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

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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. 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. 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.

  3. Strength of evidence

    Reviewers: Xinjun Wang (Memorial Sloan Kettering Cancer Center) | πŸ“—πŸ“—πŸ“—πŸ“—β—»οΈ
    Christoph Hafemeister, Maud Plaschka (St. Anna Children's Cancer Research Institute) | πŸ“—πŸ“—πŸ“—πŸ“—β—»οΈ