c-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-β-Induced Epithelial–Mesenchymal Transition and Regulates Cell Phenotypic Switch

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dc.contributor.authorAlmale Del Barrio, Laura
dc.contributor.authorGarcía-Álvaro, María
dc.contributor.authorMartínez-Palacián, Adoración
dc.contributor.authorGarcía-Bravo, María
dc.contributor.authorLazcanoiturburu, Nerea
dc.contributor.authorAddante, Annalisa
dc.contributor.authorRoncero Romero, Cesáreo
dc.contributor.authorSanz Ortega, Julián
dc.contributor.authorLópez, María de la O
dc.contributor.authorBragado Domingo, Paloma
dc.contributor.authorMikulits, Wolfgang
dc.contributor.authorFactor, Valentina M.
dc.contributor.authorThorgeirsson, Snorri S.
dc.contributor.authorIgnacio, Casal, J.
dc.contributor.authorSegovia, José-Carlos
dc.contributor.authorRial, Eduardo
dc.contributor.authorFabregat Romero, María Isabel
dc.contributor.authorHerrera González, Blanca María
dc.contributor.authorSánchez Muñoz, Aranzazu
dc.date.accessioned2024-07-18T11:20:10Z
dc.date.available2024-07-18T11:20:10Z
dc.date.issued2019-06-18
dc.description.abstractAdult hepatic progenitor cells (HPCs)/oval cells are bipotential progenitors that participate in liver repair responses upon chronic injury. Recent findings highlight HPCs plasticity and importance of the HPCs niche signals to determine their fate during the regenerative process, favoring either fibrogenesis or damage resolution. Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) are among the key signals involved in liver regeneration and as component of HPCs niche regulates HPCs biology. Here, we characterize the TGF-β-triggered epithelial–mesenchymal transition (EMT) response in oval cells, its effects on cell fate in vivo, and the regulatory effect of the HGF/c-Met signaling. Our data show that chronic treatment with TGF-β triggers a partial EMT in oval cells based on coexpression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicates that TGF-β-induced EMT is not associated with stemness but rather represents a step forward along hepatic lineage. This phenotypic transition confers advantageous traits to HPCs including survival, migratory/invasive and metabolic benefit, overall enhancing the regenerative potential of oval cells upon transplantation into a carbon tetrachloride-damaged liver. We further uncover a key contribution of the HGF/c-Met pathway to modulate the TGF-β-mediated EMT response. It allows oval cells expansion after EMT by controlling oxidative stress and apoptosis, likely via Twist regulation, and it counterbalances EMT by maintaining epithelial properties. Our work provides evidence that a coordinated and balanced action of TGF-β and HGF are critical for achievement of the optimal regenerative potential of HPCs, opening new therapeutic perspectives.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.refereedTRUE
dc.description.sponsorshipEuropean Commission-ERC
dc.description.sponsorshipMinisterio de Ciencia, Innovación y Universidades (España)
dc.description.sponsorshipComunidad Autónoma de Madrid
dc.description.statuspub
dc.identifier.citationAlmalé, Laura, et al. «C-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-β-Induced Epithelial–Mesenchymal Transition and Regulates Cell Phenotypic Switch». Stem Cells, vol. 37, n.o 8, agosto de 2019, pp. 1108-18. DOI.org (Crossref), https://doi.org/10.1002/stem.3038.
dc.identifier.doi10.1002/stem.3038
dc.identifier.issn1066-5099
dc.identifier.issn1549-4918
dc.identifier.officialurlhttps://doi.org/10.1002/stem.3038
dc.identifier.urihttps://hdl.handle.net/20.500.14352/106862
dc.journal.titleStem Cells
dc.language.isoeng
dc.page.final1118
dc.page.initial1108
dc.relation.projectIDPITN-GA-2012-316549
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2015-69145-R/ES/NUEVAS PERSPECTIVAS SOBRE LOS MECANISMOS MOLECULARES QUE REGULAN LA EXPANSION Y EL DESTINO DE LAS CELULAS PROGENITORAS HEPATICAS DURANTE LA ENFERMEDAD CRONICA HEPATICA/
dc.relation.projectIDinfo:eu-repo/grantAgreement/CAM//S2010/BMD-2402, MITOLAB
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2006-12025/ES/LA RUTA HGF/C-MET COMO MODULADORA DE LA BIOLOGÍA DE CÉLULAS PROGENITORAS HEPÁTICAS. IMPLICACIONES EN REGENERACIÓN/
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsmetadata only access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu577.1
dc.subject.cdu577.2
dc.subject.keywordHGF/c-Met
dc.subject.keywordOval cell
dc.subject.keywordTGF-β
dc.subject.keywordEMT
dc.subject.ucmBiología molecular (Farmacia)
dc.subject.ucmBioquímica (Farmacia)
dc.subject.unesco24 Ciencias de la Vida
dc.titlec-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-β-Induced Epithelial–Mesenchymal Transition and Regulates Cell Phenotypic Switch
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number37
dspace.entity.typePublication
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