%0 Journal Article
%T Loss of Integrin ¦Áv¦Â8 in Murine Hepatocytes Accelerates Liver Regeneration
%A Amha Atakilit
%A Dean Sheppard
%A Eilidh E.M. Simpson
%A Jacquelyn J. Maher
%A John P. Iredale
%A John T. Li
%A Joshua L. Pollack
%A Katherine Huang
%A Kenneth J. Simpson
%A Koy Saeteurn
%A Kylie P. Matchett
%A Mhairi C. Donnelly
%A Richard S. Taylor
%A Stephen N. Greenhalgh
%J Archive of "The American Journal of Pathology".
%D 2019
%R 10.1016/j.ajpath.2018.10.007
%X 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 ¦Áv¦Â8 has a major role in activating transforming growth factor (TGF)-¦Â, a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin ¦Áv¦Â8 would increase hepatocyte proliferation and accelerate liver regeneration after injury. Using Itgb8flox/flox;Alb-Cre mice to deplete hepatocyte ¦Áv¦Â8, 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 ¦Áv¦Â8 in vitro, with assessment of TGF-¦Â signaling pathways by real-time quantitative PCR array, supported the hypothesis that integrin ¦Áv¦Â8 inhibition alters hepatocyte TGF-¦Â 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 ¦Áv¦Â8 in healthy and injured human liver demonstrated that human hepatocytes express integrin ¦Áv¦Â8. Depletion of hepatocyte integrin ¦Áv¦Â8 results in increased hepatocyte proliferation and accelerated liver regeneration after partial hepatectomy in mice. These data demonstrate that targeting integrin ¦Áv¦Â8 may represent a promising therapeutic strategy to drive liver regeneration in patients with a broad range of liver diseases
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360354/