The EGF receptor is required for efficient liver regeneration

Department of Dermatology, Division of Immunology, Allergy, and Infectious Diseases, and Institute for Cancer Research, Department of Medicine 1, Vienna Competence Center, Medical University of Vienna, Lazarettgasse 19, A-1090 Vienna, Austria.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(43):17081-6. DOI: 10.1073/pnas.0704126104
Source: PubMed


Mice lacking the EGF receptor (EGFR) die between midgestation and postnatal day 20 with various defects in neural and epithelial organs. Here, we generated mice carrying a floxed EGFR allele to inactivate the EGFR in fetal and adult liver. Perinatal deletion of EGFR in hepatocytes resulted in decreased body weight, whereas deletion in the adult liver did not affect body mass. Although liver function was not affected, after partial hepatectomy mice lacking EGFR in the liver showed increased mortality accompanied by increased levels of serum transaminases indicating liver damage. Liver regeneration was delayed in the mutants because of reduced hepatocyte proliferation. Analysis of cell cycle progression in EGFR-deficient livers indicated a defective G(1)-S phase entry with delayed transcriptional activation and reduced protein expression of cyclin D1 followed by reduced cdk2 and cdk1 expression. Impaired liver regeneration was accompanied by compensatory up-regulation of TNFalpha in the serum and prolonged activation of c-Jun. Moreover, p38alpha and NF-kappaB activation was reduced in regenerating mutant livers, indicating an impaired stress response after hepatectomy. Our studies demonstrate that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration.

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Available from: Anuradha Natarajan, Apr 08, 2015
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    • "Mice with a floxed EGFR allele (Egfr f/f ) [19], in which the promoter and the first exon of the Egfr gene are flanked by loxP sites, and Spink3 Cre/+ mice were generated previously [20]. In Spink3 Cre/+ mice, the cre recombinase gene is expressed only in acinar cells, but not in islet or ductal cells, in the pancreas [20]. "
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    ABSTRACT: Autophagy is an intracellular degradation system in eukaryotic cells that occurs at a basal level. It can also be induced in response to environmental signals including nutrients, hormones, microbial pathogens, and growth factors, although the mechanism is not known in detail. We previously demonstrated that excessive autophagy is induced within pancreatic acinar cells deficient in Spink3, which is a trypsin inhibitor. SPINK1, the human homolog of murine Spink3, has structural similarity to epidermal growth factor (EGF), and can bind and stimulate the EGF receptor (EGFR). To analyze the role of the EGFR in pancreatic development, in the regulation of autophagy in pancreatic acinar cells, and in cerulein-induced pancreatitis, we generated and examined acinar cell-specific Egfr-deficient (Egfr-/-) mice. Egfr-/- mice showed no abnormalities in pancreatic development, induction of autophagy, or cerulein-induced pancreatitis, suggesting that Egfr is dispensable for autophagy regulation in pancreatic acinar cells.
    Biochemical and Biophysical Research Communications 03/2014; 446(1). DOI:10.1016/j.bbrc.2014.02.111 · 2.30 Impact Factor
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    • "The defective EFGR function inhibits G 1 –S phase entry with delayed transcriptional activation and reduced protein expression of cyclin-dependent kinases [24]. In conjunction with impaired HGFR function, this likely explains the ethanol-exposed hepatocyte phenotype of cell senescence or cell cycle arrest. "
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    Digestive and Liver Disease 01/2014; 46(5). DOI:10.1016/j.dld.2013.11.015 · 2.96 Impact Factor
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    • "This was accompanied with a lower lymphocyte infiltration in the liver, a reduced hepatocyte apoptosis and an increase in hepatocyte proliferation. MSCs were shown to secrete epidermal growth factor that could promote hepatocyte proliferation and function during liver regeneration (Natarajan et al., 2007). MSCs were also shown to reduce the proliferation of stellate cells and collagen type I synthesis through the secretion of TNF-α (Parekkadan et al., 2007b), and to promote hepatic stellate cell apoptosis through the secretion of nerve growth factor (Lin et al., 2009). "
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    ABSTRACT: Mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been extensively investigated in small animal models to treat both acute and chronic liver injuries. Mechanisms of action are not clearly elucidated but may include their ability to differentiate into hepatocyte-like cells, to reduce inflammation, and to enhance tissue repair at the site of injury. This approach is controversial and evidence in large animals is missing. Side effects of MSC infusion such as the contribution to a fibrotic process have been reported in experimental settings. Nevertheless, MSCs moved quickly from bench to bedside and over 280 clinical trials are registered, of which 28 focus on the treatment of liver diseases. If no severe side-effects were observed so far, long-term benefits remain uncertain. More preclinical data regarding mechanisms of action, long term safety and efficacy are warranted before initiating large scale clinical application. The proposal of this review is to visit the current state of knowledge regarding mechanisms behind the therapeutic effects of MSCs in the treatment of experimental liver diseases, to address questions about efficacy and risk, and to discuss recent clinical advances involving MSC-based therapies.
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