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Loss of Integrin αvβ8 in Murine Hepatocytes Accelerates Liver Regeneration

Research output: Contribution to journalArticle

  • Stephen N Greenhalgh
  • Kylie P Matchett
  • Richard S Taylor
  • Katherine Huang
  • John T Li
  • Koy Saeteurn
  • Mhairi C Donnelly
  • Eilidh E M Simpson
  • Joshua L Pollack
  • Amha Atakilit
  • Kenneth J Simpson
  • Jacquelyn J Maher
  • John P Iredalehttp://orcid.org/0000-0003-2174-5127
  • Dean Sheppard
  • Neil C Henderson
Original languageEnglish
Pages (from-to)258-271
Number of pages14
JournalAmerican Journal of Pathology
Volume189
Issue number2
Early online date16 Nov 2018
DOIs
DateAccepted/In press - 10 Oct 2018
DateE-pub ahead of print - 16 Nov 2018
DatePublished (current) - Feb 2019

Abstract

Recent fate-mapping studies in mice have provided substantial evidence that mature adult hepatocytes are a major source of new hepatocytes after liver injury. In other systems, integrin αvβ8 has a major role in activating transforming growth factor (TGF)-β, a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin αvβ8 would increase hepatocyte proliferation and accelerate liver regeneration after injury. Using Itgb8flox/flox;Alb-Cre mice to deplete hepatocyte αvβ8, after partial hepatectomy, hepatocyte proliferation and liver-to-body weight ratio were significantly increased in Itgb8flox/flox;Alb-Cre mice compared with control mice. Antibody-mediated blockade of hepatocyte αvβ8 in vitro, with assessment of TGF-β signaling pathways by real-time quantitative PCR array, supported the hypothesis that integrin αvβ8 inhibition alters hepatocyte TGF-β signaling toward a pro-regenerative phenotype. A diethylnitrosamine-induced model of hepatocellular carcinoma, used to examine the possibility that this pro-proliferative phenotype might be oncogenic, revealed no difference in either tumor number or size between Itgb8flox/flox;Alb-Cre and control mice. Immunohistochemistry for integrin αvβ8 in healthy and injured human liver demonstrated that human hepatocytes express integrin αvβ8. Depletion of hepatocyte integrin αvβ8 results in increased hepatocyte proliferation and accelerated liver regeneration after partial hepatectomy in mice. These data demonstrate that targeting integrin αvβ8 may represent a promising therapeutic strategy to drive liver regeneration in patients with a broad range of liver diseases.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Elsevier at https://doi.org/10.1016/j.ajpath.2018.10.007 . Please refer to any applicable terms of use of the publisher.

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