Uncovering a Novel Functional Interaction Between Adult Hepatic Progenitor Cells, Inflammation and EGFR Signaling During Bile Acids-Induced Injury

Chronic cholestatic damage is associated to both accumulation of cytotoxic levels of bile acids and expansion of adult hepatic progenitor cells (HPC) as part of the ductular reaction contributing to the regenerative response. Here, we report a bile acid-specific cytotoxic response in mouse HPC, whic...

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Bibliographic Details
Authors: García Sáez, Juan, Figueroa Fuentes, María, González Corralejo, Carlos, Roncero, Cesáreo, Lazcanoiturburu, Nerea, Gutiérrez Uzquiza, Álvaro, Vaquero, Javier, González Sánchez, Ester, Bhutia, Kunzangla, Calero Pérez, Silvia, Maina, Flavio, Traba, Javier, Valverde, Ángela M., Fabregat, Isabel, Herrera, Blanca, Sánchez, Aránzazu
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/214214
Online Access:https://hdl.handle.net/2445/214214
Access Level:Open access
Keyword:Malalties del fetge
Macròfags
Liver diseases
Macrophages
Description
Summary:Chronic cholestatic damage is associated to both accumulation of cytotoxic levels of bile acids and expansion of adult hepatic progenitor cells (HPC) as part of the ductular reaction contributing to the regenerative response. Here, we report a bile acid-specific cytotoxic response in mouse HPC, which is partially impaired by EGF signaling. Additionally, we show that EGF synergizes with bile acids to trigger inflammatory signaling and NLRP3 inflammasome activation in HPC. Aiming at understanding the impact of this HPC specific response on the liver microenvironment we run a proteomic analysis of HPC secretome. Data show an enrichment in immune and TGF-beta regulators, ECM components and remodeling proteins in HPC secretome. Consistently, HPC-derived conditioned medium promotes hepatic stellate cell (HSC) activation and macrophage M1-like polarization. Strikingly, EGF and bile acids co-treatment leads to profound changes in the secretome composition, illustrated by an abolishment of HSC activating effect and by promoting macrophage M2-like polarization. Collectively, we provide new specific mechanisms behind HPC regulatory action during cholestatic liver injury, with an active role in cellular interactome and inflammatory response regulation. Moreover, findings prove a key contribution for EGFR signaling jointly with bile acids in HPC-mediated actions.

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