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Mesenchymal stem-cell-derived microvesicles ameliorate MPTP-induced neurotoxicity in mice: a role of the gut–microbiota–brain axis

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Abstract

Rationale

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder. Increasing evidence suggests the role of the gut–microbiota–brain axis in the pathogenesis of PD. Mesenchymal stem-cell-derived microvesicles (MSC-MVs) have emerged as a therapeutic potential for neurological disorders over the last years.

Objective

The objective of this study was to investigate whether MSC-MVs could improve PD-like neurotoxicity in mice after administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

Results

MPTP-induced reductions in the dopamine transporter and tyrosine hydroxylase expressions in the striatum and substantia nigra (SNr) were attenuated after a subsequent single administration of MSC-MVs. Increases in the phosphorylated α-synuclein (p-α-Syn)/α-Syn ratio in the striatum, SNr, and colon after MPTP injection were also attenuated after MSC-MVs injection. Furthermore, MSC-MVs restored MPTP-induced abnormalities of the gut microbiota composition. Interestingly, positive correlations between the genus Dubosiella and the p-α-Syn/α-Syn ratio were observed in the brain and colon, suggesting their roles in the gut–microbiota–brain communication. Moreover, MSC-MVs attenuated MPTP-induced reduction of the metabolite, 3,6-dihydroxy-2-[3-methoxy-4-(sulfooxy)phenyl]-7-(sulfinooxy)-3,4-dihydro-2H-1-benzopyran-5-olate, in the blood. Interestingly, a negative correlation between this compound and the p-α-Syn/α-Syn ratio was observed in the brain and colon.

Conclusions

These data suggest that MSC-MVs could ameliorate MPTP-induced neurotoxicity in the brain and colon via the gut–microbiota–brain axis. Therefore, MSC-MVs would have a new therapeutic potential for neurological disorders such as PD.

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Data availability

The 16S rRNA sequencing data have been deposited to the NCBI Sequence Read Archive and are available at the accession number PRJNA833302.

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Funding

This study was supported by the National Natural Science Foundation of China (to Y. Pu, no. 82101616), the China Postdoctoral Science Foundation (to Y. Pu, no. 281269), the Post-Doctor Research Project, West China Hospital, Sichuan University (to Y. Pu, no. 2021HXBH046), and the 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (to Y. Liu, nos. ZYGD18015 and ZYJC18003).

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Yaoyu Pu, Qiuhong Wu, Qiuping Zhang, Tianwen Huang, Ji Wen & Yi Liu

  2. The Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Long Wei

  3. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan

    Kenji Hashimoto

Authors
  1. Yaoyu Pu
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  2. Qiuhong Wu
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  3. Qiuping Zhang
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  4. Tianwen Huang
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  5. Ji Wen
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  6. Long Wei
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  7. Kenji Hashimoto
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  8. Yi Liu
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Contributions

Y.P., K.H., and Y.L. contributed to conception and design of the study. Y.P., Q.W., Q.Z., T.H., J.W., and L.W. contributed to acquisition and analysis of data. Y.P. contributed to drafting the text or preparing the figures. Y.L. supervised the project. All authors approved the final version of the text.

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Correspondence to Kenji Hashimoto or Yi Liu.

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Pu, Y., Wu, Q., Zhang, Q. et al. Mesenchymal stem-cell-derived microvesicles ameliorate MPTP-induced neurotoxicity in mice: a role of the gut–microbiota–brain axis. Psychopharmacology 240, 1103–1118 (2023). https://doi.org/10.1007/s00213-023-06348-0

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