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

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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Effect of Rotavirus Strain on the Murine Model of Biliary Atresia

Journal of Virology ◽

10.1128/jvi.02094-06 ◽

2006 ◽

Vol 81 (4) ◽

pp. 1671-1679 ◽

Cited By ~ 49

Author(s):

Steven R. Allen ◽

Mubeen Jafri ◽

Bryan Donnelly ◽

Monica McNeal ◽

David Witte ◽

...

Keyword(s):

Bile Duct ◽

Epithelial Cell ◽

Biliary Atresia ◽

Murine Model ◽

Clinical Signs ◽

Bile Duct Obstruction ◽

Biliary Epithelial Cell ◽

Newborn Mice ◽

Live Virus ◽

Duct Obstruction

ABSTRACT Biliary atresia is a devastating disorder of the newborn in which afflicted infants develop inflammation and fibrosis of the extrahepatic biliary tract, resulting in cirrhosis and end-stage liver disease. Infection with a virus is thought to be a contributing factor in the etiology of biliary atresia. In the murine model of biliary atresia, perinatal exposure to rhesus rotavirus (RRV) results in biliary epithelial cell infection causing bile duct obstruction. The purpose of this study was to determine if tropism for the biliary epithelial cell was unique to RRV. Newborn mice underwent intraperitoneal injection with five strains of rotavirus: RRV (simian), SA11-FM (simian/bovine), SA11-SM (simian), EDIM (murine), and Wa (human). RRV and SA11-FM caused clinical manifestations of bile duct obstruction and high mortality. SA11-SM caused clinical signs of hepatobiliary injury but the mortality was markedly reduced. EDIM and Wa caused no sign of hepatobiliary disease. The systemic and temporal distribution of viral protein and live virus varied according to the injected strain. Immunohistochemistry revealed that RRV and SA11-FM targeted the biliary epithelial cells. In contrast, SA11-SM was found in the liver but in not in the biliary epithelium. These results indicate that strain-specific characteristics dictate tropism for cells of hepatobiliary origin which in turn impact the ability to induce the murine model of biliary atresia.

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Faculty Opinions recommendation of Regulation of epithelial injury and bile duct obstruction by NLRP3, IL-1R1 in experimental biliary atresia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733428770.793556681 ◽

2019 ◽

Author(s):

Rebecca Wells

Keyword(s):

Bile Duct ◽

Biliary Atresia ◽

Bile Duct Obstruction ◽

Epithelial Injury ◽

Duct Obstruction

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Cholangiocyte expression of α2β1-integrin confers susceptibility to rotavirus-induced experimental biliary atresia

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00442.2007 ◽

2008 ◽

Vol 295 (1) ◽

pp. G16-G26 ◽

Cited By ~ 30

Author(s):

Mubeen Jafri ◽

Bryan Donnelly ◽

Steven Allen ◽

Alex Bondoc ◽

Monica McNeal ◽

...

Keyword(s):

Monoclonal Antibody ◽

Cell Surface ◽

Biliary Atresia ◽

Cell Lines ◽

Surface Expression ◽

Cell Surface Expression ◽

Newborn Mice ◽

A Cell

Inoculation of BALB/c mice with rhesus rotavirus (RRV) in the newborn period results in biliary epithelial cell (cholangiocyte) infection and the murine model of biliary atresia. Rotavirus infection of a cell requires attachment, which is governed in part by cell-surface expression of integrins such as α2β1. We hypothesized that cholangiocytes were susceptible to RRV infection because they express α2β1. RRV attachment and replication was measured in cell lines derived from cholangiocytes and hepatocytes. Flow cytometry was performed on these cell lines to determine whether α2β1 was present. Cholangiocytes were blocked with natural ligands, a monoclonal antibody, or small interfering RNA against the α2-subunit and were infected with RRV. The extrahepatic biliary tract of newborn mice was screened for the expression of the α2β1-integrin. Newborn mice were pretreated with a monoclonal antibody against the α2-subunit and were inoculated with RRV. RRV attached and replicated significantly better in cholangiocytes than in hepatocytes. Cholangiocytes, but not hepatocytes, expressed α2β1 in vitro and in vivo. Blocking assays led to a significant reduction in attachment and yield of virus in RRV-infected cholangiocytes. Pretreatment of newborn pups with an anti-α2 monoclonal antibody reduced the ability of RRV to cause biliary atresia in mice. Cell-surface expression of the α2β1-integrin plays a role in the mechanism that confers cholangiocyte susceptibility to RRV infection.

