The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche

Gonzalez-Sanchez, Ester; Vaquero, Javier; Caballero Díaz, Daniel; Grzelak, Jan; Fusté, Noel P.; Bertran, Esther; Amengual, Josep; García Sáez, Juan; Martín-Mur, Beatriz; Gut, Marta; Esteve-Codina, Anna; Alay, Ania; Coulouarn, Cedric; Calero Pérez, Silvia; Valdecantos, Pilar; Valverde, Angela M.; Sánchez, Aránzazu; Herrera, Blanca; Fabregat, Isabel

The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche

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dc.contributor.author Gonzalez-Sanchez, Ester
dc.contributor.author Vaquero, Javier
dc.contributor.author Caballero Díaz, Daniel
dc.contributor.author Grzelak, Jan
dc.contributor.author Fusté, Noel P.
dc.contributor.author Bertran, Esther
dc.contributor.author Amengual, Josep
dc.contributor.author García Sáez, Juan
dc.contributor.author Martín-Mur, Beatriz
dc.contributor.author Gut, Marta
dc.contributor.author Esteve-Codina, Anna
dc.contributor.author Alay, Ania
dc.contributor.author Coulouarn, Cedric
dc.contributor.author Calero Pérez, Silvia
dc.contributor.author Valdecantos, Pilar
dc.contributor.author Valverde, Angela M.
dc.contributor.author Sánchez, Aránzazu
dc.contributor.author Herrera, Blanca
dc.contributor.author Fabregat, Isabel
dc.date.accessioned 2024-09-12T06:59:28Z
dc.date.available 2024-09-12T06:59:28Z
dc.date.issued 2024
dc.description.abstract Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
dc.format.mimetype application/pdf
dc.identifier.citation Gonzalez-Sanchez E, Vaquero J, Caballero-Diaz D, Grzelak J, Fusté NP, Bertran E, et al. The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche. J Pathol. 2024 Aug;263(4-5):482-95. DOI: 10.1002/path.6299
dc.identifier.doi http://dx.doi.org/10.1002/path.6299
dc.identifier.issn 0022-3417
dc.identifier.uri http://hdl.handle.net/10230/61063
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof J Pathol. 2024 Aug;263(4-5):482-95
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094079-B-100
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-122551OB-100
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-099098-B-100
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID-2021-122766OB-100
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTC2019-007125-1
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108651RJ-I00
dc.rights © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword CCl4
dc.subject.keyword Cytokines
dc.subject.keyword Extracellular matrix
dc.subject.keyword Immune microenvironment
dc.subject.keyword Inflammatory response
dc.subject.keyword Intercellular crosstalk
dc.subject.keyword Liver damage
dc.subject.keyword Liver fibrosis
dc.subject.keyword Macrophages
dc.subject.keyword Secretome
dc.title The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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