Premium
Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC ‐induced cholestatic liver injury
Author(s) -
Addante Annalisa,
Roncero Cesáreo,
Almalé Laura,
Lazcanoiturburu Nerea,
GarcíaÁlvaro María,
Fernández Margarita,
Sanz Julián,
Hammad Seddik,
Nwosu Zeribe C.,
Lee SeJin,
Fabregat Isabel,
Dooley Steven,
Dijke Peter,
Herrera Blanca,
Sánchez Aránzazu
Publication year - 2018
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.13879
Subject(s) - progenitor cell , liver injury , microbiology and biotechnology , bone morphogenetic protein , bone morphogenetic protein 2 , liver regeneration , mapk/erk pathway , fibrosis , cancer research , cell growth , protein kinase b , biology , chemistry , stem cell , regeneration (biology) , signal transduction , endocrinology , medicine , biochemistry , in vitro , gene
Background & Aims Bone morphogenetic protein 9 ( BMP 9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride‐induced chronic injury. We have now addressed the role of BMP 9 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 BMP 9 KO 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. BMP 9 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 BMP 9 effects. Results Deletion of BMP 9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP 9 results in overactivation of PI 3K/ AKT , ERK ‐ MAPK s 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, BMP 9 directly targets oval cells, it activates SMAD 1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor‐Like Kinase 2 ( ALK 2) type I receptor. Conclusions We identify BMP 9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP 9 as an attractive therapeutic target for chronic liver diseases.