Regulation of liver regeneration by growth factors and cytokines - PubMed (original) (raw)

Review

Regulation of liver regeneration by growth factors and cytokines

Friederike Böhm et al. EMBO Mol Med. 2010 Aug.

Abstract

The capability of the liver to fully regenerate after injury is a unique phenomenon essential for the maintenance of its important functions in the control of metabolism and xenobiotic detoxification. The regeneration process is histologically well described, but the genes that orchestrate liver regeneration have been only partially characterized. Of particular interest are cytokines and growth factors, which control different phases of liver regeneration. Historically, their potential functions in this process were addressed by analyzing their expression in the regenerating liver of rodents. Some of the predicted roles were confirmed using functional studies, including systemic delivery of recombinant growth factors, neutralizing antibodies or siRNAs prior to liver injury or during liver regeneration. In particular, the availability of genetically modified mice and their use in liver regeneration studies has unraveled novel and often unexpected functions of growth factors, cytokines and their downstream signalling targets in liver regeneration. This review summarizes the results obtained by functional studies that have addressed the roles and mechanisms of action of growth factors and cytokines in liver regeneration after acute injury to this organ.

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Figures

Figure 1

Figure 1. The different cell types of the liver and liver regeneration after partial hepatectomy (PH)

  1. A. The major cell types of the liver are shown schematically. They include hepatocytes (parenchymal cells of the liver), hepatic stellate cells, Kupffer cells and sinusoidal endothelial cells (SEC).
  2. B. The removal of liver tissue upon PH and the regeneration of the remaining liver are shown schematically.
  3. C, D. Liver cell proliferation as demonstrated by incorporation of 5-bromo-2′-deoxyuridine (BrdU) and subsequent staining of mouse liver sections with an antibody against BrdU is shown in non-injured liver (C) and 48 h after PH (D). BrdU-positive cells were detected using an alkaline phosphatase detection system and are indicated by arrowheads.

Figure 2

Figure 2. Regulation and function of TNF-α and IL-6 in the regenerating liver

Upon PH, expression of both TNF-α and IL-6 is induced in Kupffer cells by LPS, by the complement component C5a and by leukocyte-mediated activation of ICAM-1. TNF-α further enhances the expression of IL-6 through activation of TNFR1. IL-6 signals through a complex of GP130 and the IL-6 receptor expressed by hepatocytes. This results in activation of STAT3 and subsequent production of SOCS3 (negative feedback). STAT3 activation induces hepatocyte proliferation and enhances survival after PH.

Figure 3

Figure 3. Regulation of liver regeneration by EGFR signalling

During liver regeneration the EGFR on hepatocytes is activated in an autocrine manner by amphiregulin and TGF-α, in a paracrine manner by HB-EGF derived from Kupffer cells and sinusoidal endothelial cells (SEC) and in an endocrine manner by EGF secreted from salivary glands and from Brunner's glands in the duodenum, from where it reaches the liver through the portal vein. EGFR activation stimulates hepatocyte proliferation and is important for survival after PH.

Figure 4

Figure 4. Possible collaborative functions of TGF-β and activin in the termination of liver regeneration

Activin A and TGF-β activate their individual receptor complexes on hepatocytes, resulting in activation of SMAD2 and SMAD3 and inhibition of cell proliferation. This is likely to be important for the termination of liver regeneration. Activin A activity is inhibited by the secreted glycoprotein follistatin, which acts as a positive regulator of liver regeneration.

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