RT Journal Article SR Electronic T1 A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.10.27.514070 DO 10.1101/2022.10.27.514070 A1 Yered Pita-Juarez A1 Dimitra Karagkouni A1 Nikolaos Kalavros A1 Johannes C. Melms A1 Sebastian Niezen A1 Toni M. Delorey A1 Adam L Essene A1 Olga R. Brook A1 Deepti Pant A1 Disha Skelton-Badlani A1 Pourya Naderi A1 Pinzhu Huang A1 Liuliu Pan A1 Tyler Hether A1 Tallulah S. Andrews A1 Carly G.K. Ziegler A1 Jason Reeves A1 Andriy Myloserdnyy A1 Rachel Chen A1 Andy Nam A1 Stefan Phelan A1 Yan Liang A1 Amit Dipak Amin A1 Jana Biermann A1 Hanina Hibshoosh A1 Molly Veregge A1 Zachary Kramer A1 Christopher Jacobs A1 Yusuf Yalcin A1 Devan Phillips A1 Michal Slyper A1 Ayshwarya Subramanian A1 Orr Ashenberg A1 Zohar Bloom-Ackermann A1 Victoria M. Tran A1 James Gomez A1 Alexander Sturm A1 Shuting Zhang A1 Stephen J. Fleming A1 Sarah Warren A1 Joseph Beechem A1 Deborah Hung A1 Mehrtash Babadi A1 Robert F. Padera, Jr. A1 Sonya A. MacParland A1 Gary D. Bader A1 Nasser Imad A1 Isaac H. Solomon A1 Eric Miller A1 Stefan Riedel A1 Caroline B.M. Porter A1 Alexandra-ChloƩ Villani A1 Linus T.-Y. Tsai A1 Winston Hide A1 Gyongyi Szabo A1 Jonathan Hecht A1 Orit Rozenblatt-Rosen A1 Alex K. Shalek A1 Benjamin Izar A1 Aviv Regev A1 Yury Popov A1 Z. Gordon Jiang A1 Ioannis S. Vlachos YR 2022 UL http://biorxiv.org/content/early/2022/10/28/2022.10.27.514070.abstract AB 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.Competing Interest StatementA.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, Third Rock Ventures, Hovione, Relation Therapeutics, FL82, Senda Biosciences, Empress Therapeutics, IntrECate Biotherapeutics, and Dahlia Biosciences unrelated to this work. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020 was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and ThermoFisher Scientific. From August 1, 2020, A.R. is an employee of Genentech, a member of the Roche Group, with equity in Roche. I.S.V. consults for Guidepoint Global, Mosaic, and NextRNA. G.S. consults in Alnylam Pharmaceuticals, Merck, Generon, Glympse Bio, Inc., Mayday Foundation, Novartis Pharmaceuticals, Quest Diagnostics, Surrozen, Terra Firma, Zomagen Bioscience, Pandion Therapeutics, Inc., Durect Corporation; royalty from UpToDate Inc. and Editor service for Hepatology Communications. Y.P. receives grant support from Enanta Pharmaceuticals, CymaBay Therapeutics, Morphic Therapeutic; consulting and/or SAB in Ambys Medicines, Morphic Therapeutics, Enveda Therapeutics, BridgeBio Pharma, as well as being an Editor of American Journal of Physiology-Gastrointestinal and Liver Physiology. Z.G.J. receives grant support from Gilead Science, Pfizer and compensation for consulting from Olix Pharmaceuticals. L.P, T.H., S.W, J.B, E.M, and J.R. are employees and/or stockholders of NanoString Technologies. B.I. has received honoraria from consulting with Merck, Janssen Pharmaceuticals, AstraZeneca, and Volastra Therapeutics. A.R. and O.R.R. are inventors on multiple patents from the Broad Institute related to single cell and spatial genomics.