Protection against acetaminophen-induced acute liver failure by omentum adipose tissue derived stem cells through the mediation of Nrf2 and cytochrome P450 expression.

Yu-Jen Huang,Yao-Ming Wu,Hsuan-Shu Lee,Ming-Tsan Lin,Poda Chen,Chih-Yuan Lee,Sin-Yu Yang

doi:10.1186/s12929-016-0231-x

Abstract

BackgroundAcetaminophen (APAP) overdose causes acute liver failure (ALF) in animals and humans via the rapid depletion of intracellular glutathione (GSH) and the generation of excess reactive oxygen species (ROS) that damage hepatocytes. Stem cell therapy is a potential treatment strategy for ALF.MethodsWe isolated mesenchymal stem cells (MSCs) from mice omentum adipose tissue-derived stem cells (ASCs) and transplanted them into a mouse model of APAP-induced ALF to explore their therapeutic potential. In addition, we performed in vitro co-culture studies with omentum-derived ASCs and primary isolated hepatocytes to demonstrate the hepatoprotective effect of omentum-derived ASCs on hepatocytes that were subjected to APAP-induced damage.ResultASC transplantation significantly improved the survival rate of mice with ALF and attenuated the severity of APAP-induced liver damage by suppressing cytochrome P450 activity to reduce the accumulation of toxic nitrotyrosine and the upregulation of NF-E2-related factor 2 (Nrf2) expression, resulting in an increase in the subsequent antioxidant activity. These effects protected the hepatocytes from APAP-induced damage through the suppression of downstream MAPK signal activation and inflammatory cytokine production.Conclusionsour results demonstrate that omentum-derived ASCs are an alternative source of ASCs that regulate the antioxidant response and may represent a beneficial therapeutic strategy for ALF.

Highlights

Acetaminophen (APAP) overdose causes acute liver failure (ALF) in animals and humans via the rapid depletion of intracellular glutathione (GSH) and the generation of excess reactive oxygen species (ROS) that damage hepatocytes
The cells were cultured in α-MEM containing 20 ng/ml epidermal growth factor (EGF) and 10 ng/ml fibroblast growth factor (FGF; PeproTech, Rocky Hill, NJ, USA) for 2 days; the medium was replaced with α-MEM containing 20 ng/ ml hepatocyte growth factore (HGF; PeproTech) and 4.9 mM nicotinamine (Sigma-Aldrich, St Louis, MO, USA) for 1 week, followed by treatment with 20 ng/ml oncostatin M (PeproTech), 1 μmol/L dexamethasone (SigmaAldrich), and 50 mg/mL insulin-transferrin-selenium (ITS; Gibco, Paisley, UK) that was prepared in α-MEM for 1 week
We examined NF-E2-related factor 2 (Nrf2), HO-1 and NADPH quinone oxidoreductase 1 (NQO1) gene expression by QPCR and found that these gene expression significantly increased in the omentum-derived adipose tissue-derived stem cell (ASC) group compared with the APAP-treated group (Fig. 3e–g)

Summary

Introduction

Acetaminophen (APAP) overdose causes acute liver failure (ALF) in animals and humans via the rapid depletion of intracellular glutathione (GSH) and the generation of excess reactive oxygen species (ROS) that damage hepatocytes. Acetaminophen (APAP) is an effective analgesic and antipyretic drug, but it can cause severe liver damage. APAP overdose can result in liver failure, and it is a common cause of acute liver failure (ALF) in Western countries [1]. SOD can convert O2− into H2O2 and further convert H2O2 into H2O and O2 by GPx and catalase [3]. GSH can prevent the covalent binding of toxic metabolites and suppress oxidative stress, which is a potential approach to attenuate APAP toxicity and promote tissue repair/regeneration

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