Meta-Analysis of Human and Mouse Biliary Epithelial Cell Gene Profiles

Abstract

Background: Chronic liver diseases are frequently accompanied with activation of biliary epithelial cells (BECs) that can differentiate into hepatocytes and cholangiocytes, providing an endogenous back-up system. Functional studies on BECs often rely on isolations of an BEC cell population from healthy and/or injured livers. However, a consensus on the characterization of these cells has not yet been reached. The aim of this study was to compare the publicly available transcriptome profiles of human and mouse BECs and to establish gene signatures that can identify quiescent and activated human and mouse BECs. Methods: We used publicly available transcriptome data sets of human and mouse BECs, compared their profiles and analyzed co-expressed genes and pathways. By merging both human and mouse BEC-enriched genes, we obtained a quiescent and activation gene signature and tested them on BEC-like cells and different liver diseases using gene set enrichment analysis. In addition, we identified several genes from both gene signatures to identify BECs in a scRNA sequencing data set. Results: Comparison of mouse BEC transcriptome data sets showed that the isolation method and array platform strongly influences their general profile, still most populations are highly enriched in most genes currently associated with BECs. Pathway analysis on human and mouse BECs revealed the KRAS signaling as a new potential pathway in BEC activation. We established a quiescent and activated BEC gene signature that can be used to identify BEC-like cells and detect BEC enrichment in alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) and peribiliary sclerotic livers. Finally, we identified a gene set that can distinguish BECs from other liver cells in mouse and human scRNAseq data. Conclusions: Through a meta-analysis of human and mouse BEC gene profiles we identified new potential pathways in BEC activation and created unique gene signatures for quiescent and activated BECs. These signatures and pathways will help in the further characterization of this progenitor cell type in mouse and human liver development and disease.

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

“…Parenchymal hepatocytes comprise up to 85% of the liver volume, with sinusoidal endothelial cells, perisinusoidal stellate cells and phagocytic Kupffer cells, with intrahepatic lymphocytes making up the rest. Strong evidence suggests that different hepatic cell types possess variable gene expression profiles [6][7][8]. The liver is therefore highly heterogeneous in both gene expression and metabolic function.…”

Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation

“…Therefore, we investigated the gene expression of a large set of quiescent and activated liver progenitor cell (LPC) and biliary epithelial cell (BEC) markers. These LPCs and BECs are endogenous cells that are known to differentiate into hepatocytes and cholangiocytes, and frequently accompany chronic liver diseases ( Figure 5 A) [ 30 ]. In this context, we found that the gene expression of the LPC/BEC markers Atf3 (19-fold), Cyr61 (7-fold), Ddr1 (6-fold), Elovl7 (38-fold), Glis3 (8-fold), and Hspa1a (6-fold) was significantly increased more than 5-fold in Fah-deficient livers when NTBC therapy was discontinued for seven consecutive days using microarray analyses ( Figure 5 A,B).…”

“…To support this, we compared the LPC/BEC marker expression profile of liver tissue derived from NTBC-treated Fah-deficient mice and those that were deprived from NTBC for seven days. This gene expression profile was previously established using meta-analyses of human and mouse biliary epithelial cell gene profiles [ 30 ] and allowed us to discriminate between the two experimental groups. More specifically, we found that the gene expression of several LPC/BEC markers including Atf3 , Cyr61 , Ddr1 , Elovl7 , Epcam , Glis3 , and Hspa1a was highly increased in Fah-deficient livers when NTBC therapy was discontinued for seven consecutive days.…”

The fibrotic response of primary liver spheroids recapitulates in vivo hepatic stellate cell activation

“…To investigate whether the genes that behave opposite between in vitro and 8 in vivo activation are enriched in an HSC subpopulation, we computed the overlap of our gene list 9 (Suppl. Table 3) with the single cell data by Krenkel et al (GSE132662) as described before [6,19,20].…”

“…In brief, raw data files were downloaded from NCBI (https://www.ncbi.nlm.nih.gov/geo) and imported 11 into RStudio (https://www.rstudio.com). Gene signature scores were computed by Single-Cell Signature 12 Score in Linux and using Single-Cell Signature Merger and Single-Cell Signature Viewer the signature 13 scores could be visualized on UMAP plots [19,20].…”