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

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

doi:10.1016/j.stemcr.2021.02.008

Abstract

SummaryCOVID-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.

Highlights

With over 100 million people affected worldwide, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already left its permanent mark on human history (Hopkins, 2020; Zhu et al, 2020)
The most common cardiovascular complications observed after SARS-CoV-2 infection are myocardial injury, arrhythmias, and heart failure (Baggiano et al, 2020; Nishiga et al, 2020; Ojha et al, 2020; Ruan et al, 2020; Shi et al, 2020; Wang et al, 2020; Xu et al, 2020; Zhou et al, 2020)
We found that angiotensin I converting enzyme 2 (ACE2) is transcriptionally activated during cardiac differentiation of both RUES2 embryonic stem cell-derived cardiomyocytes and WTC11c-induced pluripotent stem cell-derived cardiomyocytes

Summary

Introduction

With over 100 million people affected worldwide, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already left its permanent mark on human history (Hopkins, 2020; Zhu et al, 2020). The most common cardiovascular complications observed after SARS-CoV-2 infection are myocardial injury (including cases with and without classic coronary occlusion), arrhythmias, and heart failure (Baggiano et al, 2020; Nishiga et al, 2020; Ojha et al, 2020; Ruan et al, 2020; Shi et al, 2020; Wang et al, 2020; Xu et al, 2020; Zhou et al, 2020). Retrospective studies show that hospitalized COVID-19 patients develop cardiac arrhythmias, including ventricular tachycardia and atrial fibrillation (Bhatla et al, 2020; Malaty et al, 2020; Wang et al, 2020; Zylla et al, 2021)

Results

Discussion

Conclusion