Pericentral hepatocytes produce IGF-2 to promote liver regeneration during special injuries

Abstract

Liver regeneration happens after various types of injuries. Unlike the well-studied liver regeneration caused by partial hepatectomy, there is accumulating evidence suggesting that liver regeneration during other injuries may result from some unknown mechanism. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long-term treatments of carbon tetrachloride (CCl₄). However, it was not observed during the early phase of acute liver injuries after partial hepatectomy or single treatment of CCl₄. Remarkably, most of IGF-2 expressing hepatocytes were located at the histological area around the central vein of liver lobule after the liver injuries caused either in Fah-deficient mice or in CCl₄ chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by the induced IGF-2 over-expression, which could be inhibited by AAV-delivered IGF-2 shRNAs or linsitinib, an inhibitor of IGF-2 signaling. Proliferating hepatocytes in vivo responded to IGF-2 via both insulin receptor and IGF-1 receptor. IGF-2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF-2 was also found to co-localize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. Conclusion: IGF-2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs after partial hepatectomy. This article is protected by copyright. All rights reserved.

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