IFN-γ-tethered hydrogels enhance mesenchymal stem cell-based immunomodulation and promote tissue repair

Because of their immunomodulatory activities, human mesenchymal stem cells (hMSCs) are being explored to treat a variety of chronic conditions such as inflammatory bowel disorders and graft-vs-host disease. Treating hMSCs with IFN-gamma prior to administration augments these immunomodulatory properties; however, this ex vivo treatment limits the broad applicability of this therapy due to technical and regulatory issues. In this study, we engineered an injectable synthetic hydrogel with tethered recombinant IFN-gamma that activates encapsulated hMSCs to increase their immunomodulatory functions and avoids the need for ex vivo manipulation. Tethering IFN-gamma to the hydrogel increases retention of IFN-gamma within the biomaterial while preserving its biological activity. hMSCs encapsulated within hydrogels with tethered IFN-gamma exhibited significant differences in cytokine secretion and showed a potent ability to halt activated T-cell proliferation and monocyte-derived dendritic cell differentiation compared to hMSCs that were pre-treated with IFN-gamma and untreated hMSCs. Importantly, hMSCs encapsulated within hydrogels with tethered IFN-gamma accelerated healing of colonic mucosal wounds in both immunocompromised and immunocompetent mice. This novel approach for licensing hMSCs with IFN-gamma may enhance the clinical translation and efficacy of hMSC-based therapies.