| First Author | Greenhalgh SN | Year | 2019 |
| Journal | Am J Pathol | Volume | 189 |
| Issue | 2 | Pages | 258-271 |
| PubMed ID | 30448409 | Mgi Jnum | J:270475 |
| Mgi Id | MGI:6276403 | Doi | 10.1016/j.ajpath.2018.10.007 |
| Citation | Greenhalgh SN, et al. (2019) Loss of Integrin alphavbeta8 in Murine Hepatocytes Accelerates Liver Regeneration. Am J Pathol 189(2):258-271 |
| abstractText | 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 alphavbeta8 has a major role in activating transforming growth factor (TGF)-beta, a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin alphavbeta8 would increase hepatocyte proliferation and accelerate liver regeneration after injury. Using Itgb8(flox/flox);Alb-Cre mice to deplete hepatocyte alphavbeta8, after partial hepatectomy, hepatocyte proliferation and liver-to-body weight ratio were significantly increased in Itgb8(flox/flox);Alb-Cre mice compared with control mice. Antibody-mediated blockade of hepatocyte alphavbeta8 in vitro, with assessment of TGF-beta signaling pathways by real-time quantitative PCR array, supported the hypothesis that integrin alphavbeta8 inhibition alters hepatocyte TGF-beta 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 Itgb8(flox/flox);Alb-Cre and control mice. Immunohistochemistry for integrin alphavbeta8 in healthy and injured human liver demonstrated that human hepatocytes express integrin alphavbeta8. Depletion of hepatocyte integrin alphavbeta8 results in increased hepatocyte proliferation and accelerated liver regeneration after partial hepatectomy in mice. These data demonstrate that targeting integrin alphavbeta8 may represent a promising therapeutic strategy to drive liver regeneration in patients with a broad range of liver diseases. |
