Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis

Zhen Wei Peng, Naoki Ikenaga, Susan B. Liu, Deanna Y. Sverdlov, Kahini A. Vaid, Richa Dixit, Paul H. Weinreb, Shelia Violette, Dean Sheppard, Detlef Schuppan, Yury Popov

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Integrin αvβ6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGFβ1). In human liver cirrhosis, αvβ6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that αvβ6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin αvβ6-dependent TGFβ1 activation. Freshly isolated αvβ6+ liver cells demonstrate clonogenic potential and differentiate into cholangiocytes and functional hepatocytes in vitro, whereas colony formation by epithelial cell adhesion molecule-positive progenitor cells is blocked by αvβ6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti-αvβ6 antibody is recapitulated by TGFβ1 neutralization and rescued by addition of bioactive TGFβ1. Genetic disruption or selective targeting of αvβ6 with 3G9 antibody potently inhibits progenitor cell responses in mouse models of chronic biliary injury and protects from liver fibrosis and tumorigenesis, two conditions clinically associated with exacerbated ductular reaction. Conclusion: These results suggest that αvβ6 is a promising target for chronic fibrotic liver diseases and associated cancers.

Original languageEnglish
Pages (from-to)217-232
Number of pages16
JournalHepatology
Volume63
Issue number1
DOIs
Publication statusPublished - Jan 1 2016
Externally publishedYes

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Integrins
Transforming Growth Factor beta
Hepatocytes
Carcinogenesis
Fibrosis
Stem Cells
Liver Cirrhosis
Wounds and Injuries
Cell Lineage
Neutralizing Antibodies
Liver Diseases
Anti-Idiotypic Antibodies
Rodentia
Antibodies
Liver
Neoplasms
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis. / Peng, Zhen Wei; Ikenaga, Naoki; Liu, Susan B.; Sverdlov, Deanna Y.; Vaid, Kahini A.; Dixit, Richa; Weinreb, Paul H.; Violette, Shelia; Sheppard, Dean; Schuppan, Detlef; Popov, Yury.

In: Hepatology, Vol. 63, No. 1, 01.01.2016, p. 217-232.

Research output: Contribution to journalArticle

Peng, ZW, Ikenaga, N, Liu, SB, Sverdlov, DY, Vaid, KA, Dixit, R, Weinreb, PH, Violette, S, Sheppard, D, Schuppan, D & Popov, Y 2016, 'Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis', Hepatology, vol. 63, no. 1, pp. 217-232. https://doi.org/10.1002/hep.28274
Peng, Zhen Wei ; Ikenaga, Naoki ; Liu, Susan B. ; Sverdlov, Deanna Y. ; Vaid, Kahini A. ; Dixit, Richa ; Weinreb, Paul H. ; Violette, Shelia ; Sheppard, Dean ; Schuppan, Detlef ; Popov, Yury. / Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis. In: Hepatology. 2016 ; Vol. 63, No. 1. pp. 217-232.
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