AMSC ‐ sEVs Ameliorated Crohn's Disease by Inhibiting Macrophage‐Myofibroblast Transition Through the Delivery of MFGE8

ABSTRACT This study elucidates the critical role of macrophage‐myofibroblast transition (MMT) in the pathogenesis of intestinal fibrosis in Crohn's disease (CD). Through analysis of stricturing intestinal tissues from CD patients and TNBS‐induced CD mouse models, we demonstrated that TGF‐β1 activates the MAPK signalling pathway to induce MMT in macrophages (Mø), resulting in increased expression of α‐SMA and collagen production. Importantly, these MMT‐derived myofibroblasts secrete CCL17, which recruits CCR4 + regulatory T cells (Tregs) to fibrotic lesions, creating a pro‐fibrotic microenvironment. Further investigation showed that the adoptive transfer of Mø exacerbated fibrosis in CD mice, whilst Mø depletion attenuated this process. Therapeutically, adipose‐derived mesenchymal stromal cells‐derived extracellular vesicles (AMSC‐sEVs) could effectively deliver MFGE8 to inhibit MAPK activation, thereby suppressing MMT and reducing CCL17‐mediated Treg recruitment. Treatment with AMSC‐sEVs significantly improved intestinal fibrosis in CD mice, as evidenced by reduced collagen deposition and improved histological scores, whereas MFGE8 knockdown in AMSC‐sEVs diminished these protective effects. These findings not only establish MMT as a key mechanism driving CD‐associated intestinal fibrosis through the CCL17‐CCR4 axis but also highlight AMSC‐sEVs as a promising cell‐free therapeutic strategy targeting this pathological process.