MSCs-exosomes can promote macrophage M2 polarization via exosomal miR-21-5p through Mesenteric injection: a promising way to attenuate murine colitis.

Background and aims: Exosome-based therapies are gaining increasing attention, with growing evidence suggesting a link between alterations in mesentery adipose tissue (MAT) and intestinal disease in Crohn's disease (CD). However, the specific mechanism by which mesenchymal stem cells (MSCs)-Exos may alleviate colitis through targeting MAT remains not fully understood.

Methods: Human umbilical cord MSCs (HucMSCs) were cultured to isolate the corresponding exosomes (HucMSCs-Exos), which were confirmed by their morphology, size distribution, and expression of markers. In vivo, 2,4,6-trinitrobenzenesulfonic acid solution (TNBS) and dextran sodium sulfate (DSS) -induced mouse colitis models were used to detect the therapeutic effects of HucMSCs-Exos. ELISA, qRT-PCR, western blotting, and immunofluorescence determined the expression of key molecules. Luciferase reporter assay was used to confirm the relationship between miR-21-5p and SPRY2.

Results: Exosomes treatment through mesenteric injection demonstrated therapeutic effects on mesenteric inflammation and colitis. These therapeutic benefits were contingent on macrophages, significantly facilitating the M2 polarization of mesenteric macrophages. The expression data from GSE159814 and GSE211008 revealed that exosomal miR-21-5p was enriched in HucMSCs-Exos and could be delivered to macrophages. Additionally, the results indicated that miR-21-5p could directly target the 3'UTR of SPRY2 and activate the phosphorylation of ERK to modify macrophage phenotypes. Mechanistically, exosomal miR-21-5p derived from HucMSCs could promote macrophage M2 polarization via the SPRY2/ERK axis.

Conclusion: Mesenteric injection of HucMSCs-Exos significantly alleviates mesenteric inflammation and colitis by promoting mesenteric macrophage M2 polarization, making it a promising approach to treat colitis and suggesting therapeutic potential role of exosomal miR-21-5p in CD.