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. (18th June 2019)

• Record Type: Journal Article
• Authors: Almalé, Laura; García-Álvaro, María; Martínez-Palacián, Adoración; García-Bravo, María; Lazcanoiturburu, Nerea; Addante, Annalisa; Roncero, Cesáreo; Sanz, Julián; López, María; Bragado, Paloma; Mikulits, Wolfgang; Factor, Valentina M.; Thorgeirsson, Snorri S.; Casal, J. Ignacio; Segovia, José-Carlos; Rial, Eduardo; Fabregat, Isabel; Herrera, Blanca; Sánchez, Aránzazu
• Is Part Of: Stem cells. Volume 37:Number 8(2019)
• Page Start: 1108
• Page End: 1118
• Publication Date: 2019-06-18
• Subjects: HGF/c-Met -- Oval cell -- TGF-β -- EMT; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.3038
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: 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. Stem Cells 2019;37:1108–1118 : Abstract : A balanced action of transforming growth factor-β and hepatocyte growth factor is critical for hepatic progenitor cells' fate and outcome of liver regeneration. Hepatocyte growth factor/c-Met signaling restrains transforming growth factor-β effects. c-Met-driven antioxidant activity is necessary to overcome senescence and allow cell expansion after epithelial–mesenchymal transition. It promotes cell survival, proliferation, invasion, and counterbalances the mesenchymal phenotypic switching, overall improving the regenerative potential of hepatic progenitor cells.