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MET and epidermal growth factor signaling: The pillars of liver regeneration?

When caring for patients with acute liver injury, a bedrock assumption is that normal hepatic function will usually be restored once the injurious stimuli have resolved. The main factor underlying the restoration of liver function is the remarkable ability of differentiated hepatocytes to undergo compensatory hyperplasia (“regeneration”), which is observed after partial liver resection, transplantation, or insults causing widespread cell death, such as viruses, alcohol, drugs, toxins, ischemia, and autoimmune hepatitis. The capacity of the liver to regenerate is conserved among species and suggests an evolutionary imperative to restore appropriate functional hepatocyte mass. Indeed, extensive studies in models of liver regeneration have shown that there is considerable redundancy in the cellular pathways and signaling molecules controlling this process, such that deletion or inhibition of key mediators delays, but does not abolish, the hyperplastic response. Furthermore, in models where hepatocyte proliferation is blocked by chemical or genetic means, proliferation of hepatic progenitor cells can reconstitute hepatocyte populations. Decades of research have shed considerable light on the myriad factors regulating liver regeneration, but the “essential” signals that trigger this response have not been clearly identified. In this issue of HEPATOLOGY, Paranjpe et al. provide new insight into the key growth-factor-mediated events that control liver regeneration. They focus on the two known “complete” growth factor signaling pathways in hepatocytes: the MET receptor (activated by hepatocyte growth factor [HGF]) and the epidermal growth factor (EGF) receptor (EGFR), which is activated by EGF and related ligands. Both HGF and EGF are sufficient to trigger proliferation of hepatocytes in culture and in vivo, and both are present in physiological concentrations in the liver. HGF is synthesized by several cell types in the liver, and during regeneration, it is liberated from stores within the hepatic extracellular matrix. EGF is primarily delivered to the liver by the portal circulation, arising from several extrahepatic sites including the Brunner’s glands of the duodenum. Additional EGFR ligands are produced in the liver, including transforming growth factor a and amphiregulin. Previous studies have shown that inhibition of either MET or EGFR signaling can impair liver regeneration in rodents, but neither is absolutely necessary for this process—in part, because each system can compensate for the loss of the other. The article by Paranjpe et al. addressed whether combined loss of both MET and EGFR signaling is sufficient to prevent liver regeneration in the most common mouse model, two-thirds partial hepatectomy (PHx). PHx stimulates robust hepatocyte proliferation within 1-2 days, and liver mass is restored within weeks. The investigators used an inducible Cre/Lox system to ablate MET function in the adult animal and eliminated EGFR signaling by feeding Canertinib, a potent irreversible inhibitor of this receptor (this compound also affects other EGFR family members with variable efficacy). As expected, inhibition of either MET or EGFR led to distinct alterations in Abbreviations: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; PHx, twothirds partial hepatectomy.