title: A methionine-choline-deficient diet elicits NASH in the immunodeficient mouse featuring a model for hepatic cell transplantation.
abstract: Non-alcoholic staetohepatitis (NASH) is associated with fat deposition in the liver favoring inflammatory processes and development of fibrosis, cirrhosis and finally hepatocellular cancer. In Western lifestyle countries, NASH has reached a 20% prevalence in the obese population with escalating tendency in the future. Very often, liver transplantation is the only therapeutic option. Recently, transplantation of hepatocyte-like cells differentiated from mesenchymal stem cells was suggested a feasible alternative to whole organ transplantation to ameliorate donor organ shortage. Hence, in the present work an animal model of NASH was established in immunodeficient mice to investigate the feasibility of human stem cell-derived hepatocyte-like cell transplantation. NASH was induced by feeding a methionine/choline-deficient diet (MCD-diet) for up to 5 weeks. Animals developed a fatty liver featuring fibrosis and elevation of the proinflammatory markers serum amyloid A (SAA) and tumor necrosis factor alpha (TNFα). Hepatic triglycerides were significantly increased as well as alanine aminotransferase demonstrating inflammation-linked hepatocyte damage. Elevation of αSMA mRNA and collagen I as well as liver architecture deterioation indicated massive fibrosis. Both short- and long-term post-transplantation human hepatocyte-like cells resided in the mouse host liver indicating parenchymal penetration and most likely functional engraftment. Hence, the NASH model in the immunodeficient mouse is the first to allow for the assessment of the therapeutic impact of human stem cell-derived hepatocyte transplantation.
authors: Department of Medicine I, Martin-Luther University of Halle-Wittenberg, Heinrich-Damerow-Straße 1, D-06120 Halle/Saale, Germany.
authors: Sandra
authors: S
authors: Pelz
authors: Peggy
authors: P
authors: Stock
authors: Sandra
authors: S
authors: Brückner
authors: Bruno
authors: B
authors: Christ
mesh_terms: D000818:Animals; D002796:Choline Deficiency / Q000150:complications*; D004268:DNA-Binding Proteins / Q000235:genetics; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005240:Feasibility Studies; D005786:Gene Expression Regulation; D016031:Liver Transplantation; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine