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Transcriptomic Analysis of Cardiomyocyte Extracellular Vesicles in Hypertrophic Cardiomyopathy Reveals Differential snoRNA Cargo

James, Victoria; Nizamudeen, Zubair A.; Lea, Daniel; Dottorini, Tania; Holmes, Terri L.; Johnson, Ben B.; Arkill, Kenton P.; Denning, Chris; Smith, James G.W.

Transcriptomic Analysis of Cardiomyocyte Extracellular Vesicles in Hypertrophic Cardiomyopathy Reveals Differential snoRNA Cargo Thumbnail


Authors

Zubair A. Nizamudeen

Daniel Lea

Terri L. Holmes

Ben B. Johnson

CHRIS DENNING chris.denning@nottingham.ac.uk
Professor of Stem Cell Biology

James G.W. Smith



Abstract

Hypertrophic cardiomyopathy (HCM) is characterised by increased left ventricular wall thickness that can lead to devastating conditions such as heart failure and sudden cardiac death. Despite extensive study, the mechanisms mediating many of the associated clinical manifestations remain unknown and human models are required. To address this, human induced pluripotent stem cell (hiPSC) lines were generated from patients with a HCM associated mutation (c.ACTC1G301A) and isogenic controls created by correcting the mutation using CRISPR/Cas9 gene editing technology. Cardiomyocytes (hiPSC-CMs) were differentiated from these hiPSCs and analysed at baseline, and at increased contractile workload (2 Hz electrical stimulation). Released extracellular vesicles (EVs) were isolated and characterised following a 24 hour culture period and transcriptomic analysis performed on both hiPSC-CMs and released EVs. Transcriptomic analysis of cellular mRNA showed the HCM mutation caused differential splicing within known HCM pathways, and disrupted metabolic pathways. Analysis at increasing contraction frequency showed further disruption of metabolic gene expression, with an additive effect in the HCM background. Intriguingly, we observed differences in snoRNA cargo within HCM released EVs, that specifically altered when HCM hiPSC-CMs were subjected to increased workload. These snoRNAs were predicted to have roles in post translational modifications and alternative splicing, processes differentially regulated in HCM. As such, the snoRNAs identified in this study may unveil mechanistic insight into unexplained HCM phenotypes and offer potential future use as HCM biomarkers or as targets in future RNA-targeting therapies.

Citation

James, V., Nizamudeen, Z. A., Lea, D., Dottorini, T., Holmes, T. L., Johnson, B. B., …Smith, J. G. (2021). Transcriptomic Analysis of Cardiomyocyte Extracellular Vesicles in Hypertrophic Cardiomyopathy Reveals Differential snoRNA Cargo. Stem Cells and Development, 30(24), 1215-1227. https://doi.org/10.1089/scd.2021.0202

Journal Article Type Article
Acceptance Date Nov 3, 2021
Online Publication Date Nov 22, 2021
Publication Date Dec 15, 2021
Deposit Date Nov 8, 2021
Publicly Available Date Mar 29, 2024
Journal Stem Cells and Development
Print ISSN 1547-3287
Electronic ISSN 1557-8534
Publisher Mary Ann Liebert Inc
Peer Reviewed Peer Reviewed
Volume 30
Issue 24
Pages 1215-1227
DOI https://doi.org/10.1089/scd.2021.0202
Keywords Cell Biology; Developmental Biology; Hematology
Public URL https://nottingham-repository.worktribe.com/output/6672967
Publisher URL https://www.liebertpub.com/doi/10.1089/scd.2021.0202
Additional Information Final publication is available from Mary Ann Liebert, Inc., publishers http://dx.doi.org/10.1089/scd.2021.0202

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