Whole transcriptome analysis of ductular reaction from patients with alcoholic hepatitis. Similarities to ductular reaction in DDC mouse model

Background: Alcoholic hepatitis (AH) is characterized by the expansion of ductular reaction (DR), and the expression of liver progenitor cell (LPC) markers correlate with bad outcome. However, the gene expression profile of DR... [ view full abstract ]

Background: Alcoholic hepatitis (AH) is characterized by the expansion of ductular reaction (DR), and the expression of liver progenitor cell (LPC) markers correlate with bad outcome. However, the gene expression profile of DR and its weight in disease progression is unknown. The aim of this study was to identify a gene set signature of the DR and to determine the best animal model to study DR expansion.

Methods: KRT7+ cells were isolated from liver biopsies (n=6) of patients with AH by laser capture microdissection and analyzed by next generation sequencing. Functional analysis was performed by Ingenuity Pathway Analysis. By gene set enrichment analysis (GSEA), expression of gene set signature was validated in an independent cohort of 15 patients with AH and compared with FACS sorted LPC from two animal models (DDC and CDE diet).

Results: Expression of LPC markers (HNF1β, KRT7, EpCAM, PROM1) was confirmed by qPCR and immunohistochemistry. A transcriptomic signature was defined and as expected, GSEA showed a high overlap in AH. At a functional level, KRT7+ showed enrichment in genes involved in tight junction signaling and cell adhesion. Moreover, GSEA revealed that DR signature from AH patients showed a higher degree of similarity with the gene expression profile of cells derived from DDC than CDE model.

Conclusions: Here we report the gene expression signature of DR in AH. This study suggests that DDC mouse model may be a useful tool to mimic DR in AH and for the development of new therapies in hepatic regeneration.