Integrin alpha v beta 6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis

• Published in: Hepatology (Baltimore, Md.) Vol. 63; no. 1; pp. 217 - 232
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: 01.01.2016
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.28274

Integrin alpha v beta 6 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 (TGF beta 1). In human liver cirrhosis, alpha v beta 6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that alpha v beta 6 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 alpha v beta 6-dependent TGF beta 1 activation. Freshly isolated alpha v beta 6 super(+) 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 alpha v beta 6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti- alpha v beta 6 antibody is recapitulated by TGF beta 1 neutralization and rescued by addition of bioactive TGF beta 1. Genetic disruption or selective targeting of alpha v beta 6 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 alpha v beta 6 is a promising target for chronic fibrotic liver diseases and associated cancers. (Hepatology 2016; 63:217-232)