Therapy of iPSC-derived CD146+ mesenchymal stem cells in ulcerative colitis

The study explored the therapeutic potential of induced pluripotent stem cell-derived CD146+ mesenchymal stem cells (CD146+iMSCs) for treating ulcerative colitis (UC). These stem cells were compared to CD146+ umbilical cord mesenchymal stem cells (UCMSCs) in terms of biological traits, anti-inflammatory effects, and immune modulation mechanisms.

CD146+iMSCs demonstrated stronger proliferation, self-renewal, and differentiation abilities, maintaining classical mesenchymal stem cell markers. They effectively shifted macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, showing superior immune modulation compared to CD146+UCMSCs. Transcriptome analysis revealed that CD146+iMSCs upregulated pathways involved in calcium signaling, TGF-β, and immune regulation, while suppressing TNF signaling, enhancing their anti-inflammatory activity.

In a UC mouse model, CD146+iMSCs significantly alleviated symptoms, reduced weight loss, restored colon length, repaired intestinal barriers, and improved mucosal architecture. They reduced inflammatory cytokines (IL-6, TNF-α, IL-1β) and normalized immune cell populations, restoring immune homeostasis. The study identified the suppression of the IL-17 signaling pathway as a critical mechanism for UC treatment. Additionally, nine key inflammatory hub genes were downregulated by CD146+iMSCs, further supporting their anti-inflammatory effects.

CD146+iMSCs also regulated the cGAS-STING pathway, promoting immune tolerance and enhancing mucosal healing. Their regenerative effects were linked to genes involved in tissue repair (TGFB2, CXCL12, VEGF, FGF). Intraperitoneal injection provided better therapeutic outcomes by improving biodistribution to inflamed sites.

Overall, CD146+iMSCs demonstrated robust regenerative, anti-inflammatory, and immunomodulatory potential, offering a promising therapy for UC through immune regulation and tissue repair mechanisms.