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.
Laura AlmaléMaría García-ÁlvaroAdoración Martínez-PalaciánMaría García-BravoNerea LazcanoiturburuAnnalisa AddanteCesáreo RonceroJulián SanzMaría de la O LópezPaloma BragadoWolfgang MikulitsValentina M FactorSnorri S ThorgeirssonJ Ignacio CasalJosé-Carlos SegoviaEduardo RialIsabel FabregatBlanca HerreraAránzazu SánchezPublished in: Stem cells (Dayton, Ohio) (2019)
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.
Keyphrases
- epithelial mesenchymal transition
- transforming growth factor
- stem cells
- induced apoptosis
- signaling pathway
- cell cycle arrest
- oxidative stress
- endoplasmic reticulum stress
- mesenchymal stem cells
- cell therapy
- growth factor
- cell death
- drug induced
- dna methylation
- liver injury
- bone marrow
- machine learning
- risk assessment
- tyrosine kinase
- high glucose
- cell fate
- young adults
- gene expression
- big data
- tissue engineering
- ischemia reperfusion injury