Extracellular vesicles derived from bone marrow mesenchymal stem cells attenuate dextran sodium sulfate-induced ulcerative colitis by promoting M2 macrophage polarization

Abstract

Extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) have shown repairing effects in tissue damage. However, their efficacy and mechanism in the treatment of ulcerative colitis (UC), a type of chronic inflammatory bowel disease, are unclear. To investigate the effects and possible mechanism of EVs in UC treatment, we established an in vitro model using lipopolysaccharide (LPS)-treated macrophages and an in vivo dextran sulfate sodium (DSS)-induced mouse model to mimic UC. In vitro, EVs promoted the proliferation and suppressed inflammatory response in LPS-induced macrophages, as demonstrated by the up-regulation of pro-inflammatory factors (TNF-α, IL-6, and IL-12) and down-regulation of the anti-inflammatory factor IL-10. In the in vivo model, EV administration ameliorated the symptoms of UC by reducing weight loss, disease activity index, and colon mucosa damage and severity while increasing colon length. This was additionally accompanied by the increase in IL-10 and TGF-β levels and the decline in VEGF-A, IFN-γ, IL-12, TNF-α, CCL-24, and CCL-17 levels. In terms of the mechanism, EVs promoted M2-like macrophage polarization, characterized by the increase in the M2 marker CD163. Furthermore, the positive effect of EVs on UC repair seemed to be related to the JAK1/STAT1/STAT6 signaling pathway. Collectively, BMSC-derived EVs exerted positive therapeutic effects against DSS-induced UC, which could be due to a negative inflammatory response.

Keywords: Bone marrow-derived mesenchymal stem cells; Extracellular vesicles; JAK1/STAT1/STAT6 signaling pathway; Macrophage polarization; Ulcerative colitis.