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

• Published in: Stem cell reports 2021-03, Vol.16 (3), p.478-492
• Main Authors: Marchiano, Silvia, Hsiang, Tien-Ying, Khanna, Akshita, Higashi, Ty, Whitmore, Leanne S., Bargehr, Johannes, Davaapil, Hongorzul, Chang, Jean, Smith, Elise, Ong, Lay Ping, Colzani, Maria, Reinecke, Hans, Yang, Xiulan, Pabon, Lil, Sinha, Sanjay, Najafian, Behzad, Sniadecki, Nathan J., Bertero, Alessandro, Gale, Michael, Murry, Charles E.
• Format: Article
• Language: English
• Subjects: arrhythmias and heart failure; cardiac infection; cardiovascular disease; Cells, Cultured; COVID-19; COVID-19 - virology; hESC-CMs; hPSC-CMs; human pluripotent stem cell-derived cardiomyocytes; Humans; Induced Pluripotent Stem Cells - virology; Myocytes, Cardiac - virology; RNA Splicing - genetics; RNA, Messenger - genetics; SARS-CoV-2; SARS-CoV-2 - genetics; SARS-CoV-2 - pathogenicity; viral myocarditis; Virus Internalization
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2021.02.008

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. [Display omitted] •SARS-CoV-2 selectively infects hPSC-CMs via ACE2, and replicates at high copy number•SARS-CoV-2 enters hPSC-CMs via endocytosis and fusion, and egresses using lysosomes•SARS-CoV-2 alters gene expression of hPSC-CMs in a dose- and time-dependent manner•Electrophysiological and contraction properties decline during SARS-CoV-2 infection In this article, Marchiano and colleagues show that SARS-CoV-2 can infect human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), where it replicates to high copy number, significantly impairs electrical and mechanical functions, and eventually causes cell death. This supports the hypothesis that cardiac disease can result from direct infection of the heart.