SARS-CoV-2 Infects Human Pluripotent Stem Cell-Derived Cardiomyocytes, Impairing Electrical and Mechanical Function

Silvia Marchiano; Tien-Ying Hsiang; Akshita Khanna; Ty Higashi; Leanne S Whitmore; Johannes Bargehr; Hongorzul Davaapil; Jean Chang; Elise Smith; Lay Ping Ong; Maria Colzani; Hans Reinecke; Xiulan Yang; Lil Pabon; Sanjay Sinha; Behzad Najafian; Nathan J Sniadecki; Alessandro Bertero; Michael Gale Jr; Charles E Murry

doi:10.1016/j.stemcr.2021.02.008

SARS-CoV-2 Infects Human Pluripotent Stem Cell-Derived Cardiomyocytes, Impairing Electrical and Mechanical Function

Stem Cell Reports. 2021 Mar 9;16(3):478-492. doi: 10.1016/j.stemcr.2021.02.008. Epub 2021 Feb 13.

Authors

Silvia Marchiano¹, Tien-Ying Hsiang², Akshita Khanna¹, Ty Higashi³, Leanne S Whitmore², Johannes Bargehr⁴, Hongorzul Davaapil⁴, Jean Chang², Elise Smith², Lay Ping Ong⁴, Maria Colzani⁴, Hans Reinecke¹, Xiulan Yang¹, Lil Pabon⁵, Sanjay Sinha⁴, Behzad Najafian⁶, Nathan J Sniadecki⁷, Alessandro Bertero¹, Michael Gale Jr⁸, Charles E Murry⁹

Affiliations

¹ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA.
² Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
³ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Department of Mechanical Engineering, University of Washington, 3720 15th Avenue NE, Seattle, WA 98105, USA.
⁴ Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Box 110, Hills Road, Cambridge CB2 0QQ, UK.
⁵ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Sana Biotechnology, 188 E Blaine Street, Seattle, WA 98102, USA.
⁶ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
⁷ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Department of Mechanical Engineering, University of Washington, 3720 15th Avenue NE, Seattle, WA 98105, USA; Department of Bioengineering, University of Washington, 3720 15th Avenue NE, Seattle, WA 98105, USA.
⁸ Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. Electronic address: mgale@uw.edu.
⁹ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Sana Biotechnology, 188 E Blaine Street, Seattle, WA 98102, USA; Department of Bioengineering, University of Washington, 3720 15th Avenue NE, Seattle, WA 98105, USA; Department of Medicine/Cardiology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA. Electronic address: murry@uw.edu.

Abstract

COVID-19 patients often develop severe cardiovascular complications, but it remains unclear if these are caused directly by viral infection or are secondary to a systemic response. Here, we examine the cardiac tropism of SARS-CoV-2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and smooth muscle cells (hPSC-SMCs). We find that that SARS-CoV-2 selectively infects hPSC-CMs through the viral receptor ACE2, whereas in hPSC-SMCs there is minimal viral entry or replication. After entry into cardiomyocytes, SARS-CoV-2 is assembled in lysosome-like vesicles and egresses via bulk exocytosis. The viral transcripts become a large fraction of cellular mRNA while host gene expression shifts from oxidative to glycolytic metabolism and upregulates chromatin modification and RNA splicing pathways. Most importantly, viral infection of hPSC-CMs progressively impairs both their electrophysiological and contractile function, and causes widespread cell death. These data support the hypothesis that COVID-19-related cardiac symptoms can result from a direct cardiotoxic effect of SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; arrhythmias and heart failure; cardiac infection; cardiovascular disease; hESC-CMs; hPSC-CMs; human pluripotent stem cell-derived cardiomyocytes; viral myocarditis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

COVID-19 / virology*
Cells, Cultured
Humans
Induced Pluripotent Stem Cells / virology*
Myocytes, Cardiac / virology*
RNA Splicing / genetics
RNA, Messenger / genetics
SARS-CoV-2 / genetics
SARS-CoV-2 / pathogenicity*
Virus Internalization

Substances

RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding