hucMSC-Derived Exosomes Alleviate the Deterioration of Colitis via the miR-146a/SUMO1 Axis

Abstract

Human umbilical cord mesenchymal stem cell-derived exosome (hucMSC-Ex) plays an important role in tissue repair and immunomodulation, leading to the mitigation of inflammatory bowel disease. However, the preventive function of hucMSC-Ex in the onset and progression of colitis-associated colon cancer (CAC) is poorly understood. In the current study, dextran sodium sulfate/azoxymethane-induced colitis mouse model was established, and the mice disease activity index, body weight, colon length, tumor counts, survival curve, tissue H&E/immunohistochemistry, and cytokines expression were analyzed to evaluate the effects of hucMSC-Ex on CAC. In addition, miR-146a mimics were transfected into colonic epithelial cells (fetal human cells) to evaluate their role in the hucMSC-Ex-mediated regulation of SUMO1. The results showed that hucMSC-Ex inhibits the expression of SUMO1 to reduce the process of CAC progression. Further analysis indicated that miR-146a targets and inhibits SUMO1 expression and its binding to β-catenin. In conclusion, our findings showed that hucMSC-Ex is effective in alleviating the deterioration of colitis via the miR-146a-mediated inhibition of SUMO1, which is crucial in this disease process.

Exosomes: Mediators in microenvironment of colorectal cancer

“…MSC‐derived exosomes contain metallothionein‐2, which is required to suppress the inflammatory response, and MSC‐Exos‐treated mouse colonic macrophages secrete IL‐10, making them significantly resistant to inflammatory restimulation and maintaining the integrity of the intestinal barrier 68 . Wang et al claimed that MSC‐Exos effectively alleviated IBD through miR‐146a‐targeted inhibition of SUMO1 69 . This suggests that MSC‐Exos inhibits the formation of an inflammatory microenvironment by regulating colonic macrophages and related miRNAs, and limit the development of CRC by alleviating IBD.…”

“…68 Wang et al claimed that MSC-Exos effectively alleviated IBD through miR-146a-targeted inhibition of SUMO1. 69 This suggests that MSC-Exos inhibits the formation of an inflammatory microenvironment by regulating colonic macrophages and related miRNAs, and limit the development of CRC by alleviating IBD. Yan et al demonstrated the CRC-derived exosomal miR-6869-5p targets and inhibits the TLR4/ NF-κB signaling pathway, suppressing the production of inflammatory cytokines and the formation of a proinflammatory microenvironment, thereby inhibiting the proliferation of CRC cells.…”

Mesenchymal Stem Cell-derived Exosomes: Novel Therapeutic Approach for Inflammatory Bowel Diseases

“…Transfer of miRNA : MSC-Exos binding to macrophages at the site of intestinal inflammation release the carried miRNA into macrophages, with targeted regulation of mRNA in macrophages, and regulate the polarization of M2 macrophages. Studies have shown that the Exo-miRNAs of MSCs, such as miR-146a, downregulate the expressions of TNF receptor-related factor 6 (TRAF-6) and IL-1 receptor-related kinase 1 (IRAK-1), inhibit the release of proinflammatory cytokines, and also promote the expression of anti-inflammatory factor IL-10[ 95 ].…”

Emerging roles of mesenchymal stem cell-derived exosomes in gastrointestinal cancers

“…Notably, MSC-derived exosomal miRNA-3940-5p can also inhibit CRC metastasis by targeting integrin α6 ( Li et al, 2021b ). The miR-146a/SUMO1 axis is also a pathway for MSC-derived exosomes to mitigate the progression of colitis and inhibit CRC progression ( Wang et al, 2022 ).…”