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Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as an In Vitro Model for Coxsackievirus B3–Induced Myocarditis and Antiviral Drug Screening Platform
Open accessAbstract
Rationale: Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. A major causative agent for viral myocarditis is the B3 strain of coxsackievirus, a positive-sense RNA enterovirus. However, human cardiac tissues are difficult to procure in sufficient enough quantities for studying the mechanisms of cardiac-specific viral infection. Objective: This study examined whether human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy. Methods and Results: hiPSC-CMs were infected with a luciferase-expressing coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs for alterations in cellular morphology and calcium handling. Viral proliferation in hiPSC-CMs was quantified using bioluminescence imaging. Antiviral compounds including interferonβ1, ribavirin, pyrrolidine dithiocarbamate, and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with reported drug effects in previous studies. Mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways after interferonβ1 treatment. Conclusions: This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to predict antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that can screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion.
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“In addition, using patient-specific hiPSC-CMs, researchers are able to model various CVDs such as long QT syndrome, LV non-compaction, hypertrophic cardiomyopathy and dilated cardiomyopathy [217,423,424].”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [424]
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Metadata
- Authors
- Sharma, A., Marceau, C., Hamaguchi, R., Burridge, P. W., Rajarajan, K., Churko, J. M., Wu, H., Sallam, K. I., Matsa, E., Sturzu, A. C., Che, Y., Ebert, A., Diecke, S., Liang, P., Red-Horse, K., Carette, J. E., Wu, S. M., & Wu, J. C.
- Affiliations
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- From the Department of Medicine, Division of Cardiology (A.S., R.H., P.W.B., K.R., J.M.C., H.W., K.I.S., E.M., A.C.S., Y.C., A.E., S.D., P.L., S.M.W., J.C.W.), Institute for Stem Cell Biology and Regenerative Medicine (A.S., R.H., P.W.B., K.R., J.M.C., H.W., K.I.S., E.M., A.C.S., Y.C., A.E., S.D., P.L., S.M.W., J.C.W.), Stanford Cardiovascular Institute (A.S., R.H., P.W.B., K.R., J.M.C., H.W., K.I.S., E.M., A.C.S., Y.C., A.E., S.D., P.L., K.R.-H., S.M.W., J.C.W.), Department of Biology (A.S., R.H.,...
- ORCID
- Venue
- Circulation Research
- Published
- 2014-08-29
- Volume
- 115
- Issue
- 6
- Pages
- 556-566
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4149868
- OpenAlex
- W1998190377
- Cited by
- 148
- References
- 50
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 14 · 2023: 8 · 2022: 17 · 2021: 19 · 2020: 14 · 2019: 8 · 2018: 16 · 2017: 12 · 2016: 12 · 2015: 18 · 2014: 2
- FWCI
- 10.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- National Institutes of Health (DP2OD004411, NS069375)
- National Heart, Lung, and Blood Institute (U01HL099776, T32HL007208, R01HL113006)
- National Institute of Allergy and Infectious Diseases (DP2AI104557, T32AI007328)
- National Institute of Neurological Disorders and Stroke (NS069375, P30NS069375)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Immunology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- coxsackievirus B3, viral myocarditis, human induced pluripotent stem cell-derived cardiomyocytes, antiviral drug screening, interferon-beta, ribavirin, pyrrolidine dithiocarbamate, fluoxetine, coxsackievirus and adenovirus receptor, calcium handling, viral RNA clearance, high-throughput screening, in vitro disease model
- MeSH terms
- Antiviral Agents, Calcium, Cells, Cultured, Drug Evaluation, Preclinical, Enterovirus Infections, Humans, Models, Cardiovascular, Myocarditis, RNA, Viral, Treatment Outcome, Enterovirus B, Human, Myocytes, Cardiac, Pluripotent Stem Cells, Cell Proliferation, In Vitro Techniques
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