HucMSC‐exosomes carrying miR‐326 inhibit neddylation to relieve inflammatory bowel disease in mice

Abstract

Background Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammation that is a risk factor for many gastrointestinal cancers. Exosomes are gradually gaining attention as an emerging treatment method for IBD due to their important biological characteristics. NF‐κB is an important pro‐inflammatory transcription factor kept inactive by IκB protein in the cytoplasm by masking the nuclear localization signal of NF‐κB. The deterioration of IκB is mainly ubiquitination, and this depends on neddylation. Methods In this study, we established a dextran sulfate sodium (DSS)‐induced IBD model in BABL/C mice to evaluate the effect of human umbilical cord mesenchymal stem cell‐derived exosomes (hucMSC‐exosomes, hucMSC‐Ex) on the repair of IBD. At the same time, human colorectal mucosa cells (FHC) were stimulated by LPS (lipopolysaccharide) in vitro to activate the inflammatory environment to study the mechanism of hucMSC‐Ex regulating neddylation. The microRNA (miRNA) obtained by sequencing and transfection with hucMSC‐Ex was used to verify the role of miR‐326/neddylation/IκB/NF‐κB signaling pathway in IBD repair. Results HucMSC‐Ex inhibited the process of neddylation in relieving DSS‐induced IBD in mice. The binding of NEDD8 (neural precursor cell‐expressed, developmentally downregulated gene 8) to cullin 1 and the activation of NF‐κB signaling pathway were suppressed along with reduced expression levels of neddylation‐related enzyme molecules. The same phenomenon was observed in FHC cells. The miRNA comparison results showed that miR‐326 was highly expressed in hucMSC‐Ex and played an important role in inhibiting the neddylation process. The therapeutic effect of hucMSC‐Ex with high expression of miR‐326 on IBD mice was significantly stronger than that of ordinary hucMSC‐Ex. Conclusions HucMSC‐Ex relieves DSS‐induced IBD in a mouse model by inhibiting neddylation through miR‐326.

Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease

“…The capacity of MSCs to modulate phenotype and function of immune cells largely depends on secreted EVs [ 124 ]. Several reports indicated that administration of EVs derived from MSCs isolated from different sources that include bone marrow, umbilical cord, or olfactory lamina propria ameliorate experimental colitis in mice [ 125 , 126 , 127 , 128 , 129 , 130 , 131 ]. In all these models, animals treated with MCS-derived EVs showed preserved intestinal barrier integrity, reduced infiltration of inflammatory cells in the damaged mucosa, reduced secretion of pro-inflammatory cytokines, and expansion of Treg cells.…”

Therapeutic Application of Exosomes in Inflammatory Diseases

“…IBD has become one of the largest disease burdens in newly industrialized countries [ 103 ]. Several groups have found that MSC-derived EVs relieved symptoms in dextran sulfate sodium (DSS)-induced IBD model mice [ 104 , 105 , 106 ]. The body weight, which normally declines in DSS-treated mice, was maintained for 10 days after the administration of UC-MSC-derived EVs, and the colon length, which was shortened by DSS treatment, was restored (64 to 77 mm) [ 104 ].…”

“…Several groups have found that MSC-derived EVs relieved symptoms in dextran sulfate sodium (DSS)-induced IBD model mice [ 104 , 105 , 106 ]. The body weight, which normally declines in DSS-treated mice, was maintained for 10 days after the administration of UC-MSC-derived EVs, and the colon length, which was shortened by DSS treatment, was restored (64 to 77 mm) [ 104 ]. In addition to this effect, structural damage to the villi caused by intestinal inflammation was alleviated, and expression levels of pro-inflammatory cytokines (IL-1β and IL-6) were observed to be significantly reduced, whereas levels of the anti-inflammatory cytokine IL-10 were increased.…”

“…Neddylation, a process in which the ubiquitin-like protein NEDD8 is covalently attached to a target protein as a post-translational modification, is proposed to be associated with IBD pathogenesis mediated by dendritic cells (DCs) [ 107 ]. EV-treated mice showed reduced levels of neddylation-related molecules (cullin 1 and NEDD8) in colon tissues [ 104 ]. MiR-326 was suggested as an important regulator, in part because of a potential binding site in the 3′ untranslated region of the NEDD8 mRNA.…”

“…MiR-326 was suggested as an important regulator, in part because of a potential binding site in the 3′ untranslated region of the NEDD8 mRNA. Thus, exosomal miR-326 may relieve IBD by inhibiting neddylation [ 104 ]. EVs also reduced levels of increased JAK1 and STAT1 phosphorylation caused by DSS-induction in the colon tissues of the mouse model.…”