Abstract
BACKGROUND: Mesenchymal stem cells (MSCs) exhibit therapeutic potential for ulcerative colitis (UC) due to their immunomodulatory, homing, and tissue repair capabilities, but clinical efficacy is constrained by heterogeneity. Induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) exhibit superior stem cell properties compared to traditional MSCs, with CD146+ MSCs exhibiting enhanced biological characteristics. Nevertheless, the biological properties of CD146+iMSCs, as well as their therapeutic potential in UC, remain unclear. METHODS: CD146+ subpopulations were isolated from iMSCs and umbilical cord-derived MSCs (UCMSCs) using magnetic beads sorting. The surface markers, proliferation capacity, differentiation potential, and regulatory effects on macrophage polarization were analyzed. Dextran sulfate sodium (DSS) - induced UC mouse models were established and treated with CD146+iMSCs. Body weight, disease activity index (DAI), colon length, and histopathological damage were evaluated. Peripheral immune cells and cytokines were analyzed by flow cytometry and ELISA. Transcriptome sequencing of colon tissues was performed and jointly analyzed with GEO datasets to identify the mechanisms of CD146+iMSCs' therapeutic efficacy in UC through differential gene expression profiling, protein-protein interaction network, functional enrichment analysis, and immune infiltration assessment. The core mechanisms were validated in vitro and vivo. RESULTS: CD146+ iMSCs exhibited similar morphology and macrophage polarization regulatory capacity to CD146+UCMSCs, with superior proliferation and differentiation potential. CD146+ iMSCs significantly ameliorated UC symptoms (weight, DAI), reduced colon damage, decreased IL-6/TNF-α, and restored immune balance. Integrated analysis of colon transcriptome sequencing data and GEO datasets revealed the pivotal role of the IL-17 signaling pathway in the therapeutic effects of CD146+iMSCs. CD146+iMSCs effectively suppressed IL-17 expression both in cell inflammation models and colon tissues, downregulated nine hub genes, and inhibited macrophage polarization via the cGAS-STING axis. CONCLUSION: CD146+iMSCs exhibited advantages in proliferative and differentiation capabilities. They could ameliorate UC by suppressing IL-17 expression, downregulating HUB genes, and modulating macrophage polarization through the cGAS-STING axis.