A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients

Pita-Juarez, Y.; Karagkouni, D.; Kalavros, N.; Melms, J. C.; Niezen, S.; Delorey, T. M.; Essene, A. L.; Brook, O. R.; Pant, D.; Skelton-Badlani, D.; Naderi, P.; Huang, P.; Pan, L.; Hether, T.; Andrews, T. S.; Ziegler, C. G. K.; Reeves, J.; Myloserdnyy, A.; Chen, R.; Nam, A.; Phelan, S.; Liang, Y.; Amin, A. D.; Biermann, J.; Hibshoosh, H.; Veregge, M.; Kramer, Z.; Jacobs, C.; Yalcin, Y.; Phillips, D.; Slyper, M.; Subramanian, A.; Ashenberg, O.; Bloom-Ackermann, Z.; Tran, V. M.; Gomez, J.; Sturm, A.; Zhang, S.; Fleming, S. J.; Warren, S.; Beechem, J.; Hung, D.; Babadi, M.; Padera, R. F.; MacParl

doi:10.1101/2022.10.27.514070

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bioRxiv · 10.1101/2022.10.27.514070

A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients

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Abstract

The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. We identified hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells. Integrated analysis and comparisons with healthy controls revealed extensive changes in the cellular composition and expression states in COVID-19 liver, reflecting hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis. We also observed Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas, resembling similar responses in liver injury in mice and in sepsis, respectively. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition was dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.

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Pita-Juarez, Y., Karagkouni, D., Kalavros, N., Melms, J. C., Niezen, S., Delorey, T. M., Essene, A. L., Brook, O. R., Pant, D., Skelton-Badlani, D., Naderi, P., Huang, P., Pan, L., Hether, T., Andrews, T. S., Ziegler, C. G. K., Reeves, J., Myloserdnyy, A., Chen, R., Nam, A., Phelan, S., Liang, Y., Amin, A. D., Biermann, J., Hibshoosh, H., Veregge, M., Kramer, Z., Jacobs, C., Yalcin, Y., Phillips, D., Slyper, M., Subramanian, A., Ashenberg, O., Bloom-Ackermann, Z., Tran, V. M., Gomez, J., Sturm, A., Zhang, S., Fleming, S. J., Warren, S., Beechem, J., Hung, D., Babadi, M., Padera, R. F., MacParl. 2022-10-28. A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients. https://doi.org/10.1101/2022.10.27.514070

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