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 language | English (US) |
|---|---|
| Pages (from-to) | 350-360 |
| Number of pages | 11 |
| Journal | Laboratory Investigation |
| Volume | 96 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes
AU - Zhang, Xiao
AU - Du, Guangli
AU - Xu, Ying
AU - Li, Xuewei
AU - Fan, Weiwei
AU - Chen, Jiamei
AU - Liu, Cheng
AU - Chen, Gaofeng
AU - Liu, Chenghai
AU - Zern, Mark A
AU - Mu, Yongping
AU - Liu, Ping
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
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U2 - 10.1038/labinvest.2015.149
DO - 10.1038/labinvest.2015.149
M3 - Article
VL - 96
SP - 350
EP - 360
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
IS - 3
ER -