Intravenous administration of multipotent stromal cells prevents the onset of non-alcoholic steatohepatitis in obese mice with metabolic syndrome

Abstract

Metabolic syndrome is secondary to obesity and characterized by dyslipidemia, insulin resistance, and hypertension. Non-alcoholic fatty liver disease is its hepatic manifestation, whose progression-limiting step is non-alcoholic steatohepatitis (NASH). The latter is characterized by lipid accumulation, hepatocyte damage, leukocyte infiltration, and fibrosis. NASH is a prodrome to cirrhosis and hepatocellular carcinoma. Multipotent stromal cells (MSCs) have been shown to be immunomodulatory and contribute to liver regeneration in acute failure conditions. Our aim was to evaluate whether MSC administration prevents the onset of NASH in obese mice with metabolic syndrome. C57BL/6 mice were chronically fed with high-fat diet. At week 33, mice received intravenously either the vehicle (obese untreated) or two doses of 0.5×10(6) syngeneic MSCs (obese MSC-treated). Four months later, liver function and structure, and metabolic syndrome markers were assessed. The persistence of donor MSCs(GFP) in obese mice was evaluated 17 weeks after their administration. Obese untreated mice presented high plasma levels of hepatic enzyme, hepatomegaly, liver fibrosis, inflammatory cell infiltration, and hepatic triglyceride accumulation. Furthermore, they showed high expression levels of fibrosis markers and pro-inflammatory cytokines. By contrast, obese MSC-treated mice only presented steatosis. Mice kept obese, hypercholesterolemic, hyperglycemic, and insulin resistant irrespective of whether they received MSCs or not. Donor MSCs(GFP) were found in liver, bone marrow, heart, and kidney of obese mice. MSC administration prevents the onset of NASH in obese mice. Observed hepatoprotection is not related to a reversion of the metabolic syndrome but to the preclusion of the inflammatory process.