title: Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models.
abstract: BACKGROUND
  Mesenchymal stem cell-conditioned medium (MSC-CM) has been shown to have protective effects against various cellular-injury models. This mechanism of protection, however, has yet to be elucidated. Recently, exosomes were identified as the active component in MSC-CM. The aim of this study is to investigate the effect of MSC-derived exosomes in an established carbon tetrachloride (CCl4)-induced liver injury mouse model. This potential effect is then validated by using in vitro xenobiotic-induced liver-injury assays: (1) acetaminophen (APAP)- and (2) hydrogen peroxide (H2O2)-induced liver injury.
  
  
  METHODS
  The exosomes were introduced concurrent with CCl4 into a mouse model through different routes of administration. Biochemical analysis was performed based on the blood and liver tissues. Subsequently the exosomes were treated in APAP and H2O2-toxicants with in vitro models. Cell viability was measured, and biomarkers indicative of regenerative and oxidative biochemical responses were determined to probe the mechanism of any hepatoprotective activity observed.
  
  
  RESULTS
  In contrast to mice treated with phosphate-buffered saline, CCl4 injury in mice was attenuated by concurrent-treatment exosomes, and characterized by an increase in hepatocyte proliferation, as demonstrated with proliferating cell nuclear antigen (PCNA) elevation. Significantly higher cell viability was demonstrated in the exosomes-treated group compared with the non-exosome-treated group in both injury models. The higher survival rate was associated with upregulation of the priming-phase genes during liver regeneration, which subsequently led to higher expression of proliferation proteins (PCNA and cyclin D1) in the exosomes-treated group. Exosomes also inhibited the APAP- and H2O2-induced hepatocytes apoptosis through upregulation of Bcl-xL protein expression. However, exosomes do not mitigate hepatocyte injury via modulation of oxidative stress.
  
  
  CONCLUSIONS
  In summary, these results suggest that MSC-derived exosomes can elicit hepatoprotective effects against toxicants-induced injury, mainly through activation of proliferative and regenerative responses.
authors.forename: Cheau Yih
authors.initials: CY
authors.lastname: Tan
authors.forename: Ruenn Chai
authors.initials: RC
authors.lastname: Lai
authors.forename: Winnie
authors.initials: W
authors.lastname: Wong
authors.forename: Yock Young
authors.initials: YY
authors.lastname: Dan
authors.forename: Sai-Kiang
authors.initials: SK
authors.lastname: Lim
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D055354:Exosomes; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000082:Acetaminophen; D006861:Hydrogen Peroxide; D002251:Carbon Tetrachloride