CD126hi umbilical cord mesenchymal stem cells sensitive to IL-6 ameliorate inflammatory bowel disease by producing TGF-β1

Orphanet J Rare Dis. 2025 Aug 27;20(1):458. doi: 10.1186/s13023-025-03993-w.

ABSTRACT

BACKGROUND: Human umbilical cord mesenchymal stem cells (HUMSCs) are effective therapies for inflammatory bowel disease. However, the mechanisms remain unresolved. We found HUMSCs express CD126 (IL-6 receptor), which indicated CD126 sub-populations might show a distinct response to inflammation. In the present study, we explored whether CD126 is a critical molecule for HUMSCs in regulating inflammation.

METHODS: We assessed the regulatory effects of CD126 high (CD126^hi) on the T lymphocyte subpopulations and related cytokines in the dextran sulfate sodium (DSS)-induced colitis model. The effect of CD126^hi was evaluated by Hematoxylin and Eosin (H&E) staining, fluorescence-activated cell sorting (FACS), and enzyme-linked immunosorbent assay (ELISA) analyses. Statistical significance was typically determined using Student’s t-test or one-way analysis of variance (ANOVA) with Tukey test.

RESULTS: The disease symptoms were markedly ameliorated and the interleukin-6 (IL-6), interleukin-17 (IL-17), interferon-γ (IFN-γ), Tumor necrosis factor-α (TNF-α), and interleukin-4 (IL-4) levels were significantly reduced in DSS-treated mice administered with CD126^hi HUMSCs but not in DSS-treated mice administered with CD126 low (CD126^lo) HUMSCs. Intriguingly, CD126^hi HUMSCs significantly increased the levels of transforming growth factor-β (TGF-β1) and interleukin-10 (IL-10) in DSS-treated mice, accompanied by an increase in regulatory T cells (Treg cells). In vitro experiments showed that CD126^hi HUMSCs secreted TGF-β1 in response to IL-6 stimulation, while CD126^lo HUMSCs were latent in the inflammatory environment. We considered that TGF-β1 secreted by CD126^hi HUMSCs regulated the balance of Treg cells and thus promoted the recovery of murine colitis.

CONCLUSION: Our results revealed a mechanism wherein CD126^hi HUMSCs function as inflammatory sensors and secrete anti-inflammatory cytokines to rebalance the population of T cells. This study shed light on the potential therapeutic application of CD126^hi HUMSCs for inflammatory diseases such as inflammatory bowel disease.

PMID:40866981 | DOI:10.1186/s13023-025-03993-w