c‐Met signaling is essential for mouse adult liver progenitor cells expansion after TGF‐β‐induced EMT and regulates cell phenotypic switch

16 p.-6 fig.-1 graph. abst.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 regulate 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 co-expression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicate 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. SIGNIFICANCE STATEMENT: The findings from this study support that a balanced action of TGF-ß and HGF could determine liver progenitors fate and the outcome of liver regeneration, and open possibilities for targeted therapies oriented at improving the regenerative capacity of these cells in chronic liver diseases.This work was supported by a Marie Curie Action FP7-2012(Grant #PITN-GA-2012-316549; IT-LIVER); Ministry of Science,Innovation and Universities, Spain (Grant #SAF2015-69145-R) and General Direction of Universities and Research of theAutonomous Community of Madrid, Spain (Grant #S2010/BMD-2402, MITOLAB consortium). LA was recipient of a pre-doctoral contract from UCM. MG-A, AMP and NL were recipients from research-training contracts from Grant #S2010/BMD-2402 and SAF2006-12025 (Ministry of Education and Sci-ence) and SAF2015-69145-R, respectively.Peer reviewe