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SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function

View ORCID ProfileSilvia Marchiano, Tien-Ying Hsiang, Ty Higashi, Akshita Khanna, Hans Reinecke, Xiulan Yang, View ORCID ProfileLil Pabon, View ORCID ProfileNathan J. Sniadecki, View ORCID ProfileAlessandro Bertero, View ORCID ProfileMichael Gale Jr, View ORCID ProfileCharles E. Murry
doi: https://doi.org/10.1101/2020.08.30.274464
Silvia Marchiano
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
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  • ORCID record for Silvia Marchiano
Tien-Ying Hsiang
4Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA, 98109, USA
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Ty Higashi
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
5Department of Mechanical Engineering, University of Washington, 3720 15th Ave NE, Seattle, WA, 98105, USA
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Akshita Khanna
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
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Hans Reinecke
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
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Xiulan Yang
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
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Lil Pabon
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
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Nathan J. Sniadecki
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
5Department of Mechanical Engineering, University of Washington, 3720 15th Ave NE, Seattle, WA, 98105, USA
6Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA, 98105, USA
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Alessandro Bertero
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
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Michael Gale Jr
4Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA, 98109, USA
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  • For correspondence: murry@uw.edu mgale@uw.edu
Charles E. Murry
1Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
2Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA
6Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA, 98105, USA
7Department of Medicine/Cardiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
8Sana Biotechnology, 188 E Blaine Street, Seattle, WA, 98102, USA
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  • ORCID record for Charles E. Murry
  • For correspondence: murry@uw.edu mgale@uw.edu
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Abstract

Global health has been threatened by the COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2)1. Although considered primarily a respiratory infection, many COVID-19 patients also suffer severe cardiovascular disease2–4. Improving patient care critically relies on understanding if cardiovascular pathology is caused directly by viral infection of cardiac cells or indirectly via systemic inflammation and/or coagulation abnormalities3,5–9. Here we examine the cardiac tropism of SARS-CoV-2 using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and three-dimensional engineered heart tissues (3D-EHTs). We observe that hPSC-CMs express the viral receptor ACE2 and other viral processing factors, and that SARS-CoV-2 readily infects and replicates within hPSC-CMs, resulting in rapid cell death. Moreover, infected hPSC-CMs show a progressive impairment in both electrophysiological and contractile properties. Thus, COVID-19-related cardiac symptoms likely result from a direct cardiotoxic effect of SARS-CoV-2. Long-term cardiac complications might be possible sequelae in patients who recover from this illness.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function
Silvia Marchiano, Tien-Ying Hsiang, Ty Higashi, Akshita Khanna, Hans Reinecke, Xiulan Yang, Lil Pabon, Nathan J. Sniadecki, Alessandro Bertero, Michael Gale Jr, Charles E. Murry
bioRxiv 2020.08.30.274464; doi: https://doi.org/10.1101/2020.08.30.274464
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SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function
Silvia Marchiano, Tien-Ying Hsiang, Ty Higashi, Akshita Khanna, Hans Reinecke, Xiulan Yang, Lil Pabon, Nathan J. Sniadecki, Alessandro Bertero, Michael Gale Jr, Charles E. Murry
bioRxiv 2020.08.30.274464; doi: https://doi.org/10.1101/2020.08.30.274464

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