Umbilical cord-derived mesenchymal stem cells alleviate liver fibrosis in rats

AIM: To evaluate the efficacy of umbilical cord-derived mesenchymal stem cells(UC-MSCs) transplantation in the treatment of liver fibrosis.METHODS: Cultured human UC-MSCs were isolated and transfused into rats with liver fibrosis induced by dimethylnitrosamine(DMN). The effects of UC-MSCs transfusion on liver fibrosis were then evaluated by histopathology; serum interleukin(IL)-4 and IL-10 levels were also measured. Furthermore, Kupffer cells(KCs) in fibrotic livers were isolated and cultured to analyze their phenotype. Moreover, UC-MSCs were cocultured with KCs in vitro to assess the effects of UCMSCs on KCs' phenotype, and IL-4 and IL-10 levels were measured in cell culture supernatants. Finally, UCMSCs and KCs were cultured in the presence of IL-4 antibodies to block the effects of this cytokine, followed by phenotypical analysis of KCs.RESULTS: UC-MSCs transfused into rats were recruited by the injured liver and alleviated liver fibrosis, increasing serum IL-4 and IL-10 levels. Interestingly, UC-MSCs promoted mobilization of KCs not only in fibrotic livers, but also in vitro. Co-culture of UC-MSCs with KCs resulted in increased production of IL-4 and IL-10. The addition of IL-4 antibodies into the coculture system resulted in decreased KC mobilization.CONCLUSION: UC-MSCs could increase IL-4 and promote mobilization of KCs both in vitro and in vivo, subsequently alleviating the liver fibrosis induced by DMN.

Sophocarpine attenuates liver fibrosis by inhibiting the TLR4 signaling pathway in rats

AIM:To explore the effect of sophocarpine on experimental liver fibrosis and the potential mechanism involved.METHODS:Sophocarpine was injected intraperitoneally in two distinct rat hepatic fibrosis models induced either by dimethylnitrosamine or bile duct ligation.Masson’s trichrome staining,Sirius red staining and hepatic hydroxyproline level were used for collagen determination.Primary hepatic stellate cells(HSCs)were isolated and treated with different concentrations of sophocarpine.Real-time reverse transcription-polymerase chain reaction was used to detect the mRNA levels of fibrotic markers and cytokines.The expression of pathway proteins was measured by Western blot.The Cell Counting Kit-8 test was used to detect the proliferation rate of activated HSCs treated with a gradient concentration of sophocarpine.RESULTS:Sophocarpine decreased serum levels of aminotransferases and total bilirubin in rats under chronic insult.Moreover,administration of sophocarpine suppressed extracellular matrix deposition and prevented the development of hepatic fibrosis.Furthermore,sophocarpine inhibited the expression ofα-smooth muscle actin(SMA),interleukin(IL)-6,transforming growth factor-β1(TGF-β1),Toll-like receptor 4(TLR4),and extracellular-related kinase(ERK)in rats.Sophocarpine also down-regulated the mRNA expression ofα-SMA,collagenⅠ,collagenⅢ,TGF-β1,IL-6,tumor necrosis factor-αand monocyte chemoattractant protein-1,and decreased protein levels of TLR4,p-ERK,p-JNK,p-P38 and p-IKK in vitro after Lipopolysaccharide induction.In addition,sophocarpine inhibited the proliferation of HSCs accompanied by a decrease in the expression of Cyclin D1.The protein level of proliferating cell nuclear antigen was decreased in activated HSCs following a gradient concentration of sophocarpine.CONCLUSION:Sophocarpine can alleviate liver fibrosis mainly by inhibiting the TLR4 pathway.Sophocarpine may be a potential chemotherapeutic agent for chronic liver diseases.