Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes

Xiao Zhang, Guangli Du, Ying Xu, Xuewei Li, Weiwei Fan, Jiamei Chen, Cheng Liu, Gaofeng Chen, Chenghai Liu, Mark A Zern, Yongping Mu, Ping Liu

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Although hepatic progenitor cells (HPCs) are known to contribute to cholestatic liver fibrosis (CLF), how Notch signaling modulates the differentiation of HPCs to cholangiocytes in CLF is unknown. Thus, using a rat model of CLF that is induced by bile duct ligation, we inhibited Notch signaling with DAPT. In vivo, CK19, OV6, Sox9, and EpCAM expression was increased significantly. Notch signaling increased after bile duct ligation, and DAPT treatment reduced the expression of CK19, OV6, Sox9, and EpCAM and blocked cholangiocyte proliferation and CLF. In vitro, treatment of a WB-F344 cell line with sodium butyrate resulted in increased mRNA and protein expression of CK19, Sox9, and EpCAM, but Notch signaling was activated. Both of these processes were inhibited by DAPT. This study reveals that Notch signaling activation is required for HPC differentiation into cholangiocytes in CLF, and inhibition of the Notch signaling pathway may offer a therapeutic approach for treating CLF.

Original languageEnglish (US)
Pages (from-to)350-360
Number of pages11
JournalLaboratory Investigation
Volume96
Issue number3
DOIs
StatePublished - Mar 1 2016

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Liver Cirrhosis
Hepatocytes
Stem Cells
Bile Ducts
Ligation
Butyric Acid
Cell Differentiation
Cell Line
Messenger RNA
Epithelial Cell Adhesion Molecule
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes. / Zhang, Xiao; Du, Guangli; Xu, Ying; Li, Xuewei; Fan, Weiwei; Chen, Jiamei; Liu, Cheng; Chen, Gaofeng; Liu, Chenghai; Zern, Mark A; Mu, Yongping; Liu, Ping.

In: Laboratory Investigation, Vol. 96, No. 3, 01.03.2016, p. 350-360.

Research output: Contribution to journalArticle

Zhang, Xiao ; Du, Guangli ; Xu, Ying ; Li, Xuewei ; Fan, Weiwei ; Chen, Jiamei ; Liu, Cheng ; Chen, Gaofeng ; Liu, Chenghai ; Zern, Mark A ; Mu, Yongping ; Liu, Ping. / Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes. In: Laboratory Investigation. 2016 ; Vol. 96, No. 3. pp. 350-360.
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AU - Chen, Jiamei

AU - Liu, Cheng

AU - Chen, Gaofeng

AU - Liu, Chenghai

AU - Zern, Mark A

AU - Mu, Yongping

AU - Liu, Ping

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