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

  1. Yered Pita-Juarez
  2. Dimitra Karagkouni
  3. Nikolaos Kalavros
  4. Johannes C. Melms
  5. Sebastian Niezen
  6. Toni M. Delorey
  7. Adam L. Essene
  8. Olga R. Brook
  9. Deepti Pant
  10. Disha Skelton-Badlani
  11. Pourya Naderi
  12. Pinzhu Huang
  13. Liuliu Pan
  14. Tyler Hether
  15. Tallulah S. Andrews
  16. Carly G. K. Ziegler
  17. Jason Reeves
  18. Andriy Myloserdnyy
  19. Rachel Chen
  20. Andy Nam
  21. Stefan Phelan
  22. Yan Liang
  23. Mark Gregory
  24. Shanshan He
  25. Michael Patrick
  26. Tushar Rane
  27. Aster Wardhani
  28. Amit Dipak Amin
  29. Jana Biermann
  30. Hanina Hibshoosh
  31. Molly Veregge
  32. Zachary Kramer
  33. Christopher Jacobs
  34. Yusuf Yalcin
  35. Devan Phillips
  36. Michal Slyper
  37. Ayshwarya Subramanian
  38. Orr Ashenberg
  39. Zohar Bloom-Ackermann
  40. Victoria M. Tran
  41. James Gomez
  42. Alexander Sturm
  43. Shuting Zhang
  44. Stephen J. Fleming
  45. Sarah Warren
  46. Joseph Beechem
  47. Deborah Hung
  48. Mehrtash Babadi
  49. Robert F. Padera
  50. Sonya A. MacParland
  51. Gary D. Bader
  52. Nasser Imad
  53. Isaac H. Solomon
  54. Eric Miller
  55. Stefan Riedel
  56. Caroline B. M. Porter
  57. Alexandra-Chloé Villani
  58. Linus T.-Y. Tsai
  59. Winston Hide
  60. Gyongyi Szabo
  61. Jonathan Hecht
  62. Orit Rozenblatt-Rosen
  63. Alex K. Shalek
  64. Benjamin Izar
  65. Aviv Regev
  66. Yury V. Popov
  67. Z. Gordon Jiang
  68. Ioannis S. Vlachos

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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.

Article activity feed

  1. Version published to 10.1186/s13059-025-03499-5
  2. Rapid Reviews Infectious Diseases

    Christoph Hafemeister, Maud Plaschka

    Review 2: "A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients"

    This study investigates the molecular underpinnings of liver dysfunction in deceased patients with severe COVID-19. Reviewers find the study reliable with caution towards the applicability of findings to mild COVID-19 phenotypes and current demographics of vaccinated individuals.

  3. Rapid Reviews Infectious Diseases

    Christoph Hafemeister, Maud Plaschka

    Review 2: "A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients"

    This study investigates the molecular underpinnings of liver dysfunction in deceased patients with severe COVID-19. Reviewers find the study reliable with caution towards the applicability of findings to mild COVID-19 phenotypes and current demographics of vaccinated individuals.

  4. Rapid Reviews Infectious Diseases

    Xinjun Wang

    Review 1: "A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients"

    This study investigates the molecular underpinnings of liver dysfunction in deceased patients with severe COVID-19. Reviewers find the study reliable with caution towards the applicability of findings to mild COVID-19 phenotypes and current demographics of vaccinated individuals.

  7. Version published to 10.1101/2022.10.27.514070 on bioRxiv