Liver regeneration, growth factors, and amphiregulin

Abstract

The sequence of events triggering liver regeneration after acute loss of hepatic mass has been the subject of much investigation during the past 20 years. 1 Rapid changes in gene expression and activation of receptors and transcription factors occur immediately after partial hepatectomy (PHx). 2,3 Several potential signaling stimuli are released in the liver or in circulation after the loss of hepatic parenchyma. These stimuli have effects on liver and on hepatocytes (or other hepatic cells) in culture. Such stimuli include cytokines (eg, tumor necrosis factor α, interleukin-6, norepinephrine, transforming growth factor [TGF]-β 1) and several growth factors. Cytokines are not direct mitogens for hepatocytes in culture and, after removal of their effects (eg, in mouse genetic models or by pharmacologic agents), liver regeneration is retarded or decreased, but hepatic mass is eventually restored nonetheless. Although this may suggest that the role of cytokines is not critical or essential, this should not imply that the events they mediate are not important or that they do not actually occur. The preponderance of evidence suggests that the cytokine effects facilitate optimal timing and orchestration of the early signaling events after PHx, summarized under the term priming of hepatocytes. 4The effects of growth factors are mediated through their receptors. Two receptor-ligand and growth factor signaling systems appear to be mainly involved in liver regeneration: hepatocyte growth factor and its receptor (Met) and the epidermal growth factor receptor (EGFR) and its relatively large family of ligands and coreceptors. The receptor for EGFR was the first one that was shown to play a role in liver regeneration. A seminal publication by Earp et al 5 showed that EGFR was phosphorylated and downregulated after PHx, suggesting binding of ligands and endocytosis.The signaling scenario related to EGFR family members and its ligands is quite complex. The EGFR itself (also known as ErbB or HER) is a member of a family of four. The other members are ErbB-2 (HER-2, NEU), ErbB-3 (HER-3), and ErbB-4 (HER-4). 6 Of these, HER-4 is expressed in only a limited number of tissues and it does not appear to be expressed in adult or embryonic liver. There are many ligands for EGFR, including epidermal growth factor (EGF), TGF-α, amphiregulin, heparin-binding EGF ( HB-EGF), cripto, epiregulin, and betacellulin.All of these considerations are relevant in putting in context the significant findings presented by Berasain et al 7 in this issue of Gastroenterology. The authors found that amphiregulin, a ligand for EGFR, is expressed early (within 30 minutes) during liver regeneration after PHx. In addition, they also found that liver regeneration is substantially decreased and retarded in mice with homozygous deletion of amphiregulin. The findings suggest a unique role for amphiregulin that cannot be substituted by the other ligands for EGFR. The time course of expression of amphiregulin corresponds well with the pattern of tyrosine phosphorylat...

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…Numerous growth factors and cytokines have been implicated in the initiation and control of this regenerative response [1,[10][11][12][13][14][15][16], with the activation of seemingly critical transcription factors, such as AP-1, NFκB and STAT-3. Liver injury can be associated with a defective intestinal barrier, leading to exposure to bacterial products such as lipopolysaccharides and components of the innate immune system (complement fragments), and their activation of the NFκB pathway in Kupffer cells, leading to the production and secretion Figure 1.…”

Hepatocyte-specific deletion of Cdc42 results in delayed liver regeneration after partial hepatectomy in mice

“…Cell cycle progression is driven by growth factors, especially by hepatocyte growth factor (HGF) and the epidermal growth factor receptor ligand family, which can activate various mitogenic signaling pathways, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), phosphoinositide-3 kinase, and S6 kinase. 3,4 Signaling cascades triggered by cytokines and growth factors have been extensively studied because they seem to play central roles in liver regeneration after PH. 5 Recently, it has been demonstrated that liver regeneration is also tightly regulated by physiological functions of the liver, such as lipid 6,7 and bile acid 8 metabolism.…”

Role of ischaemic preconditioning in liver regeneration following major liver resection and transplantation

“…Following this priming phase, cell cycle progression is then dependent on growth factors, such as hepatocyte growth factor (HGF), transforming growth factor-alpha (TGF-α) and epidermal growth factor (EGF) [56,57] . The two main growth-promoting signaling systems involved in liver regeneration are the HGF and its receptor (Met) and the epidermal growth factor receptor (EGFR) and its relatively large family of ligands.…”

“…EGF is mainly produced in the salivary glands in rodents and plays an important role in hepatocyte proliferation by binding to the EGFR on hepatocytes [57] . Sialoadenectomy-induced decrease in circulating EGF in mice and rat models resulted in impaired liver regeneration following partial hepatectomy, which was reversed by the administration of EGF [70,71] .…”

“…Mead and Fausto demonstrated that TGF-α may function as a physiological inducer of hepatocyte DNA synthesis during liver regeneration by an autocrine mechanism by binding to EGFR in both rat and culture models [73] . Besides TGF-α, there are many ligands for EGFR, including EGF, amphiregulin, heparin-binding EGF-like growth factor (HB-EGF) and epiregulin [57] . Although TGF-α expression increases following partial hepatectomy in mice, TGF-α lacking mice do not display diminished liver regeneration [74,75] .…”