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

Zhang, Xiao; Du, Guanhua; Xu, Ying; Li, Xuewei; Fan, Weiwei; Chen, Jiamei; Liu, Cheng; Zeng, Xianhai; Liu, Chenghai; Zern, Mark Α.; Mu, Yongping; Liu, Ping

doi:10.1038/labinvest.2015.149

Cited by 52 publications

(40 citation statements)

References 34 publications

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“…Disruption of this pathway, as characterized by Alagille syndrome, results in disorganized or absent biliary morphogenesis, [34,35]. In our study, we found that inhibition of the Notch pathway led to a decrease in the differentiation of HPCs into bile duct epithelium in experimental BA mice, which is consistent with the results of previous studies in cholestatic mice induced by bile duct ligation [20]. In this study, we found that DAPT suppressed the mRNA expression of Notch pathwayrelated genes, namely, Notch1, Notch2, and Dll1, which is consistent with a previous report [17].…”

Section: Cellular Physiology and Biochemistrysupporting

confidence: 92%

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Inhibition of the Notch Signaling Pathway Reduces the Differentiation of Hepatic Progenitor Cells into Cholangiocytes in Biliary Atresia

Mao

Tang

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Viral infections, especially with rotavirus, are often considered an initiator of the pathogenesis of biliary atresia (BA). However, the mechanism by which rotavirus induces BA is still unclear. Methods: A BA mouse model was induced in newborn mice by i.p. inoculation with rhesus rotavirus within 6 h of birth. The expression of Notch pathway-associated molecules (JAG1, JAG2, Notch1, Notch2, Notch3, Notch4, DII1, DII3, and DII4) was measured by quantitative PCR and western blot analysis. Bile duct obstruction was detected by hematoxylin and eosin staining and CK-19 immunohistochemical staining. DAPT was used to inhibit the Notch pathway in vivo and in vitro. Results: In the livers of patients with BA and rotavirus-induced BA mice, the expression of JAG1 and Notch2 was significantly increased. Inhibition of the Notch pathway by DAPT in vivo ameliorated bile duct obstruction and delayed BA-induced mortality. The serum levels of inflammation cytokines (TNF-α, IL-2, IL-8, and IL-18) were reduced by inhibiting the Notch pathway. The expression of CK19, Sox9, and EpCAM was significantly increased in BA liver, while DAPT treatment decreased the expression of CK19, Sox9, and EpCAM. Conclusion: Notch activation is involved in the pathogenesis of BA by promoting the differentiation of hepatic progenitor cells into cholangiocytes.

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Section: Cellular Physiology and Biochemistrysupporting

confidence: 92%

“…The study protocol complied with the ethical guidelines of the 1975 Declaration of Helsinki and was reflected by the a priori approval of our institution's human research committee. Quantitative PCR (qPCR) and western blotting qPCR and western blot analyses were performed as described previously [20]. All PCR primers used are shown in Table 2.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of the Notch Signaling Pathway Reduces the Differentiation of Hepatic Progenitor Cells into Cholangiocytes in Biliary Atresia

Mao

Tang

Yang

et al. 2018

Cell Physiol Biochem

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“…Transfection of Notch3 shRNA in a rat CCl 4 induced liver fibrosis model reverses EMT in fibrotic livers by reducing TGFβ1 expression [125]. Consistent with the Notch inhibitor study[48, 116, 123, 124], the inhibition of Notch3 has no effect on hepatocyte proliferation but reduces hepatocyte apoptosis [125]. Inhibiting RBPJ function with a synthetic decoy oligodeoxynucleotide (ODN) in the 3,5-Diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet mouse fibrosis model is also effective in reducing fibrosis [47].…”

Section: Notch and Liver Fibrosismentioning

confidence: 57%

“…Interestingly inhibition of Notch signaling in activated HSCs or myofibroblasts induces a mesenchymal-to-epithelial-like transition[116]. In a rat model of cholestatic liver fibrosis, inhibition of Notch signaling with DAPT is also effective in reducing fibrosis [48]. Treatment with another Notch inhibitor, RO4929097 reduces liver fibrosis partly through its effects on hepatic cell differentiation [123].…”

Section: Notch and Liver Fibrosismentioning

confidence: 99%

Notch in fibrosis and as a target of anti-fibrotic therapy

Phan

2016

Pharmacological Research

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The Notch pathway represents a highly conserved signaling network with essential roles in regulation of key cellular processes and functions, many of which are critical for development. Accumulating evidence indicates that it is also essential for fibrosis and thus the pathogenesis of chronic fibroproliferative diseases in diverse organs and tissues. Different effects of Notch activation are observed depending on cellular and tissue context as well as in both physiologic and pathologic states. Close interactions of Notch signaling pathway with other signaling pathways have been identified. In this review, current knowledge on the role of the Notch signaling with special focus on fibrosis and its potential as a therapeutic target is summarized.

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“…Inhibition of Notch signaling with DAPT, a γ-secretase inhibitor, blocked expression of cholangiocyte-specific markers, cholangiocyte proliferation, and cholestatic liver fibrosis 131 . These recent insights into Hh, Wnt, and Notch signaling pathways represent potential novel therapeutic targets into the management of cholestatic liver disease, but more research is needed to determine the feasibility of targeting these pathways for future clinical trials.…”

Section: Linking Cholangiocyte Proliferation With Portal Fibrosismentioning

confidence: 99%

Regulators of Cholangiocyte Proliferation

Hall

Sato²,

Wu³

et al. 2017

gene expr

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Cholangiocytes, a small population of cells within the normal liver, have been the focus of a significant amount of research over the past two decades because of their involvement in cholangiopathies such as primary sclerosing cholangitis and primary biliary cholangitis. This article summarizes landmark studies in the field of cholangiocyte physiology and aims to provide an updated review of biliary pathogenesis. The historical approach of rodent extrahepatic bile duct ligation and the relatively recent utilization of transgenic mice have led to significant discoveries in cholangiocyte pathophysiology. Cholangiocyte physiology is a complex system based on heterogeneity within the biliary tree and a number of signaling pathways that serve to regulate bile composition. Studies have expanded the list of neuropeptides, neurotransmitters, and hormones that have been shown to be key regulators of proliferation and biliary damage. The peptide histamine and hormones, such as melatonin and angiotensin, angiotensin, as well as numerous sex hormones, have been implicated in cholangiocyte proliferation during cholestasis. Numerous pathways promote cholangiocyte proliferation during cholestasis, and there is growing evidence to suggest that cholangiocyte proliferation may promote hepatic fibrosis. These pathways may represent significant therapeutic potential for a subset of cholestatic liver diseases that currently lack effective therapies.

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

Cited by 52 publications

References 34 publications

Inhibition of the Notch Signaling Pathway Reduces the Differentiation of Hepatic Progenitor Cells into Cholangiocytes in Biliary Atresia

Inhibition of the Notch Signaling Pathway Reduces the Differentiation of Hepatic Progenitor Cells into Cholangiocytes in Biliary Atresia

Notch in fibrosis and as a target of anti-fibrotic therapy

Regulators of Cholangiocyte Proliferation

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