Liver international : official journal of the International Association for the Study of the Liver · 2026
PPL+ Cholangiocytes Define a Pro-Regenerative Subset Associated With NRG1-ERBB3-PI3K/AKT Signalling During Liver Fibrosis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Xu Meiyining, Huang Yun, Jiang Kefeng, Zhang Lichao, Huang Wanxian, Shen Jia, Lei Junxia, Huang Yan, Sun Xi, Wu Zhongdao
Аннотация
BACKGROUND & AIMS: Chronic biliary injury drives liver fibrosis, yet mechanisms governing injury resolution and hepatocyte regeneration remain unclear. Periplakin (PPL), a cholangiocyte-enriched cytoskeletal linker, is upregulated during biliary injury, but its functional contribution to fibrosis and repair has not been defined.
METHODS: Single-nucleus RNA-seq (snRNA-seq) datasets from wild-type and DDC-treated mouse livers were analysed to map PPL expression. Hepatic PPL-overexpression and knockdown models were generated using adenoviral (Ad) and adeno-associated viral (AAV) vectors, respectively. Fluorescence-activated cell sorting (FACS)-sorted PPL+ and PPL- cholangiocytes were isolated for morphological characterisation, adoptive transfer, and hepatocyte co-culture assays. Liver fibrosis, proliferation, extracellular matrix (ECM) remodelling, cytokines, and growth factors were assessed by histology, qRT-PCR, Western blot, ELISA, and IHC. CellChat was used to infer intercellular signalling, and NRG1-ERBB3-PI3K/AKT signalling was validated in vitro.
RESULTS: SnRNA-seq identified PPL as a cholangiocyte-enriched marker defining a morphologically distinct subset. PPL overexpression reduced, whereas PPL knockdown aggravated, DDC-induced fibrosis. Adoptive transfer of PPL+ cholangiocytes improved liver function, limited ductular reaction and collagen deposition, increased MMP2/MMP12/MMP13/MMP14, elevated IL-10, EGF, and HGF, and reduced TGF-β1 and TIMP1. PPL+ cholangiocytes enhanced hepatocyte proliferation in vivo and in vitro. CellChat and co-culture assays demonstrated that PPL+ cells activate hepatocytes via an NRG1-ERBB3-PI3K/AKT axis.
CONCLUSIONS: PPL+ cholangiocytes represent a pro-regenerative epithelial subset that is associated with attenuated fibrosis and enhanced hepatocyte proliferation, potentially involving NRG1-ERBB3-PI3K/AKT signalling.
METHODS: Single-nucleus RNA-seq (snRNA-seq) datasets from wild-type and DDC-treated mouse livers were analysed to map PPL expression. Hepatic PPL-overexpression and knockdown models were generated using adenoviral (Ad) and adeno-associated viral (AAV) vectors, respectively. Fluorescence-activated cell sorting (FACS)-sorted PPL+ and PPL- cholangiocytes were isolated for morphological characterisation, adoptive transfer, and hepatocyte co-culture assays. Liver fibrosis, proliferation, extracellular matrix (ECM) remodelling, cytokines, and growth factors were assessed by histology, qRT-PCR, Western blot, ELISA, and IHC. CellChat was used to infer intercellular signalling, and NRG1-ERBB3-PI3K/AKT signalling was validated in vitro.
RESULTS: SnRNA-seq identified PPL as a cholangiocyte-enriched marker defining a morphologically distinct subset. PPL overexpression reduced, whereas PPL knockdown aggravated, DDC-induced fibrosis. Adoptive transfer of PPL+ cholangiocytes improved liver function, limited ductular reaction and collagen deposition, increased MMP2/MMP12/MMP13/MMP14, elevated IL-10, EGF, and HGF, and reduced TGF-β1 and TIMP1. PPL+ cholangiocytes enhanced hepatocyte proliferation in vivo and in vitro. CellChat and co-culture assays demonstrated that PPL+ cells activate hepatocytes via an NRG1-ERBB3-PI3K/AKT axis.
CONCLUSIONS: PPL+ cholangiocytes represent a pro-regenerative epithelial subset that is associated with attenuated fibrosis and enhanced hepatocyte proliferation, potentially involving NRG1-ERBB3-PI3K/AKT signalling.