Exosomes Derived from liver failure patients' plasma stimulated Mesenchymal Stem Cells alleviate acute liver failure

Background: Exosomes derived from pre-stimulated mesenchymal stem cells have been found have a different therapeutic effect in disease, and bio-artificial liver therapy has been shown to play an effective role in liver failure; Here, we proposed to investigate the therapeutic potential of liver failure patients’ plasma stimulated MSCs-derived exosomes (LF-Exos). Methods: We extracted untreated exosomes(NC-Exos) and LF-Exos, identified them using NTA, TEM and Western blotting, followed by miRNA sequencing. CCK-8, flow cytometry, H&E staining, immunohistochemistry, and Western blot were used to detect the protective effects of LF-Exos on D-GalN/LPS induced acute injured hepatocytes and the ALF mouse model. Results: Our study shows that after stimulated with liver failure patients’ plasma, the morphology of MSCs was significantly changed, and proliferation activity was weakened. A total of 31 differentially expressed miRNAs were screened using a gene chip, and further analysis showed that the differentially expressed miRNAs might affect the PI3K-AKT signaling pathway. In addition, LF-Exos could induce AKT phosphorylation and reduce activation of the NLRP3 inflammasome in hepatocytes or liver tissue, inhibit D-GalN/LPS induced apoptosis in hepatocytes, and reduce pathological liver injury of ALF mouse. Conclusion: The biological effects of LF-Exos will be altered after stimulated with liver failure patients’ plasma (LF plasma), and LF-Exos may inhibit the activity of NLRP3 inflammasome and activating the PI3K-AKT signaling pathway to exert a better protective effect on acute injured hepatocytes and ALF mouse models than NC-Exos.