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SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level

Juli Liu, Yucheng Zhang, Shiyong Wu, Lei Han, Cheng Wang, Sheng Liu, Ed Simpson, Ying Liu, Yue Wang, Weinian Shou, Yunlong Liu, Michael Rubart-von der Lohe, View ORCID ProfileJun Wan, Lei Yang
doi: https://doi.org/10.1101/2022.01.20.477147
Juli Liu
1Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
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Yucheng Zhang
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Shiyong Wu
1Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
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Lei Han
1Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
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Cheng Wang
1Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
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Sheng Liu
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Ed Simpson
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Ying Liu
1Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
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Yue Wang
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Weinian Shou
1Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
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Yunlong Liu
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Michael Rubart-von der Lohe
1Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
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Jun Wan
2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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  • ORCID record for Jun Wan
Lei Yang
1Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
3Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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  • For correspondence: lyang7@iu.edu
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Abstract

Cardiac manifestations are commonly observed in COVID-19 patients and prominently contributed to overall mortality. Human myocardium could be infected by SARS-CoV-2, and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are susceptible to SARS-CoV-2 infection. However, molecular mechanisms of SARS-CoV-2 gene-induced injury and dysfunction of human CMs remain elusive. Here, we find overexpression of three SARS-CoV-2 coding genes, Nsp6, Nsp8 and M, could globally compromise transcriptome of hPSC-CMs. Integrated transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with hPSC-CMs of Nsp6, Nsp8 or M overexpression identified concordantly activated genes enriched into apoptosis and immune/inflammation responses, whereas reduced genes related to heart contraction and functions. Further, Nsp6, Nsp8 or M overexpression induce prominent apoptosis and electrical dysfunctions of hPSC-CMs. Global interactome analysis find Nsp6, Nsp8 and M all interact with ATPase subunits, leading to significantly reduced cellular ATP level of hPSC-CMs. Finally, we find two FDA-approved drugs, ivermectin and meclizine, could enhance the ATP level, and ameliorate cell death and dysfunctions of hPSC-CMs overexpressing Nsp6, Nsp8 or M. Overall, we uncover the global detrimental impacts of SARS-CoV-2 genes Nsp6, Nsp8 and M on the whole transcriptome and interactome of hPSC-CMs, define the crucial role of ATP level reduced by SARS-CoV-2 genes in CM death and functional abnormalities, and explore the potentially pharmaceutical approaches to ameliorate SARS-CoV-2 genes-induced CM injury and abnormalities.

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. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 23, 2022.
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SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level
Juli Liu, Yucheng Zhang, Shiyong Wu, Lei Han, Cheng Wang, Sheng Liu, Ed Simpson, Ying Liu, Yue Wang, Weinian Shou, Yunlong Liu, Michael Rubart-von der Lohe, Jun Wan, Lei Yang
bioRxiv 2022.01.20.477147; doi: https://doi.org/10.1101/2022.01.20.477147
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SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level
Juli Liu, Yucheng Zhang, Shiyong Wu, Lei Han, Cheng Wang, Sheng Liu, Ed Simpson, Ying Liu, Yue Wang, Weinian Shou, Yunlong Liu, Michael Rubart-von der Lohe, Jun Wan, Lei Yang
bioRxiv 2022.01.20.477147; doi: https://doi.org/10.1101/2022.01.20.477147

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