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In vivo evidence for transintestinal cholesterol efflux in patients with complete common bile duct obstruction

Journal of Clinical Lipidology ◽

10.1016/j.jacl.2018.09.010 ◽

2019 ◽

Vol 13 (1) ◽

pp. 213-217.e1 ◽

Cited By ~ 2

Author(s):

François Moreau ◽

Claire Blanchard ◽

Christophe Perret ◽

Laurent Flet ◽

Frédéric Douane ◽

...

Keyword(s):

Bile Duct ◽

Common Bile Duct ◽

Cholesterol Efflux ◽

Bile Duct Obstruction ◽

Duct Obstruction ◽

Common Bile Duct Obstruction

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Plasma cholesterol is excreted in the feces of patients with complete common bile duct obstruction : In vivo evidence for TICE pathway in humans

Atherosclerosis ◽

10.1016/j.atherosclerosis.2017.06.037 ◽

2017 ◽

Vol 263 ◽

pp. e2-e3 ◽

Cited By ~ 1

Author(s):

Francois Moreau ◽

Claire Blanchard ◽

Christophe Perret ◽

Laurent Flet ◽

Frédéric Douane ◽

...

Keyword(s):

Bile Duct ◽

Common Bile Duct ◽

Plasma Cholesterol ◽

Bile Duct Obstruction ◽

Duct Obstruction ◽

Common Bile Duct Obstruction

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Three-dimensional Co-culture of hepatic progenitor cells and mesenchymal stem cells in vitro and in vivo

Microscopy Research and Technique ◽

10.1002/jemt.22526 ◽

2015 ◽

Vol 78 (8) ◽

pp. 688-696 ◽

Cited By ~ 7

Author(s):

Li Zhong ◽

Juhua Gou ◽

Nian Deng ◽

Hao Shen ◽

Tongchuan He ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Progenitor Cells ◽

Three Dimensional ◽

Hepatic Progenitor Cells

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TGF-β1 Induces the Dual Regulation of Hepatic Progenitor Cells with Both Anti- and Proliver Fibrosis

Stem Cells International ◽

10.1155/2016/1492694 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Ai-Ting Yang ◽

Dou-Dou Hu ◽

Ping Wang ◽

Min Cong ◽

Tian-Hui Liu ◽

...

Keyword(s):

Liver Fibrosis ◽

Progenitor Cells ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Dependent Manner ◽

Hepatic Progenitor Cells ◽

Serum Aminotransferase ◽

Dose Dependent

Transforming growth factor-beta 1 (TGF-β1) plays a central role in hepatic progenitor cells- (HPCs-) mediated liver repair and fibrosis. However, different effects of TGF-β1 on progenitor cells have not been described. In this study, both in vitro (HPCs cocultured with hepatic stellate cells (HSCs) in transwells) and in vivo (CCl4-injured liver fibrosis rat) systems were used to evaluate the impacts. We found that HPCs pretreated with TGF-β1 for 12 hours inhibited the activation of HSCs, while sensitization for 48 hours increased the activation of HSCs. Consistent with these in vitro results, the in vivo fibrosis rat model showed the same time-dependent dual effect of TGF-β1. Regression of liver fibrosis as well as normalization of serum aminotransferase and albumin levels was detected in the rats transplanted with HPCs pretreated with TGF-β1 for 12 hours. In contrast, severe liver fibrosis and elevated collagen-1 levels were detected in the rats transplanted with HPCs pretreated with TGF-β1 for 48 hours. Furthermore, the TGF-β1-pretreated HPCs were shown to deactivate HSCs via enhancing SERPINE1 expression. Inhibition of SERPINE1 reversed the deactivation response in a dose-dependent manner.

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Advances in Liver Regeneration: Revisiting Hepatic Stem/Progenitor Cells and Their Origin

Stem Cells International ◽

10.1155/2016/7920897 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 17

Author(s):

Ali-Reza Sadri ◽

Marc G. Jeschke ◽

Saeid Amini-Nik

Keyword(s):

Liver Regeneration ◽

Progenitor Cells ◽

Liver Dysfunction ◽

Current Knowledge ◽

Hepatic Progenitor Cells ◽

Adult Liver ◽

Chronic Injury ◽

Serotonin Pathway

The liver has evolved to become a highly plastic organ with extraordinary regenerative capabilities. What drives liver regeneration is still being debated. Adult liver stem/progenitor cells have been characterized and used to produce functional hepatocytes and biliary cellsin vitro. However,in vivo, numerous studies have questioned whether hepatic progenitor cells have a significant role in liver regeneration. Mature hepatocytes have recently been shown to be more plastic than previously believed and give rise to new hepatocytes after acute and chronic injury. In this review, we discuss current knowledge in the field of liver regeneration and the importance of the serotonin pathway as a clinical target for patients with liver dysfunction.

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