title: Efficacy of adipose tissue-mesenchymal stem cell transplantation in rats with acetaminophen liver injury.
abstract: OBJECTIVE
  Acetaminophen intoxication is a leading cause of acute liver failure. Liver transplantation for acute liver failure is limited by the availability of donor organs. In this study, we aimed at identifying if the transplantation of adipose tissue-mesenchymal stem cells (ASCs) may exert therapeutic effects on acetaminophen-induced liver injury.
  
  
  METHODS
  ASCs were isolated from human subcutaneous tissue and were transfected with a green fluorescent protein (GFP). Sprague-Dawley rats were administrated 300mg/kg of acetaminophen intraperitoneally and were transplanted with ASCs or vehicle. After 24h from acetaminophen administration, rats were sacrificed. Hepatic levels of isoprostanes, 8-hydroxyguanosine (8-OHG), nitrites/nitrates and reduced glutathione (GSH) were determined as markers of oxidative stress; JNK phosphorylation and hepatic levels of inflammatory cytokines and regeneration factors were also assessed.
  
  
  RESULTS
  Transplantation of ASCs decreased AST, ALT and prothrombin time to the levels observed in control rats. Transplanted animals had normal plasma ammonia and did not display clinical encephalopathy. Liver sections of intoxicated rats treated with vehicle showed lobular necrosis and diffuse vacuolar degeneration; in rats transplanted with ASCs liver injury was almost absent. Transplantation of ASCs decreased liver isoprostanes, 8-OHG and nitrite-nitrates to the levels of control rats, while preserving GSH. Consistently, hepatic levels of TNF-α, MCP-1, IL-1β, ICAM-1 and phospho-JNK were markedly increased in rats treated with vehicle and were restored to the levels of controls in animals transplanted with ASCs. Furthermore, ASC transplantation increased liver expression of cyclin D1 and PCNA, two established hepatocyte regeneration factors, whereas ASCs were not able to metabolize acetaminophen in vitro.
  
  
  CONCLUSIONS
  In this study, we demonstrated that ASC transplantation is effective in treating acetaminophen liver injury by enhancing hepatocyte regeneration and inhibiting liver stress and inflammatory signaling.
authors: U.O.C. di Gastroenterologia, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy. Electronic address: federicosalomone@rocketmail.com.
authors: Federico
authors: F
authors: Salomone
authors: Ignazio
authors: I
authors: Barbagallo
authors: Lidia
authors: L
authors: Puzzo
authors: Cateno
authors: C
authors: Piazza
authors: Giovanni
authors: G
authors: Li Volti
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000502:physiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D000082:Acetaminophen
keywords: 8-OHG; 8-hydroxyguanosine; ALF; ASCs; BM-MSCs; GFP; GSH; MSCs; OLT; PCNA; acute liver failure; adipose tissue mesenchymal stem cells; bone marrow mesenchymal stem cells; green fluorescent protein; mesenchymal stem cells; orthotopic liver transplantation; proliferating cell nuclear antigen; reduced glutathione