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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.

Published onDec 09, 2022
Review 2: "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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A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients
Description

AbstractThe 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.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

Decision-makers should consider the claims in this study actionable with limitations based on the methods and data.

COVID-19 disease has a multi-faceted pathology comprising multi-organ dysfunctions. Understanding tissue-specific molecular and cellular alterations are fundamental to designing better treatments and managing post-COVID-19 conditions. This work extends existing COVID-19 cell atlases to the context of liver function and presents a rich resource of single-nucleus and spatial transcriptional data.

This study consists of a rich, granular single nucleus gene expression dataset, from 17 livers of patients who died from COVID-19. The liver atlas recapitulates the liver composition of five major compartments (hepatocytes, immune/blood, endothelial, mesenchymal, and biliary epithelial cells BEC) and includes rare cells. The authors also generated a high-resolution spatial transcriptomic atlas from 62 Regions of Interest (ROIs) from 4 donors. This allowed them to associate spatially specific pathological functions with potential failures of the COVID-19 liver. The restructured cellular composition and gene expression point to several pathological conditions including hepatocellular injury, ductal reaction, neo-vascular expansion, and fibrogenesis.

The methodologies employed to generate and validate the single-nucleus expression atlas are appropriate, and the integration with the healthy reference data follows current best practices. We also appreciate the use of conventional IF/IHC staining to support the spatial liver atlas and validate the observations. However, while 17 patients were used to generate the dataset, the degree of the cellular and expression changes was not consistently reported per individual. This does not allow a thorough assessment of the frequency of the pathological alterations, and the variability of the effects. Also, as noted by the authors, the study is restricted to the first SARS-CoV-2 variant in a non-vaccinated population. It is unclear how the results demonstrated in this study compare with the current situation. This should be considered in future meta-analyses or integration of this dataset.

Disclaimer: Due to our lack of expertise in liver biology (and COVID-19 disease), we decline the complete evaluation of advanced biological conclusions.

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