RT Journal Article
T1 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
A1 Almale Del Barrio, Laura
A1 García-Álvaro, María
A1 Martínez-Palacián, Adoración
A1 García-Bravo, María
A1 Lazcanoiturburu, Nerea
A1 Addante, Annalisa
A1 Roncero Romero, Cesáreo
A1 Sanz Ortega, Julián
A1 López, María de la O
A1 Bragado Domingo, Paloma
A1 Mikulits, Wolfgang
A1 Factor, Valentina M.
A1 Thorgeirsson, Snorri S.
A1 Ignacio, Casal, J.
A1 Segovia, José-Carlos
A1 Rial, Eduardo
A1 Fabregat Romero, María Isabel
A1 Herrera González, Blanca María
A1 Sánchez Muñoz, Aranzazu
AB 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-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.
SN 1066-5099
SN 1549-4918
YR 2019
FD 2019-06-18
LK https://hdl.handle.net/20.500.14352/106862
UL https://hdl.handle.net/20.500.14352/106862
LA eng
NO Almalé, 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.
NO European Commission-ERC
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Comunidad Autónoma de Madrid
DS Docta Complutense
RD 20 jul 2024