Cell-derived vesicles extruded from adipose mesenchymal stem cells attenuate intestinal inflammation and augment epithelial regeneration in a colitis model

Abstract

Adipose-derived stem cell (ADSC) cell-derived vesicles (CDVs) have been developed to overcome the limitations of ADSCs and ADSC extracellular vesicles (EVs). This study aims to analyze the characteristics and therapeutic effects of ADSC CDVs compared to ADSCs and ADSC EVs through ex vivo organoid and in vivo colitis experiments. ADSC CDVs were generated from ADSCs through serial extrusions using polycarbonate membrane filters. The characteristics and regenerative efficacy of ADSC CDVs were compared to those of ADSC EVs. The therapeutic effect of ADSC CDVs was evaluated by assessing epithelial regeneration and inflammatory cytokines in vitro, utilizing organoid models ex vivo, and using the dextran sodium sulfate (DSS)-induced colitis model in vivo. Both ADSC EVs and ADSC CDVs exhibited circular shapes, but the mean size of ADSC CDVs (164.3 nm) was significantly larger than that of ADSC EVs (134.8 nm). ADSC CDVs showed a stronger effect on proliferation, migration, and wound healing compared to ADSC EVs. Furthermore, ADSC CDVs upregulated the S phase of the cell cycle and the expression of gut regeneration markers, including β-catenin, OLFM4, and Ki-67. ADSC CDVs increased the formation and growth of colon organoids after IFN-γ treatment. Additionally, ADSC CDV treatment reduced the elevated levels of inflammatory cytokines in the organoid model. Treatment with ADSC CDVs also attenuated acute inflammation in the DSS-induced colitis model. ADSC CDVs attenuate gut epithelial inflammation and induce epithelial regeneration ex vivo in organoids and in vivo in a mouse model of colitis.