Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
Xiaoqiang ChaiiD, Longfei Hu, Yan ZhangiD, Weiyu Han, Lu ZhouiD, Ai‐Wu KeiD, Jian ZhouiD, Guo‐Ming ShiiD, Nan FangiD, Jia FaniD, Jiabin CaiiD, Jue FaniD, Fei LaniD
Abstract
A newly identified coronavirus, 2019-nCoV, has been posing significant threats to public health since December 2019. ACE2, the host cell receptor for severe acute respiratory syndrome coronavirus (SARS), has recently been demonstrated in mediating 2019-nCoV infection. Interestingly, besides the respiratory system, substantial proportion of SARS and 2019-nCoV patients showed signs of various degrees of liver damage, the mechanism and implication of which have not yet been determined. Here, we performed an unbiased evaluation of cell type specific expression of ACE2 in healthy liver tissues using single cell RNA-seq data of two independent cohorts, and identified specific expression in cholangiocytes. The results indicated that virus might directly bind to ACE2 positive cholangiocytes but not necessarily hepatocytes. This finding suggested the liver abnormalities of SARS and 2019-nCoV patients may not be due to hepatocyte damage, but cholangiocyte dysfunction and other causes such as drug induced and systemic inflammatory response induced liver injury. Our findings indicate that special care of liver dysfunction should be installed in treating 2019-nCoV patients during the hospitalization and shortly after cure.
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Claude Opus 5.5 · xhigh effort · 17 Oct 2026 · from the full text of version 1 (4 Feb 2020) · CC BY-NC-ND 4.0
In healthy human liver scRNA-seq, ACE2 is detected in 59.7% of cholangiocytes but 2.6% of hepatocytes, so 2019-nCoV may target bile duct cells rather than hepatocytes.
Many SARS and 2019-nCoV patients develop liver abnormalities, but bulk RNA-seq and antibody staining could not establish which liver cell types carry the viral receptor ACE2. Using single-cell RNA-seq from a public cohort and a new in-house donor cohort, the work maps ACE2 expression cell type by cell type to ask whether hepatocytes or cholangiocytes could be directly infected.
Key results
ShownIn the in-house healthy-donor cohort, ACE2 is concentrated in cholangiocytes, with few positive hepatocytes and none among immune or stromal cells.
4 donors, 11550 cells, 16 annotated cell types: 59.7% of cholangiocytes express ACE2 vs 2.6% of hepatocytes, whose mean expression is 20-fold lower; immune and stromal compartments are ACE2-negative. No statistical test is reported. · Results; Quality control, cell type clustering and…
ShownA public normal-liver dataset shows the same broad pattern, with sparse ACE2 in cholangiocytes and hepatocytes and none in immune or stromal cells.
Normal liver from 9 colorectal cancer patients (GEO124395), re-analysed with the original cell labels; no percentages are given for this cohort. Unlike earlier antibody staining, which found hepatocytes ACE2-negative, scRNA-seq picked up low-frequency hepatocyte expression. · Results; Public dataset acquisition and processing
ClaimedACE2 levels in cholangiocytes are said to be comparable to those in alveolar type 2 cells, the main lung target of SARS and 2019-nCoV.
Stated in the results without any lung dataset, method or numbers described in this text. · Results
ClaimedThe authors propose that liver abnormalities in 2019-nCoV patients may stem from cholangiocyte infection, drug toxicity or systemic inflammation rather than direct infection of hepatocytes.
Inferred from receptor expression in uninfected tissue; the introduction cites 43 of 99 early patients with abnormal ALT or AST, but no patient liver tissue or infection experiments are analysed. · Abstract; Introduction; Discussion and Conclusion
Methods, data and reproducibility
ACE2 expression was compared across liver cell types in a public normal-liver scRNA-seq dataset (author cell labels) and in new Singleron GEXSCOPE scRNA-seq of fresh liver from deceased transplant donors, processed with Seurat (top 2000 variable genes, 20 principal components, tSNE, clustering at resolution 0.8) and annotated by canonical markers.
- Public scRNA-seq of normal liver from colorectal cancer patients, with the original authors' cell labels · human · n = 9 patients · GEO124395
- In-house scRNA-seq (Singleron GEXSCOPE, Illumina HiSeq X10, 150bp paired-end) of fresh normal liver from deceased liver-transplant donors · human · n = 4 donors (average age 41); 11550 cells after QC
- Methods & tools
- Seurat 2.3, tSNE, principal component analysis, Singleron GEXSCOPE Single Cell RNAseq Library Kit, Illumina HiSeq X10, GRCh38 with Ensembl version 92 annotation, internal read-processing pipeline
- Reagents & environment
- Seurat 2.3; reads aligned to GRCh38 with Ensembl version 92 gene annotation.
- Reproducibility gaps
- The public dataset is GEO124395, but no accession is given for the in-house donor data, and raw reads were processed with an internal pipeline for which no code is given.
Limitations (3)
- Technical limits may prevent detection of very low ACE2 expression in hepatocytes. · stated by the authors
- Only ACE2 mRNA in uninfected tissue is measured, with no infection, protein or patient liver data, and the in-house cohort has 4 donors with no statistical testing, so the proposed cause of liver damage is an inference. · noted in this summary
- Hepatocytes also express ACE2 (2.6% of cells in-house, sparse in the public data), and the comparison with alveolar type 2 cells relies on lung data not described in the methods. · noted in this summary
Who should read:Read this if you study 2019-nCoV tropism or virus-associated liver injury and want single-cell data on which liver cell types express the ACE2 receptor.
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