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

Liu, J.; Zhang, Y.; Wu, S.; Han, L.; Wang, C.; Liu, S.; Simpson, E.; Liu, Y.; Wang, Y.; Shou, W.; Rubart-von der Lohe, M.; Wan, J.; Yang, L.

doi:10.1101/2022.01.20.477147

bioRxiv · 10.1101/2022.01.20.477147

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

Liu, J.·Zhang, Y.·Wu, S.·Han, L.·Wang, C.·Liu, S.·Simpson, E.·Liu, Y.·Wang, Y.·Shou, W.·Rubart-von der Lohe, M.·Wan, J.·Yang, L.

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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.

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Liu, J., Zhang, Y., Wu, S., Han, L., Wang, C., Liu, S., Simpson, E., Liu, Y., Wang, Y., Shou, W., Rubart-von der Lohe, M., Wan, J., Yang, L.. 2022-01-23. SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level. https://doi.org/10.1101/2022.01.20.477147

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