Genome Biology (Mar 2025)
A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients
- Yered Pita-Juarez,
- Dimitra Karagkouni,
- Nikolaos Kalavros,
- Johannes C. Melms,
- Sebastian Niezen,
- Toni M. Delorey,
- Adam L. Essene,
- Olga R. Brook,
- Deepti Pant,
- Disha Skelton-Badlani,
- Pourya Naderi,
- Pinzhu Huang,
- Liuliu Pan,
- Tyler Hether,
- Tallulah S. Andrews,
- Carly G. K. Ziegler,
- Jason Reeves,
- Andriy Myloserdnyy,
- Rachel Chen,
- Andy Nam,
- Stefan Phelan,
- Yan Liang,
- Mark Gregory,
- Shanshan He,
- Michael Patrick,
- Tushar Rane,
- Aster Wardhani,
- Amit Dipak Amin,
- Jana Biermann,
- Hanina Hibshoosh,
- Molly Veregge,
- Zachary Kramer,
- Christopher Jacobs,
- Yusuf Yalcin,
- Devan Phillips,
- Michal Slyper,
- Ayshwarya Subramanian,
- Orr Ashenberg,
- Zohar Bloom-Ackermann,
- Victoria M. Tran,
- James Gomez,
- Alexander Sturm,
- Shuting Zhang,
- Stephen J. Fleming,
- Sarah Warren,
- Joseph Beechem,
- Deborah Hung,
- Mehrtash Babadi,
- Robert F. Padera,
- Sonya A. MacParland,
- Gary D. Bader,
- Nasser Imad,
- Isaac H. Solomon,
- Eric Miller,
- Stefan Riedel,
- Caroline B. M. Porter,
- Alexandra-Chloé Villani,
- Linus T.-Y. Tsai,
- Winston Hide,
- Gyongyi Szabo,
- Jonathan Hecht,
- Orit Rozenblatt-Rosen,
- Alex K. Shalek,
- Benjamin Izar,
- Aviv Regev,
- Yury V. Popov,
- Z. Gordon Jiang,
- Ioannis S. Vlachos
Affiliations
- Yered Pita-Juarez
- Department of Pathology, Beth Israel Deaconess Medical Center
- Dimitra Karagkouni
- Department of Pathology, Beth Israel Deaconess Medical Center
- Nikolaos Kalavros
- Department of Pathology, Beth Israel Deaconess Medical Center
- Johannes C. Melms
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center
- Sebastian Niezen
- Harvard Medical School
- Toni M. Delorey
- Klarman Cell Observatory, Broad Institute of MIT and Harvard
- Adam L. Essene
- Department of Medicine, Beth Israel Deaconess Medical Center
- Olga R. Brook
- Department of Radiology, Beth Israel Deaconess Medical Center
- Deepti Pant
- Department of Medicine, Beth Israel Deaconess Medical Center
- Disha Skelton-Badlani
- Harvard Medical School
- Pourya Naderi
- Department of Pathology, Beth Israel Deaconess Medical Center
- Pinzhu Huang
- Harvard Medical School
- Liuliu Pan
- NanoString Technologies, Inc.
- Tyler Hether
- NanoString Technologies, Inc.
- Tallulah S. Andrews
- Ajmera Transplant Centre, Toronto General Research Institute, University Health Network
- Carly G. K. Ziegler
- Harvard Medical School
- Jason Reeves
- NanoString Technologies, Inc.
- Andriy Myloserdnyy
- Harvard Medical School
- Rachel Chen
- Harvard Medical School
- Andy Nam
- NanoString Technologies, Inc.
- Stefan Phelan
- NanoString Technologies, Inc.
- Yan Liang
- NanoString Technologies, Inc.
- Mark Gregory
- NanoString Technologies, Inc.
- Shanshan He
- NanoString Technologies, Inc.
- Michael Patrick
- NanoString Technologies, Inc.
- Tushar Rane
- NanoString Technologies, Inc.
- Aster Wardhani
- NanoString Technologies, Inc.
- Amit Dipak Amin
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center
- Jana Biermann
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center
- Hanina Hibshoosh
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
- Molly Veregge
- Department of Medicine, Beth Israel Deaconess Medical Center
- Zachary Kramer
- Department of Medicine, Beth Israel Deaconess Medical Center
- Christopher Jacobs
- Department of Medicine, Beth Israel Deaconess Medical Center
- Yusuf Yalcin
- Harvard Medical School
- Devan Phillips
- Present Address: Genentech, 1 DNA Way
- Michal Slyper
- Present Address: Genentech, 1 DNA Way
- Ayshwarya Subramanian
- Klarman Cell Observatory, Broad Institute of MIT and Harvard
- Orr Ashenberg
- Klarman Cell Observatory, Broad Institute of MIT and Harvard
- Zohar Bloom-Ackermann
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard
- Victoria M. Tran
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard
- James Gomez
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard
- Alexander Sturm
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard
- Shuting Zhang
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard
- Stephen J. Fleming
- Data Sciences Platform, Broad Institute of MIT and Harvard
- Sarah Warren
- NanoString Technologies, Inc.
- Joseph Beechem
- NanoString Technologies, Inc.
- Deborah Hung
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard
- Mehrtash Babadi
- Data Sciences Platform, Broad Institute of MIT and Harvard
- Robert F. Padera
- Department of Pathology, Brigham and Women’s Hospital
- Sonya A. MacParland
- Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology
- Gary D. Bader
- Department of Molecular Genetics, University of Toronto
- Nasser Imad
- Department of Pathology, Beth Israel Deaconess Medical Center
- Isaac H. Solomon
- Department of Pathology, Brigham and Women’s Hospital
- Eric Miller
- NanoString Technologies, Inc.
- Stefan Riedel
- Department of Pathology, Beth Israel Deaconess Medical Center
- Caroline B. M. Porter
- Klarman Cell Observatory, Broad Institute of MIT and Harvard
- Alexandra-Chloé Villani
- Broad Institute of MIT and Harvard
- Linus T.-Y. Tsai
- Harvard Medical School
- Winston Hide
- Department of Pathology, Beth Israel Deaconess Medical Center
- Gyongyi Szabo
- Harvard Medical School
- Jonathan Hecht
- Department of Pathology, Beth Israel Deaconess Medical Center
- Orit Rozenblatt-Rosen
- Klarman Cell Observatory, Broad Institute of MIT and Harvard
- Alex K. Shalek
- Harvard Medical School
- Benjamin Izar
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center
- Aviv Regev
- Klarman Cell Observatory, Broad Institute of MIT and Harvard
- Yury V. Popov
- Harvard Medical School
- Z. Gordon Jiang
- Harvard Medical School
- Ioannis S. Vlachos
- Department of Pathology, Beth Israel Deaconess Medical Center
- DOI
- https://doi.org/10.1186/s13059-025-03499-5
- Journal volume & issue
-
Vol. 26,
no. 1
pp. 1 – 46
Abstract
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.
Keywords
