Journal
STEM CELL REPORTS
Volume 16, Issue 3, Pages 478-492Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2021.02.008
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Funding
- UW Institute for Stem Cell and Regenerative Medicine
- National Science Foundation [CMMI-166173]
- NIH [R01 HL149734, R01 AI118916, R01 AI127463, R01 AI145296, R21 AI145359, U01 AI151698, UM1 AI148684, U19 AI100625, R01 HL128362, R01 HL146868]
- British Heart Foundation [FS/18/46/33663, RG/17/5/32936, RM/17/2/33380]
- Robert B. McMillen Foundation
- State of Washington
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Research shows that SARS-CoV-2 selectively infects human pluripotent stem cell-derived cardiomyocytes, leading to a shift in host gene expression and impairment of cellular functions. This suggests that COVID-19-related cardiac symptoms may be a result of the direct cardiotoxic effect of the virus.
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.
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