Improved efficacy and long‐term protective effects of CXCR4 / IL10 bioengineered mesenchymal stromal cells in a model of inflammatory bowel disease

Mesenchymal stromal cell (MSCs)-based therapies have emerged as a promising approach for inflammatory bowel disease (IBD) treatment due to their immunosuppressive and regenerative properties. However, clinical trials have shown limited therapeutic effectiveness, largely because of low efficiency in penetrating the inflamed colon and their inconsistent in vivo immunomodulatory ability. In this study, we generated genetically engineered adipose-derived human MSCs constitutively expressing CXC chemokine receptor 4 and interleukin 10 (CXCR4-IL10-MSCs) to promote their delivery to the inflamed colon and enhance their immunosuppressive capability. Compared to unmodified MSCs, CXCR4-IL10-MSCs exhibited enhanced trafficking to the inflamed colon and achieved improved therapeutic effects in dextran sulfate sodium (DSS)-challenged colitic mice. Upon a chronic DSS re-challenge, CXCR4-IL10-MSCs showed enhanced long-term protective effects. These findings demonstrate that stable ectopic expression of CXCR4 and IL10 enhances the therapeutic efficacy of MSCs and supports the development of an optimized MSC-based product capable of inducing an improved long-term protective immune memory in IBD.