Loss of integrin αvβ8 in murine hepatocytes accelerates liver regeneration

Stephen Greenhalgh, Kylie Matchett, Richard Taylor, Katherine Huang, John T Li, Koy Saeteurn, Mhairi C Donnelly, Eilidh E M Simpson, Joshua L Pollack, Amha Atakilit, Kenneth Simpson, Jacquelyn J. Maher, John Iredale, Dean Sheppard, Neil Henderson

Research output: Contribution to journalArticlepeer-review

Abstract

Recent fate-mapping studies in mice have provided substantial evidence that mature adult hepatocytes are a major source of new hepatocytes following liver injury. In other systems, integrin αvβ8 has a major role in activating transforming growth factor beta (TGFβ), a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin αvβ8 would increase hepatocyte proliferation and accelerate liver regeneration following injury. Using Itgb8flox/flox;Alb-Cre mice to deplete hepatocyte αvβ8, we found that, following partial hepatectomy, hepatocyte proliferation and liver to body weight ratio were significantly increased in Itgb8flox/flox;Alb-Cre mice compared to control. Antibody-mediated blockade of hepatocyte αvβ8 in vitro, with assessment of TGFβ signaling pathways by qPCR array, supported the hypothesis that integrin αvβ8 inhibition alters hepatocyte TGFβ signaling towards a pro-regenerative phenotype. A diethylnitrosamine-induced model of hepatocellular carcinoma, employed 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 αvβ8 results in increased hepatocyte proliferation and accelerated liver regeneration following 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.
Original languageEnglish
Pages (from-to)258-271
JournalAmerican Journal of Pathology
Volume189
Issue number2
Early online date16 Nov 2018
DOIs
Publication statusPublished - 1 Feb 2019

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