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
doi:10.1101/2022.01.20.477147
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.
Author contributions JL and LY initiated and designed studies. JL performed all experiments and data analyses. SW, LH, CW, ES, YW and YLL assisted in whole RNA-seq. YZ and JW assisted in bioinformatics. YL, WS and ML supported calcium handling and MEA experiments and data analyses. JL, JW, ML and LY wrote the manuscript.
Declaration of interest The authors declare no competing interests. Supplementary Figure 1
Supplemental Information acquisition a minimum AGC of 2e3 and charge exclusion of 1, and ≥7 were used.
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