Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Feb 26, 2021; 13(2): 177-192
Published online Feb 26, 2021. doi: 10.4252/wjSC.v13.i2.177
Prior transfusion of umbilical cord mesenchymal stem cells can effectively alleviate symptoms of motion sickness in mice through interleukin 10 secretion
Hua-Su Zhu, Dong Li, Cong Li, Jin-Xian Huang, Shan-Shan Chen, Lan-Bo Li, Qing Shi, Xiu-Li Ju
Hua-Su Zhu, Cong Li, Jin-Xian Huang, Shan-Shan Chen, Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
Dong Li, Qing Shi, Stem Cell and Regenerative Medicine Research Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
Lan-Bo Li, Department of Animal Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
Xiu-Li Ju, Department of Pediatrics, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Zhu HS performed and supervised all the experiments, compiled and analyzed the results, drew the figures, conceived the manuscript, and contributed to all revision phases and writing of the text; Li D conceived the study, designed the experiments, interpreted the results, wrote the discussion, and contributed to the discussion of the draft and revised versions; Li C assisted with the mRNA isolation from animal tissues and gene expression experiments; Huang JX assisted with the Morris water maze experiments; Chen SS was responsible for histological examination and Western blot; Li LB contributed to the collection of blood samples from animals; Zhu HS, Li D, Shi Q, and Ju XL wrote the manuscript; all coauthors have reviewed and agreed the final manuscript.
Supported by Department of Science & Technology of Shandong Province, No. ZR2018MH012; Quancheng Industrial Leader Project, No. 2017018; and Ji'nan Science and Technology Development Foundation, No. 201704066.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee on Scientific Research of Shandong University Qilu Hospital.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals by the Ethics Committee on Animal Experiment of Shandong University Qilu Hospital (DWLL-2019-023, Shandong, China).
Conflict-of-interest statement: The authors report no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiu-Li Ju, PhD, Doctor, Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan 250012, Shandong Province, China. jxlqlyy@163.com
Received: July 31, 2020
Peer-review started: July 31, 2020
First decision: October 21, 2020
Revised: October 31, 2020
Accepted: November 11, 2020
Article in press: November 11, 2020
Published online: February 26, 2021
Processing time: 208 Days and 0.6 Hours
Abstract
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 immuno-suppressive 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 UC-MSCs 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.

Keywords: Mesenchymal stem cell; Motion sickness; Inflammation; Immune microenvironment; Interleukin-10; JAK2/STAT3

Core Tip: This study demonstrated that prophylactic transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) can alleviate motion sickness (MS) in mice, particularly at 3-5 d after transplantation. After the MS model was established, molecular biology experiments confirmed the upregulation of interleukin-10 (IL-10) in the cochlea tissues. The transplanted UC-MSCs have activated the JAK2/STAT3 signaling pathway. They reduced the sensitivity of the vestibular cortex to imbalanced movements by secreting IL-10. Accordingly, MSC transplantation is expected to be a new strategy for the prevention and treatment of MS.