Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas

Abstract

Liver regeneration after partial hepatectomy is one of the most studied models of cell, organ, and tissue regeneration. The complexity of the signaling pathways initiating and terminating this process have provided paradigms for regenerative medicine. Many aspects of the signaling mechanisms involved in hepatic regeneration are under active investigation. The purpose of this review is to focus on the areas still not well understood. The review also aims to provide insights into the ways by which current concepts of liver regeneration can provide understanding regarding malfunction of the regenerative process in liver diseases, such as acute liver failure.

Figure 1

Hepatocyte proliferation after partial hepatectomy (PHx) depends on a concerted action between MET (the HGF receptor), EGFR (EGF receptor), and several cytokines, including tumor necrosis factor (TNF). TNF can have a promitogenic effect if it can activate NF-κB. If this activation does not occur, TNF can lead hepatocytes to apoptosis. NF-κB activation is dependent on activation of Akt. Both MET and EGFR are strong inducers of Akt activation. In the event that MET and EGFR fail to act, absence of Akt activation may tip the balance and lead TNF to an apoptotic role, potentially causing liver failure.

Figure 2

Interaction between HGF and TGFβ1 during initiation of liver regeneration. HGF is a mitogen for hepatocytes, whereas TGFβ1 is known as a mito-inhibitor. HGF binds to glycosaminoglycans and TGFβ1 to decorin, both of which are present in the pericellular matrix surrounding hepatocytes. After PHx, activation of urokinase leads to remodeling and degradation of the pericellular matrix. HGF is therefore released and activated by urokinase, where it can have a local mitogenic effect on hepatocytes. Concentrations of both HGF and TGFβ1 rapidly increase in plasma after PHx. Whereas HGF can exert effects on hepatocytes from plasma, TGFβ1 is neutralized by binding to α-2 macroglobulin. The tilt in the balance between HGF and TGFβ1 at the earliest stages of liver regeneration is a key component of the early stimuli leading hepatocytes to proliferation.