29 EFFICACY OF ADIPOSE TISSUE-MESENCHYMAL STEM CELLS TRANSPLANTATION IN RATS WITH ACETAMINOPHEN LIVER INJURY

Abstract

Abstract Objective Acetaminophen intoxication is a leading cause of acute liver failure. Liver transplantation foracute liver failure is limited by the availability of donor organs. In this study, we aimed at identifying if the transplantation ofadipose 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 300 mg/kg of acetaminophen intraperitoneally and were transplanted with ASCsor vehicle. After 24 h 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 phosphorylationand 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. Transplantedanimals had normal plasma ammonia and did not display clinical encephalopathy. Liver sections of intoxicated rats treatedwith vehicle showed lobular necrosis and diffuse vacuolar degeneration; in rats transplanted with ASCs liver injury was almostabsent. 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 increasedin 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, whereasASCs were not able to metabolize acetaminophen in vitro.Conclusion In this study, we demonstrated that ASC transplantation is effective in treating acetaminophen liver injury byenhancing hepatocyte regeneration and inhibiting liver stress and inflammatory signaling.© 2013 Elsevier B.V. All rights reserved.Abbreviations: ALF,acuteliverfailure; GSH,reduced glutathione; OLT,orthotopic liver transplantation; MSCs,mesenchymal stem cells;ASCs, adipose tissue mesenchymal stem cells; GFP, green fluorescent protein; 8-OHG, 8-hydroxyguanosine; BM-MSCs, bone marrowmesenchymal stem cells; PCNA, proliferating cell nuclear antigen.☆ This work was presented in part at the 45th Annual Meeting of the Italian Association for the Study of the Liver (AISF) in 2012 and wasawarded as Best Oral Communication — Basic.⁎ Corresponding author at: U.O.C. di Gastroenterologia, Ospedale S. Marta S. Venera, Via Caronia, 95024 Acireale (Catania), Italy.E-mail address: federicosalomone@rocketmail.com (F. Salomone).1873-5061/$ - see front matter © 2013 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.scr.2013.07.003Available online atwww.sciencedirect.comwww.elsevier.com/locate/scrStem Cell Research (2013) 11, 1037–1044