Background:Mesenchymal stem cells (MSCs)-derived exosomes have been previously
demonstrated to promote tissue regeneration in various animal disease models. This study investigated
the protective effect of exosome treatment in carbon tetrachloride (CCl4)-induced acute liver
injury and delineated possible underlying mechanismMethods:Exosomes collected from conditioned media of previously characterized human umbilical
cord-derived MSCs were intravenously administered into male CD-1 mice with CCl4-induced
acute liver injury. Biochemical, histological and molecular parameters were used to evaluate the
severity of liver injury. A rat hepatocyte cell line, Clone-9, was used to validate the molecular
changes by exosome treatment.Results:Exosome treatment significantly suppressed plasma levels of AST, ALT, and pro-inflammatory
cytokines, including IL-6 and TNF-α, in the mice with CCl4-induced acute liver injury. Histological
morphometry revealed a significant reduction in the necropoptic area in the injured livers
following exosome therapy. Consistently, western blot analysis indicated marked elevations in hepatic
expression of PCNA, c-Met, Ets-1, and HO-1 proteins after exosome treatment. Besides, the
phosphorylation level of signaling mediator JNK was significantly increased, and that of p38 was
restored by exosome therapy. Immunohistochemistry double staining confirmed nuclear Ets-1 expression
and cytoplasmic localization of c-Met and HO-1 proteins. In vitro studies demonstrated
that exosome treatment increased the proliferation of Clone-9 hepatocytes and protected them from
CCl4-induced cytotoxicity. Kinase inhibition experiment indicated that the exosome-driven hepatoprotection
might be mediated through the JNK pathway.Conclusion:Exosome therapy activates the JNK signaling activation pathway as well as up-regulates
Ets-1 and HO-1 expression, thereby protecting hepatocytes against hepatotoxin-induced cell
death.