Using extracellular vesicles derived from human umbilical cord mesenchymal stem cells for a topical coating promotes oral mucositis healing in rats

Background: Oral mucositis (OM) affects the quality of life and therapeutic outcomes of cancer patients. More effective drugs and methods for treating OM are urgently required for clinical application. Extracellular vesicles can play important roles in cutaneous wound healing. However, their role in OM remains unclear. Our aim was to investigate the function and mechanisms of topical coatings of extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUC-MSC-EVs) in OM. Methods: HUC-MSC-EVs were isolated by differential ultracentrifugation. We used glacial acetic acid to induce the formation of OM in rats. HUC-MSC-EVs were covered on the OM topically once a day. Rats' body weights were measured on alternative days. The healing degree of OM was evaluated with macroscopic observations and histological examinations. We also analyzed the mechanisms of hUC-MSC-EVs when promoting the healing of OM. The expression levels of NF-kappa B, IL-6, TNF-alpha, and IL-1 beta in mucosal tissue were evaluated using immunohistochemistry. Results: The median healing time of OM in the blank control, rhaFGF, 0.25 mu g/mu L EVs, 0.75 mu g/mu L EVs, and 1.50 mu g/mu L EVs groups was 14, 11, 10, 7, and 11 days, respectively. The most significant effect of hUC-MSC-EVs in promoting healing was at the concentration of 0.75 mu g/mu L. The median healing scores in the 0.75 mu g/mu L EVs group were 4 on day 5 and 3 on day 8 (*P<0.05 vs. the blank control group). After modeling, the body weight of rats started to recover from day 8 in the blank control group and day 4 in the 0.75 mu g/mu L EVs group. The 0.75 mu g/mu L EVs group showed lower immunostaining intensity of NF-kappa B, IL-6, and TNF-alpha on day 5 and 8 (*P<0.05 vs. the blank control group). However, there was no significant difference between the blank control group and the 0.75 mu g/mu L EVs group in IL-1 beta. Conclusions: Our results showed for the first time that coating hUC-MSC-EVs topically can promote healing of OM because it may inhibit the activation of the NF-kappa B signaling pathway.