Notch signaling and progenitor/ductular reaction in steatohepatitis

Carola M. Morell, Romina Fiorotto, Marica Meroni, Aileen Raizner, Barbara Torsello, Massimiliano Cadamuro, Gaia Spagnuolo, Eleanna Kaffe, Salvatore Sutti, Emanuele Albano, Mario Strazzabosco

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere0187384
JournalPLoS One
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2017

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Fatty Liver
hepatocytes
Hepatocytes
stem cells
Stem Cells
Hepatic Stellate Cells
fibrosis
Liver
liver
Fibrosis
choline
Nutrition
Choline
Chemical activation
Methionine
methionine
Diet
diet
cells
Notch Receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Morell, C. M., Fiorotto, R., Meroni, M., Raizner, A., Torsello, B., Cadamuro, M., ... Strazzabosco, M. (2017). Notch signaling and progenitor/ductular reaction in steatohepatitis. PLoS One, 12(11), [e0187384]. https://doi.org/10.1371/journal.pone.0187384

Notch signaling and progenitor/ductular reaction in steatohepatitis. / Morell, Carola M.; Fiorotto, Romina; Meroni, Marica; Raizner, Aileen; Torsello, Barbara; Cadamuro, Massimiliano; Spagnuolo, Gaia; Kaffe, Eleanna; Sutti, Salvatore; Albano, Emanuele; Strazzabosco, Mario.

In: PLoS One, Vol. 12, No. 11, e0187384, 01.11.2017.

Research output: Contribution to journalArticle

Morell, CM, Fiorotto, R, Meroni, M, Raizner, A, Torsello, B, Cadamuro, M, Spagnuolo, G, Kaffe, E, Sutti, S, Albano, E & Strazzabosco, M 2017, 'Notch signaling and progenitor/ductular reaction in steatohepatitis', PLoS One, vol. 12, no. 11, e0187384. https://doi.org/10.1371/journal.pone.0187384
Morell CM, Fiorotto R, Meroni M, Raizner A, Torsello B, Cadamuro M et al. Notch signaling and progenitor/ductular reaction in steatohepatitis. PLoS One. 2017 Nov 1;12(11). e0187384. https://doi.org/10.1371/journal.pone.0187384
Morell, Carola M. ; Fiorotto, Romina ; Meroni, Marica ; Raizner, Aileen ; Torsello, Barbara ; Cadamuro, Massimiliano ; Spagnuolo, Gaia ; Kaffe, Eleanna ; Sutti, Salvatore ; Albano, Emanuele ; Strazzabosco, Mario. / Notch signaling and progenitor/ductular reaction in steatohepatitis. In: PLoS One. 2017 ; Vol. 12, No. 11.
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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.",
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AU - Torsello, Barbara

AU - Cadamuro, Massimiliano

AU - Spagnuolo, Gaia

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