β-Catenin-NFkB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction
- Tsinghua University, China
- Boston Children's Hospital, United States
- University of Pittsburgh, United States
Abstract
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.
Data availability
Raw RNA-seq data and gene count quantification were submitted to NCBI GEO data base with accession ID GSE155981
Article and author information
Author details
Satdarshan P Monga
Funding
National Institutes of Health (1R01DK62277,1R01DK100287,1R01DK116993,R01CA204586,1R01CA251155-01)
- Satdarshan P Monga
National Institutes of Health (1R01CA258449)
- Sungjin Ko
National Institutes of Health (T32EB0010216,1F31DK115017)
- Jacquelyn O Russell
National Institutes of Health (P30DK120531)
- Satdarshan P Monga
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Paul W Noble, Cedars-Sinai Medical Centre, United States
Ethics
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).
Version history
- Received: June 16, 2021
- Preprint posted: September 17, 2021 (view preprint)
- Accepted: October 1, 2021
- Accepted Manuscript published: October 5, 2021 (version 1)
- Version of Record published: October 29, 2021 (version 2)
- Version of Record updated: November 1, 2021 (version 3)
Copyright
© 2021, Hu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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β-Catenin-NFkB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction
eLife 10:e71310.
https://doi.org/10.7554/eLife.71310
Further reading
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Large-scale cell flow characterizes gastrulation in animal development. In amniote gastrulation, particularly in avian gastrula, a bilateral vortex-like counter-rotating cell flow, called ‘polonaise movements’, appears along the midline. Here, through experimental manipulations, we addressed relationships between the polonaise movements and morphogenesis of the primitive streak, the earliest midline structure in amniotes. Suppression of the Wnt/planar cell polarity (PCP) signaling pathway maintains the polonaise movements along a deformed primitive streak. Mitotic arrest leads to diminished extension and development of the primitive streak and maintains the early phase of the polonaise movements. Ectopically induced Vg1, an axis-inducing morphogen, generates the polonaise movements, aligned to the induced midline, but disturbs the stereotypical cell flow pattern at the authentic midline. Despite the altered cell flow, induction and extension of the primitive streak are preserved along both authentic and induced midlines. Finally, we show that ectopic axis-inducing morphogen, Vg1, is capable of initiating the polonaise movements without concomitant PS extension under mitotic arrest conditions. These results are consistent with a model wherein primitive streak morphogenesis is required for the maintenance of the polonaise movements, but the polonaise movements are not necessarily responsible for primitive streak morphogenesis. Our data describe a previously undefined relationship between the large-scale cell flow and midline morphogenesis in gastrulation.
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Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.
