{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T14:06:40Z","timestamp":1778508400320,"version":"3.51.4"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2019,6,18]],"date-time":"2019-06-18T00:00:00Z","timestamp":1560816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2019,6,18]],"date-time":"2019-06-18T00:00:00Z","timestamp":1560816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,6,18]],"date-time":"2019-06-18T00:00:00Z","timestamp":1560816000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"General Direction of Universities and Research of the Autonomous Community of Madrid, Spain","award":["Grant #S2010\/BMD-2402"],"award-info":[{"award-number":["Grant #S2010\/BMD-2402"]}]},{"name":"General Direction of Universities and Research of the Autonomous Community of Madrid, Spain","award":["#S2010\/BMD-2402"],"award-info":[{"award-number":["#S2010\/BMD-2402"]}]},{"name":"Marie Curie Action of FP7-2012","award":["Grant #PITN-GA-2012-316549; IT-LIVER"],"award-info":[{"award-number":["Grant #PITN-GA-2012-316549; IT-LIVER"]}]},{"name":"Ministry of Science, Innovation and Universities, Spain","award":["Grant #SAF2015-69145-R"],"award-info":[{"award-number":["Grant #SAF2015-69145-R"]}]},{"name":"Ministry of Science, Innovation and Universities, Spain","award":["#SAF2015-69145-R"],"award-info":[{"award-number":["#SAF2015-69145-R"]}]},{"name":"Marie Curie Action FP7-2012","award":["PITN-GA-2012-316549"],"award-info":[{"award-number":["PITN-GA-2012-316549"]}]},{"name":"General Direction of Universities and Research of the Autonomous Community of Madrid, Spain","award":["Grant #S2010\/BMD-2402"],"award-info":[{"award-number":["Grant #S2010\/BMD-2402"]}]},{"name":"General Direction of Universities and Research of the Autonomous Community of Madrid, Spain","award":["#S2010\/BMD-2402"],"award-info":[{"award-number":["#S2010\/BMD-2402"]}]},{"name":"Marie Curie Action of FP7-2012","award":["Grant #PITN-GA-2012-316549; IT-LIVER"],"award-info":[{"award-number":["Grant #PITN-GA-2012-316549; IT-LIVER"]}]},{"name":"Ministry of Science, Innovation and Universities, Spain","award":["Grant #SAF2015-69145-R"],"award-info":[{"award-number":["Grant #SAF2015-69145-R"]}]},{"name":"Ministry of Science, Innovation and Universities, Spain","award":["#SAF2015-69145-R"],"award-info":[{"award-number":["#SAF2015-69145-R"]}]},{"name":"Marie Curie Action FP7-2012","award":["PITN-GA-2012-316549"],"award-info":[{"award-number":["PITN-GA-2012-316549"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Adult 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-\u03b2 (TGF-\u03b2) 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-\u03b2-triggered epithelial\u2013mesenchymal 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-\u03b2 triggers a partial EMT in oval cells based on coexpression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicates that TGF-\u03b2-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-\u03b2-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-\u03b2 and HGF are critical for achievement of the optimal regenerative potential of HPCs, opening new therapeutic perspectives. Stem Cells \u00a02019;37:1108\u20131118<\/jats:p>\n               <jats:sec>\n                  <jats:title\/>\n               <\/jats:sec>","DOI":"10.1002\/stem.3038","type":"journal-article","created":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T17:00:47Z","timestamp":1558371647000},"page":"1108-1118","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["c-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-\u03b2-Induced Epithelial\u2013Mesenchymal Transition and Regulates Cell Phenotypic Switch"],"prefix":"10.1093","volume":"37","author":[{"given":"Laura","family":"Almal\u00e9","sequence":"first","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Garc\u00eda-\u00c1lvaro","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adoraci\u00f3n","family":"Mart\u00ednez-Palaci\u00e1n","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Garc\u00eda-Bravo","sequence":"additional","affiliation":[{"name":"b Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energ\u00e9ticas, Medioambientales y Tecnol\u00f3gicas (CIEMAT), Madrid, Spain"},{"name":"c Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Madrid, Spain"},{"name":"d Advanced Therapies Mixed Unit, CIEMAT\/IIS Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nerea","family":"Lazcanoiturburu","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Addante","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ces\u00e1reo","family":"Roncero","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juli\u00e1n","family":"Sanz","sequence":"additional","affiliation":[{"name":"e Department of Pathology, Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paloma","family":"Bragado","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Mikulits","sequence":"additional","affiliation":[{"name":"f Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina M.","family":"Factor","sequence":"additional","affiliation":[{"name":"g Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Snorri S.","family":"Thorgeirsson","sequence":"additional","affiliation":[{"name":"g Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"name":"h Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Ignacio","family":"Casal","sequence":"additional","affiliation":[{"name":"i Department of Functional Proteomics, Centro de Investigaciones Biol\u00f3gicas (CIB-CSIC), Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9-Carlos","family":"Segovia","sequence":"additional","affiliation":[{"name":"b Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energ\u00e9ticas, Medioambientales y Tecnol\u00f3gicas (CIEMAT), Madrid, Spain"},{"name":"c Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Madrid, Spain"},{"name":"d Advanced Therapies Mixed Unit, CIEMAT\/IIS Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Rial","sequence":"additional","affiliation":[{"name":"j Department of Cellular and Molecular Medicine, Centro de Investigaciones Biol\u00f3gicas (CIB-CSIC), Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Fabregat","sequence":"additional","affiliation":[{"name":"k TGF-\u03b2 and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain"},{"name":"l Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanca","family":"Herrera","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9145-6633","authenticated-orcid":false,"given":"Ar\u00e1nzazu","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Cl\u00ednico San Carlos, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,6,18]]},"reference":[{"key":"2022022514400017300_stem3038-bib-0001","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1002\/hep.26753","article-title":"Liver regeneration by stem\/progenitor cells","volume":"59","author":"Itoh","year":"2014","journal-title":"Hepatology"},{"key":"2022022514400017300_stem3038-bib-0002","doi-asserted-by":"crossref","first-page":"G143","DOI":"10.1152\/ajpgi.00215.2015","article-title":"The role of liver progenitor cells 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