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, Gregory, M, He, S, Patrick, M, Rane, T, Wardhani, A, 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 Jr, R. F, MacParland, S. A, Bader, G. D, Imad, N, Solomon, I. H, Miller, E, Riedel, S, Porter, C. B. M, Villani, A, Tsai, L. T.-Y, Hide, W, Szabo, G, Hecht, J, Rozenblatt-Rosen, O, Shalek, A. K, Izar, B, Regev, A, Popov, Y. V, Jiang, Z. G, Vlachos, I. S.

Genome Biology, 26, March, 2025

Abstract

Background The molecular underpinnings of organ dysfunction in severe COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we perform single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. Results We identify hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells, and a central role in a pro-fibrotic TGFβ signaling cell–cell communications network. Integrated analysis and comparisons with healthy controls reveal extensive changes in the cellular composition and expression states in COVID-19 liver, providing the underpinning of hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis characteristic of COVID-19 cholangiopathy.

We also observe Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition is dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. Conclusions Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.

Download