RT Journal Article T1 Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC‐induced cholestatic liver injury A1 Addante, Annalisa A1 Roncero Romero, Cesáreo A1 Almale Del Barrio, Laura A1 Lazcanoiturburu, Nerea A1 García‐Álvaro, María A1 Fernández García De Castro, Margarita A1 Sanz Ortega, Julián A1 Hammad, Seddik A1 Nwosu, Zeribe C. A1 Lee, Se‐Jin A1 Fabregat Romero, María Isabel A1 Dooley, Steven A1 Dijke, Peter ten A1 Herrera González, Blanca María A1 Sánchez Muñoz, Aranzazu AB Background & Aims: Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachlorideinduced 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 shorthairpin 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. PB Wiley SN 1478-3223 SN 1478-3231 YR 2018 FD 2018-05-26 LK https://hdl.handle.net/20.500.14352/107171 UL https://hdl.handle.net/20.500.14352/107171 LA eng NO Addante A, Roncero C, Almalé L, et al. Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury. Liver Int. 2018;00:1–12. https://doi.org/10.1111/liv.13879 NO Ministerio de Economía y Competitividad NO European Commission-ERC NO Instituto de Salud Carlos III DS Docta Complutense RD 4 abr 2025