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Int J Biol Sci 2024; 20(7):2339-2355. doi:10.7150/ijbs.90645 This issue Cite

Research Paper

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

Juan García-Sáez1, María Figueroa-Fuentes1, Carlos González-Corralejo1, Cesáreo Roncero1, Nerea Lazcanoiturburu1, Álvaro Gutiérrez-Uzquiza1, Javier Vaquero2,3, Ester González-Sánchez2,3, Kunzangla Bhutia4, Silvia Calero-Pérez5, Flavio Maina6, Javier Traba7, Ángela M. Valverde5, Isabel Fabregat2,3, Blanca Herrera1,3*, Aránzazu Sánchez1,3*✉

1. Dept. of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the “Hospital Clínico San Carlos” (IdISSC), Madrid, Spain.
2. TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
3. Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD-ISCIII), Madrid, Spain.
4. Dept. Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid (UCM), Madrid, Spain.
5. Biomedical Research Institute Sols-Morreale, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM); Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders of the Carlos III Health Institute (CIBERdem-ISCIII), Madrid, Spain.
6. Aix Marseille Univ, Inserm, CNRS, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Turing Center for Living Systems, Marseille, France.
7. Dept. for Molecular Biology, Center for Molecular Biology Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
* Co-senior authors.

✉ Corresponding author: A. Sánchez. Dept. of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Madrid, Spain. e-mail: munozases.

Citation:
García-Sáez J, Figueroa-Fuentes M, González-Corralejo C, Roncero C, Lazcanoiturburu N, Gutiérrez-Uzquiza Á, Vaquero J, González-Sánchez E, Bhutia K, Calero-Pérez S, Maina F, Traba J, Valverde ÁM, Fabregat I, Herrera B, Sánchez A. Uncovering a Novel Functional Interaction Between Adult Hepatic Progenitor Cells, Inflammation and EGFR Signaling During Bile Acids-Induced Injury. Int J Biol Sci 2024; 20(7):2339-2355. doi:10.7150/ijbs.90645. https://www.ijbs.com/v20p2339.htm
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Abstract

Graphic abstract

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-β 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.

Keywords: EGFR, Bile acids, Hepatic Progenitor Cell, Inflammation, Secretome, Liver Disease

Citation styles

APA
García-Sáez, J., Figueroa-Fuentes, M., González-Corralejo, C., Roncero, C., Lazcanoiturburu, N., Gutiérrez-Uzquiza, Á., Vaquero, J., González-Sánchez, E., Bhutia, K., Calero-Pérez, S., Maina, F., Traba, J., Valverde, Á.M., Fabregat, I., Herrera, B., Sánchez, A. (2024). Uncovering a Novel Functional Interaction Between Adult Hepatic Progenitor Cells, Inflammation and EGFR Signaling During Bile Acids-Induced Injury. International Journal of Biological Sciences, 20(7), 2339-2355. https://doi.org/10.7150/ijbs.90645.

ACS
García-Sáez, J.; Figueroa-Fuentes, M.; González-Corralejo, C.; Roncero, C.; Lazcanoiturburu, N.; Gutiérrez-Uzquiza, Á.; Vaquero, J.; González-Sánchez, E.; Bhutia, K.; Calero-Pérez, S.; Maina, F.; Traba, J.; Valverde, Á.M.; Fabregat, I.; Herrera, B.; Sánchez, A. Uncovering a Novel Functional Interaction Between Adult Hepatic Progenitor Cells, Inflammation and EGFR Signaling During Bile Acids-Induced Injury. Int. J. Biol. Sci. 2024, 20 (7), 2339-2355. DOI: 10.7150/ijbs.90645.

NLM
García-Sáez J, Figueroa-Fuentes M, González-Corralejo C, Roncero C, Lazcanoiturburu N, Gutiérrez-Uzquiza Á, Vaquero J, González-Sánchez E, Bhutia K, Calero-Pérez S, Maina F, Traba J, Valverde ÁM, Fabregat I, Herrera B, Sánchez A. Uncovering a Novel Functional Interaction Between Adult Hepatic Progenitor Cells, Inflammation and EGFR Signaling During Bile Acids-Induced Injury. Int J Biol Sci 2024; 20(7):2339-2355. doi:10.7150/ijbs.90645. https://www.ijbs.com/v20p2339.htm

CSE
García-Sáez J, Figueroa-Fuentes M, González-Corralejo C, Roncero C, Lazcanoiturburu N, Gutiérrez-Uzquiza Á, Vaquero J, González-Sánchez E, Bhutia K, Calero-Pérez S, Maina F, Traba J, Valverde ÁM, Fabregat I, Herrera B, Sánchez A. 2024. Uncovering a Novel Functional Interaction Between Adult Hepatic Progenitor Cells, Inflammation and EGFR Signaling During Bile Acids-Induced Injury. Int J Biol Sci. 20(7):2339-2355.

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