Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury

• Verfasst von: Addante, Annalisa [VerfasserIn]
• Verfasst von: Hammad, Seddik [VerfasserIn]
• Verfasst von: Nwosu, Zeribe C. [VerfasserIn]
• Verfasst von: Dooley, Steven [VerfasserIn]
• Titel: Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury
• Verf.angabe: Annalisa Addante, Cesáreo Roncero, Laura Almalé, Nerea Lazcanoiturburu, María García‐Álvaro, Margarita Fernández, Julián Sanz, Seddik Hammad, Zeribe C. Nwosu, Se-Jin Lee, Isabel Fabregat, Steven Dooley, Peter ten Dijke, Blanca Herrera, Aránzazu Sánchez
• E-Jahr: 2018
• Jahr: 11 May 2018
• Umfang: 12 S.
• Fussnoten: Gesehen am 07.05.2019
• Titel Quelle: Enthalten in: Liver international
• Ort Quelle: Oxford : Wiley-Blackwell, 2003
• Jahr Quelle: 2018
• Band/Heft Quelle: 38(2018), 9, Seite 1664-1675
• ISSN Quelle: 1478-3231
• DOI: doi:10.1111/liv.13879
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: BMP9
• Sach-SW: DDC
• Sach-SW: liver regeneration
• Sach-SW: oval cell
• K10plus-PPN: 1663508992

Abstract

Background & Aims Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. Methods WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. Results Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. Conclusions We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases.