Loss of Integrin ?v?8 in Murine Hepatocytes Accelerates Liver Regeneration.

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 ?v?8 has a major role in activating transforming growth factor (TGF)-?, a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin ?v?8 would increase hepatocyte proliferation and accelerate liver regeneration after injury. Using Itgb8flox/flox;Alb-Cre mice to deplete hepatocyte ?v?8, 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 ?v?8 in vitro, with assessment of TGF-? signaling pathways by real-time quantitative PCR array, supported the hypothesis that integrin ?v?8 inhibition alters hepatocyte TGF-? 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 ?v?8 in healthy and injured human liver demonstrated that human hepatocytes express integrin ?v?8. Depletion of hepatocyte integrin ?v?8 results in increased hepatocyte proliferation and accelerated liver regeneration after partial hepatectomy in mice. These data demonstrate that targeting integrin ?v?8 may represent a promising therapeutic strategy to drive liver regeneration in patients with a broad range of liver diseases.

SUBMITTER: Greenhalgh SN 

PROVIDER: S-EPMC6360354 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature