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. Amit Dipak Amin
  24. Jana Biermann
  25. Hanina Hibshoosh
  26. Molly Veregge
  27. Zachary Kramer
  28. Christopher Jacobs
  29. Yusuf Yalcin
  30. Devan Phillips
  31. Michal Slyper
  32. Ayshwarya Subramanian
  33. Orr Ashenberg
  34. Zohar Bloom-Ackermann
  35. Victoria M. Tran
  36. James Gomez
  37. Alexander Sturm
  38. Shuting Zhang
  39. Stephen J. Fleming
  40. Sarah Warren
  41. Joseph Beechem
  42. Deborah Hung
  43. Mehrtash Babadi
  44. Robert F. Padera
  45. Sonya A. MacParland
  46. Gary D. Bader
  47. Nasser Imad
  48. Isaac H. Solomon
  49. Eric Miller
  50. Stefan Riedel
  51. Caroline B.M. Porter
  52. Alexandra-Chloé Villani
  53. Linus T.-Y. Tsai
  54. Winston Hide
  55. Gyongyi Szabo
  56. Jonathan Hecht
  57. Orit Rozenblatt-Rosen
  58. Alex K. Shalek
  59. Benjamin Izar
  60. Aviv Regev
  61. Yury Popov
  62. Z. Gordon Jiang
  63. Ioannis S. Vlachos

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Abstract

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.

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  1. 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.

  2. 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.

  4. Version published to 10.1101/2022.10.27.514070v1 on bioRxiv