[Untargeted metabolomics-based analysis of metabolites influencing the efficacy of liver progenitor cell transplantation and their underlying mechanisms].

To explore the mechanisms underlying the therapeutic efficacy of cell transplantation in mouse liver, liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics was employed to screen the differential metabolites in the liver tissue of mice undergoing cell transplantation. We then explored the biological significance of differential metabolites through pathway analysis, correlation analysis, and cluster analysis, aiming to decipher the potential mechanisms affecting the therapeutic outcomes of cell transplantation. The augmenter of liver regeneration (ALR) has been reported to regulate stem/progenitor cell fate. An acute liver failure (ALF) model was induced in mice with carbon tetrachloride (CCl4), and the mice were allocated into three groups (n=5) and transplanted with liver epithelial progenitor cells (LEPCs) with normal expression, overexpression, and knockdown of ALR via splenic injection. Liver tissue samples were collected for LC-MS-based untargeted metabolomics analysis. Differential metabolites were screened and subjected to Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis to identify potential targets influencing the efficacy of cell transplantation. A total of 4 861 metabolites were detected in both positive and negative ion modes. Comparisons were conducted among the three groups with the threshold of fold change (FC)≥2 or≤0.5. The overexpression group and the normal expression group showed minor differences in metabolomic profiles, demonstrating high metabolic similarity. Therefore, we focused on comparing the overexpression group with the knockdown group. Twenty-four differential metabolites were identified between the two groups, with the overexpression group showing 16 upregulated metabolites and 8 downregulated metabolites. Among them, geniposidic acid (GPA) exhibited the most significant upregulation. KEGG pathway enrichment analysis revealed that the overexpression group was primarily associated with six metabolic pathways. Importantly, GPA has been repeatedly reported to participate in the regulation of the bile acid metabolism pathway. ALR overexpression in LEPCs may enhance the therapeutic efficacy by upregulating GPA expression and modulating the bile acid metabolism pathway, thereby creating a favorable liver microenvironment for transplanted cells.