Prior transfusion of umbilical cord mesenchymal stem cells can effectively alleviate symptoms of motion sickness in mice through interleukin 10 secretion

BACKGROUND Motion sickness(MS)is a disease that occurs during unbalanced movement,characterized by gastrointestinal symptoms and autonomic nervous system activation.Current clinical treatments for MS are limited.Recent evidence indicates that the levels of pro-inflammatory cytokines increase during MS and are associated with an inner ear immune imbalance.In the present study,mesenchymal stem cells(MSCs)have been shown to exert strong immunosuppressive effects.AIM To explore whether umbilical cord-derived mesenchymal stem cells(UC-MSCs)can prevent the occurrence of MS,and the underlying mechanism regulated by MSCs in a mouse model of MS.METHODS A total of 144(equal numbers of males and females)5wkold BALB/c mice were randomly divided into five groups:Normal group(n=16),MS group(n=32),MSCs group(n=32),MS+MSCs group(n=32),and MS+AS101/MSCs group(n=32).The MSCs group(n=32),MS+MSCs group(n=32),and MS+AS101/MSCs group(n=32)were preventively transplanted with UC-MSCs or AS101-treated UC-MSCs(1×106 cells/mouse).Mice in the MS(n=32),MS+MSCs,and MS+AS101/MSCs groups were subjected to rotation on a centrifuge for 10 min at 8×g/min for MS model establishment on days 3,5,8,and 10 after UC-MSCs injection.The Morris water maze(MWM)test was used to observe the symptom of dizziness.Enzyme-linked immunosorbent assay(ELISA)and reverse transcription-quantitative polymerase chain reaction(RT-qPCR)were used to detect the levels of inflammatory cytokines in mice peripheral blood and the petrous part of the temporal bone samples.Western blot analysis was performed to analyze the JAK2/STAT3 signaling pathway in the cochlear tissues.Histological examination was performed by hematoxylin and eosin(HE)staining for conventional morphological evaluation in the petrous part of temporal bone samples.RESULTS The MWM test demonstrated that UC-MSCs improved the symptoms of MS.The MS+MSCs group was faster than the MS group on days 3 and 5(P=0.036 and P=0.002,respectively).ELISA and RT-qPCR showed that the serum and mRNA levels of interleukin-10(IL-10)in the cochlear tissues were increased after transplantation with UC-MSCs(MS+MSCs group vs MS group at 3 and 5 d,P=0.002 and cP<0.001,respectively).RT-qPCR results confirmed a significant increase in IL-10 levels at four time points(MS+MSCs group vs MS group,P=0.009,P=0.009,P=0.048,and P=0.049,respectively).This suggested that UCMSCs reduced the sensitivity of the vestibular microenvironment by secreting IL-10.Moreover,Western blot analysis showed that the MSCs activated the JAK2/STAT3 signaling pathway in the cochlear tissues.The levels of IL-10,IL-10RA,JAK2,STAT3,and phosphorylated JAK2 and STAT3 in the MS+MSCs group were increased compared to those of the MS group(P<0.05).The morphological changes in the four groups showed no significant differences.The role of IL-10 secretion on the ability of UC-MSCs to successfully improve the symptoms of MS was confirmed by the diminished therapeutic effects associated with treatment with the IL-10 inhibitor ammonium trichloro(dioxoethylene-o,o′)tellurate(AS101).CONCLUSION Prophylactic transplantation of UC-MSCs can alleviate the clinical symptoms of MS in mice,particularly at 3-5 d after preventive transplantation.The mechanism for UC-MSCs to reduce the sensitivity of vestibular cortex imbalance may be the secretion of IL-10.The next step is to demonstrate the possibility of curing MS in the vestibular environment by intermittent transplantation of MSCs.Above all,MSCs are expected to become a new method for the clinical prevention and treatment of MS.

Role of Histamine H1 Receptors in Vestibular Nucleus in Motion Sickness

Objectives To investigate the expression of histamine H1 receptors （H1R） in the vestibular nucleus of brainstem in rats and the role of H1R in motion sickness （MS）. Methods A total of 24 healthy Sprague-Dawley rats were divided randomly into four groups （n=6 each） which determined if the animals would receive induction of MS or drug （promethazine） treatment： MS （ - ）/Drug （ - ）; MS（＋）/Drug （ - ）; MS （ - ）/Drug （ ＋ at 0.25 mg）; and MS （ ＋ ）/ Drug（＋）. MS was induced by complex motion stimulation and the conditioned taste aversion was used as a behavioral indicator of MS. The volume of 0.15% sodium saccharin solution （SS） intake within 45 minutes after motion stimulation was measured. H1R in the vestibular nucleus was examined by immunofluorescence staining. The expression of H 1R protein in brainstem tissue at vestibular nucleus level was detected by western blot. Results The mean SS intake volume in the MS （ ＋ ）/Drug （ - ） group （8.8 ml） was significantly less than that of the MS （ - ）/Drug （ - ） group （15.1 ml） （P 〈 0.01）. The mean SS intake volume of the MS （-）/Drug （＋） group （14.8 ml） was similar to that of the MS（-）/Drug（-） group. The mean SS intake volume （9.6 ml） of the MS（＋）/Drug（＋） group was more than that of the MS（＋）/Drug（-）group （P〈0.01）, but less than that of the MS（-）/Drug（-） group or MS（-）/Drug（＋） group （P 〈 0.01）. Immunofluorescence staining showed positive expression of H1R in the vestibular nucleus of brainstem and the expression was enhanced by motion stimulation. Western blot analysis showed that H1R protein expressed in the brainstem tissue at vestibular nucleus level and the expression also increased significantly after motion stimulation. The MS-induced increase of H1R was not affected significantly by promethazine. Conclusions H1Rs exist in the vestibular nucleus in rats and H 1R expression is up-regulated by motion stimulation, but not affected by promethazine. The findings indicate that the histaminergic system is involved in MS. Promethazine, as an H1R blocker, may play its anti-MS role by competing the binding site on H1Rs with histamine rather than inhibiting H1R expression.