Journal Article

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

Pita-Juarez, Yered, Reeves, Jason, Imad, Nasser, Slyper, Michal, Fleming, Stephen J., Liang, Yan, Essene, Adam L., Amin, Amit Dipak, Delorey, Toni M., Karagkouni, Dimitra, Jiang, Z. Gordon, Hung, Deborah, Szabo, Gyongyi, Brook, Olga R., Shalek, Alex K., Niezen, Sebastian, MacParland, Sonya A., Miller, Eric, Phelan, Stefan, Regev, Aviv, Naderi, Pourya, Huang, Pinzhu, Sturm, Alexander, Veregge, Molly, Rane, Tushar, Hibshoosh, Hanina, Tsai, Linus T.-Y., Myloserdnyy, Andriy, Ziegler, Carly G. K., Nam, Andy, Phillips, Devan, Hide, Winston, Tran, Victoria M., He, Shanshan, Wardhani, Aster, Porter, Caroline B. M., Jacobs, Christopher, Chen, Rachel, Pan, Liuliu, Yalcin, Yusuf, Bader, Gary D., Zhang, Shuting, Hether, Tyler, Biermann, Jana, Warren, Sarah, Hecht, Jonathan, Vlachos, Ioannis S., Riedel, Stefan, Beechem, Joseph, Subramanian, Ayshwarya, Melms, Johannes C., Gomez, James, Villani, Alexandra-Chloé, Andrews, Tallulah S., Ashenberg, Orr, Padera, Robert F., Kalavros, Nikolaos, Bloom-Ackermann, Zohar, Kramer, Zachary, Gregory, Mark, Rozenblatt-Rosen, Orit, Solomon, Isaac H., Pant, Deepti, Babadi, Mehrtash, Izar, Ben

2025

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Aged / Animal Genetics and Genomics / Autopsies / Bioinformatics / Biomedical and Life Sciences / Biosynthesis / Cell proliferation / Complications / complications (disease) / COVID-19 / COVID-19 - genetics / COVID-19 - metabolism / COVID-19 - pathology / COVID-19 - virology / COVID-19 infection / Endothelial cells / Epithelial cells / epithelium / erythrocytes / Evolutionary Biology / Female / Gene Expression Profiling / genome / Genotype & phenotype / Hepatocytes / Hepatocytes - metabolism / Hepatocytes - pathology / Hepatocytes - virology / Human Genetics / Humans / Hypoxia / Infections / Life Sciences / Liver / Liver - metabolism / Liver - pathology / Liver - virology / Liver diseases / liver function / lungs / Male / Mesenchyme / Metabolism / Microbial Genetics and Genomics / Middle Aged / Patients / phenotype / Phenotypes / Plant Genetics and Genomics / Progenitor cells / RNA / SARS-CoV-2 / SARS-CoV-2 - genetics / sequence analysis / Severe acute respiratory syndrome coronavirus 2 / Single-Cell Analysis / Single-cell sequencing / Single-nucleus sequencing / Spatial transcriptomics / topology / Transcriptome / Transcriptomics / Veins & arteries / Viral infections