Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis
Open accessAbstract
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. (H epatology 2016;63:217–232)
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Integrin αvβ6 is highly expressed by ductal cells.
“Integrin αvβ6 is highly expressed by ductal cells.58”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [58]
IL-17A signaling has a confirmed role in fibrosis development in multiple tissues, based on IL-17A- and IL-17RA-deficient mice and neutralizing monoclonal antibodies.
“Experiments with IL-17A- and IL-17RA-deficient mice, as well as therapeutic studies with IL-17A neutralizing monoclonal antibodies confirmed a role for IL-17A signaling in the development of fibrosis in multiple tissues110–112,116–118”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [111]
IL-17A is a key inducer of fibrosis in several organ systems, including lung, liver, kidney, heart, and skin.
“The pro-inflammatory cytokine IL-17A was identified as a key inducer of fibrosis in several different organ systems, including the lung, liver, kidney, heart, and skin109–114”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [111]
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Self-citation
- Authors
- Peng, Z., Ikenaga, N., Liu, S. B., Sverdlov, D. Y., Vaid, K. A., Dixit, R., Weinreb, P. H., Violette, S., Sheppard, D., Schuppan, D., & Popov, Y.
- Affiliations
- Department of Oncology,The First Affiliated Hospital of Sun Yat‐sen University,Guangzhou,China
- Beth Israel Deaconess Medical Center (US)
- Biogen (United States) (US)
- University of California, San Francisco (US)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Popov, Yury
- Venue
- Hepatology
- Published
- 2015-11-23
- Volume
- 63
- Issue
- 1
- Pages
- 217-232
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC5312042
- OpenAlex
- W2119171121
- Cited by
- 118
- References
- 52
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 12 · 2023: 7 · 2022: 12 · 2021: 11 · 2020: 15 · 2019: 10 · 2018: 15 · 2017: 14 · 2016: 5 · 2015: 1
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Biogen Idec, Inc.
- Stomedix, Inc.
- Department of Medicine (BIDMC)
- Yat-sen University (Guangzhou, China)
- National Natural Science Foundation of China (81301842)
- Pearl River S&T Nova Program (2014J2200087)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- integrin αvβ6, hepatic progenitor cells, ductular reaction, liver fibrosis, liver cirrhosis, hepatocellular carcinoma, cholangiocyte differentiation, hepatocyte differentiation, liver regeneration
- MeSH terms
- Animals, Antigens, Neoplasm, Fibrosis, Humans, Liver, Liver Cirrhosis, Liver Neoplasms, Male, Mice, Inbred C57BL, Stem Cells, Cholangitis, Sclerosing, Integrins, Hepatocytes, Mice, Carcinogenesis
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