Therapeutic effects of hUC-MSCs on collagen-induced arthritis are associated with immune rebalancing and systemic metabolic changes.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive joint destruction. Although current therapies can control symptoms, many patients still have limited responses or safety concerns. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have shown therapeutic potential in autoimmune diseases, but their effects on joint-associated pathways and systemic metabolism in RA remain unclear. METHODS: hUC-MSCs were commercially obtained, expanded, and characterized. A collagen-induced arthritis (CIA) mouse model was established to evaluate therapeutic efficacy. Disease severity was assessed by arthritis scoring, gross observation, and histopathology. Flow cytometry and ELISA were used to analyze Th17/Treg balance and circulating cytokines. NF-κB- and Wnt/β-catenin-related molecules, together with components of the RANKL/OPG axis, were examined by Western blotting and RT-qPCR. Untargeted plasma metabolomics was performed to assess systemic metabolic changes. RESULTS: hUC-MSC treatment reduced arthritis scores and joint swelling in CIA mice. Histological analysis showed reduced synovial hyperplasia and less cartilage and bone damage. hUC-MSCs shifted the immune profile toward an anti-inflammatory state, with decreased Th17 cells, increased Treg cells, and lower serum TNF-α, IL-6, IL-1β, and IL-17 levels. In synovial tissue, hUC-MSC treatment was associated with lower expression of NF-κB p65, Wnt-4, and β-catenin, as well as a decreased RANKL/OPG ratio. Exploratory untargeted metabolomics further suggested treatment-associated changes in the systemic metabolic profile. CONCLUSION: hUC-MSCs alleviated arthritis in CIA mice and were associated with immune rebalancing, lower expression of inflammation-related molecular markers, and systemic metabolic changes. Key Points • hUC-MSCs attenuate synovitis and bone destruction in CIA mice. • hUC-MSC treatment restores Th17/Treg balance and is associated with lower expression of NF-κB/Wnt-related markers. • Untargeted metabolomics suggests treatment-associated systemic metabolic changes.