| First Author | Morell CM | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 11 | Pages | e0187384 |
| PubMed ID | 29140985 | Mgi Jnum | J:251636 |
| Mgi Id | MGI:6094719 | Doi | 10.1371/journal.pone.0187384 |
| Citation | Morell CM, et al. (2017) Notch signaling and progenitor/ductular reaction in steatohepatitis. PLoS One 12(11):e0187384 |
| abstractText | 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-beta1 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-beta1 treatment in primary hepatic stellate cells (HSC) induced Jag1 expression. In MCD diet-fed mice, alphaSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-beta1 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. |
