Embryonic stem cell-derived mesenchymal stem cells promote colon epithelial integrity and regeneration by elevating circulating IGF-1 in colitis mice.

Abstract

Rationale: Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating inflammatory bowel disease (IBD) due to their immunomodulatory and trophic functions. However, their efficacy is influenced by tissue origin, donator condition, isolation, and expansion methods. Here, we generated phenotypically uniform MSCs from human embryonic stem cells (T-MSCs) and explored the molecular mechanisms involved in promoting mucosal integrity and regeneration in colitis mice.Methods: T-MSCs were injected intravenously into mice with dextran sulfate sodium (DSS)-induced colitis, and the in vivo distribution and therapeutic efficacy were evaluated. We performed serum cytokine antibody microarrays to screen potentially effective proteins and examined the therapeutic effect of insulin-like growth factor-1 (IGF-1). Colon epithelial regeneration potential was evaluated, and RNA sequencing was employed to determine the underlying molecular mechanisms. Finally, in vitro IGF-1 stimulation was performed to assess its effect on cell functions and organoid growth.Results: Intravenous administration of T-MSCs alleviated colitis in both acute and chronic DSS mouse models. Labeled T-MSCs were mainly distributed in the lungs, liver, and spleen after systemic infusion. The antibody array analysis of serum cytokines indicated that the IGF-1 level was increased in the treatment group, and serum ELISA further confirmed its elevation in the regeneration stage. Intraperitoneal injection of IGF-1 receptor inhibitors abrogated the anti-inflammatory activity of T-MSCs. The colonic epithelium of the treatment group showed greater regenerative potency than the controls and the IGF1R-PI3K-AKT pathway was up-regulated. RNA sequencing showed that T-MSC treatment contributed to colonic cell integrity and promoted xenobiotic metabolism. In vitro IGF-1 stimulation promoted the growth and proliferation of colon cells and organoids.Conclusions: Intravenous infusion of T-MSCs alleviated colitis in mice by elevating the circulating IGF-1 level. Increased IGF-1 maintained the integrity of epithelial cells and contributed to their repair and regeneration. Our study has identified T- MSCs as a potential cell resource for IBD treatment.