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PLoS One. 2017 Nov 15;12(11):e0187384. doi: 10.1371/journal.pone.0187384. eCollection 2017.

Notch signaling and progenitor/ductular reaction in steatohepatitis.

Author information

1
International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy.
2
Liver Center, Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America.
3
Department of Health Sciences, University "A. Avogadro" of East Piedmont, Novara, Italy.

Abstract

BACKGROUND AND OBJECTIVE:

Persistent hepatic progenitor cells (HPC) activation resulting in ductular reaction (DR) is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis.

METHODS:

Steatohepatitis was generated using methionine-choline deficient (MCD) diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre.

RESULTS:

MCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-β1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent) Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-β1 treatment in primary hepatic stellate cells (HSC) induced Jag1 expression. In MCD diet-fed mice, αSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-β1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression.

CONCLUSION:

Our data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.

PMID:
29140985
PMCID:
PMC5687773
DOI:
10.1371/journal.pone.0187384
[Indexed for MEDLINE]
Free PMC Article

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