Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of b-catenin, one with b-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived b-catenin-positive hepatocytes, and resolution of injury. KO1 showed persistent loss of b-catenin, NF-kB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of b-catenin, NFkB and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or b-catenin led to NF-kB activation, DR and inflammation. Thus, we report a novel b-catenin-NFkB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.
Raw RNA-seq data and gene count quantification were submitted to NCBI GEO data base with accession ID GSE155981
β-Catenin-NFkB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reactionNCBI Gene Expression Omnibus, GSE155981.
- Satdarshan P Monga
- Sungjin Ko
- Jacquelyn O Russell
- Satdarshan P Monga
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) Protocol #: 19126451 of the University of Pittsburgh.
Human subjects: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of the University of Pittsburgh (STUDY19070068, STUDY20010114, and STUDY20040276 on 3/23/2021).
- Paul W Noble, Cedars-Sinai Medical Centre, United States
- Received: June 16, 2021
- Accepted: October 1, 2021
- Accepted Manuscript published: October 5, 2021 (version 1)
© 2021, Hu et al.
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