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

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 inhibiti...

Full description

Saved in:
Bibliographic Details
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: United States 01.01.2016
Subjects:
Animals
Antigens, Neoplasm - physiology
Carcinogenesis
Cholangitis, Sclerosing - etiology
Fibrosis - etiology
Hepatocytes
Humans
Integrins - physiology
Liver - pathology
Liver Cirrhosis - etiology
Liver Neoplasms - etiology
Male
Mice
Mice, Inbred C57BL
Stem Cells - physiology
ISSN:0270-9139, 1527-3350
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. (Hepatology 2016;63:217–232)
Bibliography:Potential conflict of interest: Dr. Sheppard consults and owns stock in Pliant Therapeutics. He holds intellectual property rights and received grants from Biogen. He advises Genentech. Dr. Schuppan consults and received grants from Boehringer‐Ingelheim. He consults for MSD, Mitsubishi‐Tanabe, and Takeda. Dr. Popov received grants from Biogen and Stromedix. Dr. Violette is employed by and owns stock in Biogen. Dr. Weinreb is employed by and owns stock in Biogen.
Supported by research grants from Biogen, Inc., and Stomedix, Inc.; an institutional grant from Department of Medicine, Beth Israel Deaconess Medical Center (to Y.P.); a career development award from The First Affiliated Hospital of Sun Yat‐sen University (to Z.‐W.P.); and grants from the National Natural Science Foundation of China (81301842) and the Pearl River S&T Nova Program (2014J2200087).
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.28274