| Background:Liver fibrosis is generally caused by scar reaction caused by chronic liver injury,including chronic hepatitis B/C,autoimmune liver disease,alcoholic liver disease,fatty liver,etc.,and is characterized by deposition of extracellular matrix such as excessive collagen[1].However,currently available treatments for liver fibrosis remain limited.The pathogenesis of hepatic fibrosis is believed to be the activation and transdifferentiation of hepatic stellate cells（HSCs）into myofibroblasts,resulting in massive collagen synthesis and contraction of liver structures[2].Therefore,targeting hematopoietic stem cells,including activation inhibition and induction of apoptosis,is considered to be an ideal strategy for the treatment of liver fibrosis.Mesenchymal stem cell（MSC）therapy is a promising strategy for inhibiting HSC activation and treating liver fibrosis,and it has been widely used in various tissue injuries,including bone,nerve,skin and various organs[3].Generally,MSCs can be isolated from adult adipose tissue,bone marrow,umbilical cord blood,and placenta[4].The cellular plasticity of MSCs decreases with the increase of donor age,which greatly limits the application of MSCs[5].On the contrary,fetal stem cells have strong differentiation potential,especially amniotic stem cells collected during amniotic fluid reduction in late pregnancy,cesarean section or routine amniocentesis[6].Amniotic fluid stem cells（AFSCs）have been proven to alleviate liver fibrosis through collagen reduction and function improvement[7].However,the mechanism of action of AFSCs on liver fibrosis remains unclear.In addition,the risks of TCM derived tumor formation,cell rejection and infusion toxicity in mesenchymal stem cell transplantation remain unresolved[8].More importantly,only a few mesenchymal stem cells can eventually survive in the damaged area and participate in the formation of new tissues after cell transplantation[9].Therefore,current researchers believe that MSCs secreted factors may be the main reason for its therapeutic effect[10].Exosomes are nanoparticles that attach to biofilms and carry DNA,mi RNA,proteins and carbohydrates.They play an important role in bioinformation storage and cell communication and can be used as secretory biomarkers[11].In recent years,exosomes from MSCs have been widely used in tissue repair and regeneration[12].Afsc-derived exosomes（AFSC-EXOS）may be an ideal alternative strategy for AFSC to reduce liver fibrosis and promote liver regeneration.Objective:The purpose of this study was to explore the effect and mechanism of human amniotic stem cell exosomes in alleviating liver fibrosis.Methods:In this experiment,a rat liver fibrosis model induced by CCl4 was established for8 weeks,and then exosomes derived from h AFSc（h AFSC-exos）was injected for 4weeks.Human Amniotic Fluid Stem cells（h AFSc）were used as positive treatment group.The effect of h AFSC-exos on liver fibrosis was verified by histopathological analysis,liver function and expression of inflammatory cytokines.Dimethyloxaloylglycine-stittmulated human bone marrow mesenchymal stem cell-derived exosomes enhance bone regeneration through angiogenesis by targeting the AKT/m TOR pathway.In addition,we investigated the anti-fibrosis mechanism of h AFSC-exos in Hepatic stellate cells（HSCs）and Hepatic fibrosis tissues by Western Blot assay,and detected the expression of TGF-β/Smad signaling pathway related genes.Results:The results showed that in vivo injection of h AFSC-exos effectively reduced liver fibrosis in rats,including reducing collagen deposition,enhancing liver function,inhibiting inflammation and promoting liver cell regeneration.Conclusion:These results suggest that h AFSC-exos therapy can reduce CCL4-induced liver fibrosis by inhibiting Dimethyloxaloylglycine-stittmulated human bone marrow mesenchymal stem cell-derived exosomes enhance bone regeneration through angiogenesis by targeting the AKT/m TOR pathway.HSC activation through the TGF-β/Smad signaling pathway. |
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