IGF-1C hydrogel improves the therapeutic effects of MSCs on colitis in mice through PGE₂-mediated M2 macrophage polarization

Abstract

<b>Background:</b> Mesenchymal stem cell (MSC)-based therapies hold great promise for the treatment of inflammatory bowel disease (IBD). In order to optimize and maximize the therapeutic benefits of MSCs, we investigated whether cotransplantation of a chitosan (CS)-based injectable hydrogel with immobilized IGF-1 C domain peptide (CS-IGF-1C) and human placenta-derived MSCs (hP-MSCs) could ameliorate colitis in mice. <b>Methods:</b> IGF-1C hydrogel was generated by immobilizing IGF-1C to CS hydrogel. Colitis was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. We initially applied hP-MSCs and CS-IGF-1C hydrogel for the treatment of colitis by <i>in situ</i> injection, and molecular imaging methods were used for real-time imaging of reactive oxygen species (ROS) and tracking of transplanted hP-MSCs by bioluminescence imaging (BLI). Furthermore, the effects of CS-IGF-1C hydrogel on prostaglandin E₂ (PGE₂) secretion of hP-MSCs and polarization of M2 macrophages were investigated as well. <b>Results:</b> The CS-IGF-1C hydrogel significantly increased hP-MSC proliferation and promoted the production of PGE₂ from hP-MSCs <i>in vitro</i>. Moreover, <i>in vivo</i> studies indicated that the CS-IGF-1C hydrogel promoted hP-MSC survival as visualized by BLI and markedly alleviated mouse colitis, which was possibly mediated by hP-MSC production of PGE₂ and interleukin-10 (IL-10) production by polarized M2 macrophages. <b>Conclusions:</b> The CS-IGF-1C hydrogel improved the engraftment of transplanted hP-MSCs, ameliorated inflammatory responses, and further promoted the functional and structural recovery of colitis through PGE₂-mediated M2 macrophage polarization. Molecular imaging approaches and therapeutic strategies for hydrogel application provide a versatile platform for exploring the promising therapeutic potential of MSCs in the treatment of IBD.