Melatonin-primed ADMSCs elicit an efficacious therapeutic response in improving high-fat diet induced non-alcoholic fatty liver disease in C57BL/6J mice

Abstract

Abstract Background Stem cells are widely used for therapy including treatment of liver damage. Adipose-derived mesenchymal stem cells (ADMSCs) administered to treat fatty liver are known to improve liver function but their use is restricted due to a poor success rate. This study investigates efficacy of melatonin-primed ADMSCs (Mel. MSCs) in experimentally induced non-alcoholic fatty liver disease (NAFLD). Results MSCs treated with LPS showed prominent DCFDA fluorescence as compared to the untreated cells. Also, the JC-1 staining had accounted for higher intensity of green monomer and a weak fluorescence of red dimer indicating weaker mitochondrial membrane potential. But melatonin co-treatment could make necessary corrective changes as evidenced by reverse set of results. The overall cell survival was also found to be improved following melatonin treatment as evidenced by the MTT assay. Also, the antioxidant (Nrf2 and Ho-1) and anti-inflammatory genes (Il-4 and Il-10) showed a decrement in their mRNA levels following LPS treatment whereas the pro-inflammatory genes (Tnf-α, Il-6, Tlr-4, and Lbp) showed a reciprocal increment in the said group. Melatonin co-treatment accounted for an improved status of antioxidant and anti-inflammatory genes as evidenced by their mRNA levels. High-fat high-fructose diet (HFFD) fed C57BL/6J mice recorded higher serum AST and ALT levels and fatty manifestation in histology of liver along with lowered mRNA levels of antioxidant (Nrf2, Catalase, and Gss) genes and Hgf. These set of parameters showed a significant improvement in HFFD + Mel.MSC group. Conclusion A significant improvement in viability of MSCs was recorded due to lowered intracellular oxidative stress and improves mitochondrial membrane potential. Further, melatonin-primed MSCs accounted for a significant decrement in fatty manifestations in liver and an improved physiological status of NAFLD in HFFD fed C57BL/6J mice. Taken together, it is hypothesized that melatonin priming to MSCs prior to its use can significantly augment the success of stem cell therapy.