# Cross talk between epithelial, inflammatory and mesenchymal cells in the development of portal fibrosis

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $508,599

## Abstract

There is considerable interest in understanding the mechanistic relationships between biliary 
damage and portal fibrosis, the main mechanism of progression in chronic cholangiopathies. 
Congenital Hepatic Fibrosis (CHF) and Caroli disease (CD) are genetic cholangiopathies 
caused by mutations in PKHD1, the gene encoding for fibrocystin, characterized by biliary 
dysgenesis, segmental ductal dilations and progressive portal fibrosis with portal hypertension. In 
CHF and CD, cholangiocyte dysfunction and portal fibrosis are caused by a genetic defect in the 
biliary epithelium, rather than by necroinflammatory damage and thus, represent a model disease for 
 elucidating the role of cholangiocytes in portal fibrosis of biliary diseases. We 
propose to study these mechanisms in a mouse model of CHF/CD, harbouring a deleting mutation in 
Pkhd1 (Pkhd1del4/del4 mice). Our published and preliminary data have established that in 
Pkhd1del4/del4 mice biliary fibrosis develops in conjunction with accumulation of a 
peribiliary cell infiltrate by macrophages and by aSMA-negative, but collagen positive 
cells like fibrocytes. Furthermore, we have shown Pkhd1del4/del4 cholangiocytes 
are characterized by an increased PKA-dependent phosphorylation of β-catenin at 
Ser675, the nuclear translocation of pSer-675-β-catenin and its increased transcriptional 
 activity. ß-catenin interacts with FXR inhibiting its anti-inflammatory signaling and 
thereby activating NF-kB and the inflammasome-dependent secretion IL-1β and consequently of 
CXCL1 and CXCL10, that are, in turn, able to attract macrophages. By inhibiting CXCR3, the cognate 
receptor of CXCL10, or by administration of an FXR agonist (obeticholic acid) macrophage 
infiltration was significantly reduced as well as cyst growth, spleen size and liver fibrosis. 
Finally, in Pkhd1del4/del4 cholangiocytes, nuclear shuttling of YAP is a pre-requisite for 
β-catenin activation and thus, for the expression of the pro-fibrogenic mediators CTGF, CXCL1, and 
CXCL10.
Based on these observations, we propose that, when fibrocystin is defective, the interplay among 
β-catenin, YAP, FXR signalling regulates the secretion from the biliary epithelium of several 
chemokines that orchestrate sequential changes in the peribiliary infiltrate and are responsible 
for the establishment of portal inflammation and fibrosis. To demonstrate this novel hypothesis, we 
will investigate in specific aim 1 the relationship among YAP, β-catenin and FXR signalling in 
 Pkhd1del4/del4 mice, their role in controlling, cyst growth, inflammation, fibrosis and 
their relevance as therapeutic targets. While in specific aim 2 we will investigate the nature of 
the pericystic infiltrate in Pkhd1del4/del4 mice, and its dynamic changes during the establishment 
of fibrosis and the effects of treatment strategies.
These studies will provide a new model for role of cholangiocyte dysfunction in portal fibrosis. 
Knowledge of the regulatory signaling could...

## Key facts

- **NIH application ID:** 10364642
- **Project number:** 5R01DK101528-07
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mario Strazzabosco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $508,599
- **Award type:** 5
- **Project period:** 2015-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364642

## Citation

> US National Institutes of Health, RePORTER application 10364642, Cross talk between epithelial, inflammatory and mesenchymal cells in the development of portal fibrosis (5R01DK101528-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10364642. Licensed CC0.

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