间充质干细胞在急性肝衰竭小鼠生存预后中的作用及其机制研究OA

Objective To investigate the role and mechanisms of mesenchymal stem cells(MSC)in the survival prognosis of mice with acute liver failure(ALF).Methods A thioacetamide(TAA)-induced mouse model of ALF was established and treated with MSC via tail vein infusion.The therapeutic effects of MSC were evaluated through survival analysis,measurement of serum biochemical indicators,HE staining of liver tissues and determination of proinflammatory cytokines.Liquid chromatography-mass spectrometry was used to analyze the metabolic profiles of liver tissues,hepatic transcriptomic analysis was performed based on high-throughput sequencing,and integrated multi-omics analysis was conducted.Comparisons of normally distributed data between two groups were performed using the unpaired t test.Comparisons among multiple groups were conducted using one-way analysis of variance,and pairwise comparisons between groups were performed using the Bonferroni method.Comparisons of rates between two groups were conducted using the Chi-square test.Survival curves were plotted using the Kaplan-Meier method,and differences between groups were compared using the Log-rank test.Results MSC treatment increased the survival rate of ALF mice(P＜0.05),reduced serum AST and ALT levels(both P＜0.05),alleviated histopathological liver injury,and inhibited the production of proinflammatory cytokines(all P＜0.05).Metabolomic analysis showed that MSC restored pathways related to carbohydrate metabolism and energy production(all P＜0.05).Transcriptomic analysis indicated that MSC might inhibit the mitogen-activated protein kinase(MAPK)signaling pathway and reduced neutrophil infiltration(both P＜0.05).Integrated multi-omics analysis showed that MSC-induced upregulation of Pfkfb1 was correlated with increased levels of fructose-1,6-bisphosphate(F1,6P),a metabolite with anti-inflammatory properties(P＜0.05).In addition,F1,6P levels were negatively correlated with the expression levels of numerous differentially expressed genes in the MAPK signaling pathway and with the degree of neutrophil infiltration(both P＜0.05).Conclusions MSC effectively alleviate TAA-induced ALF,and the underlying systemic immunometabolic mechanism may involve the Pfkfb1-F1,6P pathway.This pathway may participate in inhibiting the MAPK signaling pathway and reducing neutrophil infiltration,thereby ultimately alleviating hepatic inflammation in ALF.