reports and providing thorough discussion regarding their advantages and limitations.

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“…Captured video frames were analyzed using motion vector analysis tools (MathWorks v 9.0). Additionally, cells were exposed to 10 mM isoproterenol and contractility was evaluated [12].…”

Section: P7 Cardiomyocytes In Long-term Embryonic Culture Conditionsmentioning

confidence: 99%

Biologically Derived, Three-Dimensional, Embryonic Scaffolds for Long-Term Cardiomyocyte Culture

Garry

Kren

Wenger

et al. 2021

Stem Cells and Development

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The ability to maintain viable cultures of mature, primary cardiomyocytes is challenging. The lack of viable cardiomyocyte cultures severely limits in vitro biochemical assays, toxicology assays, drug screening assays, and other analyses. Here, we describe a novel three-dimensional (3D) embryonic scaffold, which supports the culture of postnatal day 7 murine cardiomyocytes within the embryonic heart for, at least, 28 days. We have observed that these cardiomyocytes display normal differentiation, protein expression, and function after extended culture. This novel culture system will allow for prolonged treatment of cardiomyocytes in a natural 3D orientation and has the potential for providing a superior tool for the screening of therapeutic compounds.

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Stem Cell–Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy

Cited by 51 publications

References 25 publications

Degenerative and regenerative pathways underlying Duchenne muscular dystrophy revealed by single-nucleus RNA sequencing

Degenerative and regenerative pathways underlying Duchenne muscular dystrophy revealed by single-nucleus RNA sequencing

Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research

Biologically Derived, Three-Dimensional, Embryonic Scaffolds for Long-Term Cardiomyocyte Culture

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