Attenuation of hepatic ischemia-reperfusion injury by adipose stem cell-derived exosome treatment via ERK1/2 and GSK-3β signaling pathways

Exosomes are an emerging therapeutic tool for the treatment of tissue injuries. In the present study, the protective effect of isolated exosomes from adipose-derived stem cells (ADSCs-exo) against hepatic ischemia-reperfusion (I/R) injury was explored. Hepatic I/R injury was achieved by inducing ischemia for 60 min followed by reperfusion for 2 and 6 h. Pre-treatment with ADSCs-exo revealed a significant reduction in necrosis and apoptosis in liver tissue induced by I/R injury. Hypoxic oxidative stress was managed by exosome-mediated reduced reactive oxygen species and increased superoxide dismutase that in turn protected mitochondrial damage and apoptosis. Reduction in inflammatory mediators such as IL-1β and TNF-α was also observed and protection of hepatocytes from I/R injury was evidenced by a significant decrease in biochemical markers of liver damage (alanine transaminase, aspartate transaminase and lactate dehydrogenase). Exosomal prostaglandin E2 (PGE2)-mediated ERK1/2 and GSK-3β phosphorylation were revealed to increase Bcl-2 and decrease Bax expression with mitochondrial permeability transition pore-inhibition which may be considered a prime mechanism of exosome-mediated hepatoprotection. In conclusion, our results indicated that ADSCs-exo pre-treatment is effective in protecting liver I/R injury.