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Ameliorating Effect of Umbilical Cord Mesenchymal Stem Cells in a Human Induced Pluripotent Stem Cell Model of Dravet Syndrome

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Abstract

Dravet syndrome (DS) is a form of severe childhood-onset refractory epilepsy typically caused by a heterozygous loss-of-function mutation. DS patient-derived induced pluripotent stem cells (iPSCs) are appropriate human cells for exploring disease mechanisms and testing new therapeutic strategies in vitro. Repeated spontaneous seizures can cause neuroinflammatory reactions and oxidative stress, resulting in neuronal toxicity, neuronal dysfunction, blood–brain barrier disruption, and hippocampal inflammation. Antiepileptic drug therapy does not delay the development of chronic epilepsy. The application of mesenchymal stem cells (MSCs) is one therapeutic strategy for thwarting epilepsy development. This study evaluated the effects of human umbilical cord mesenchymal stem cell-conditioned medium (HUMSC-CM) in a new in vitro model of neurons differentiated from DS patient-derived iPSCs. In the presence of HUMSC-CM, increases in superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), glutathione peroxidase (GPX), and glutathione (GSH) levels were found to contribute to a reduction in reactive oxygen species (ROS) levels. In parallel, inflammation was rescued in DS patient-derived neuronal cells via increased expression of anti-inflammatory cytokines (TGF-β, IL-6, and IL-10) and significant downregulation of tumor necrosis factor-α and interleukin-1β expression. The intracellular calcium concentration ([Ca2+]i) and malondialdehyde (MDA) and ROS levels were decreased in DS patient-derived cells. In addition, action potential (AP) firing ability was enhanced by HUMSC-CM. In conclusion, HUMSC-CM can effectively eliminate ROS, affect migration and neurogenesis, and promote neurons to enter a highly functional state. Therefore, HUMSC-CM is a promising therapeutic strategy for the clinical treatment of refractory epilepsy such as DS.

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Data Availability

The datasets and materials used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Jean de Dieu Habimana for checking the English grammar of this manuscript.

Funding

This study was supported by Frontier Research Programs of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (Grant No. 2018GZR110105020), the Science and Technology Planning Project of Guangdong Province of China (No.2020B1212060052), and the Guangdong Provincial Natural Science Foundation (2021A1515010526).

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Authors and Affiliations

  1. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China

    Huifang Zhao & Zhiyuan Li

  2. CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China

    Huifang Zhao, Shuai Li, Feng Tang, Xiaobo Han, Zuoxian Lin, Rongqi Huang & Zhiyuan Li

  3. Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China

    Zhiyuan Li

  4. CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China

    Xiaobo Han & Zhiyuan Li

  5. Guangzhou Medical University, Guangzhou, 511436, China

    Xiaobo Han & Zhiyuan Li

  6. Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China

    Weiyue Deng & Zhiyuan Li

  7. University of Chinese Academy of Sciences, Beijing, 100049, China

    Shuai Li, Feng Tang, Xiaobo Han & Zhiyuan Li

  8. Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Lang He & Zhiyuan Li

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  1. Huifang Zhao
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Contributions

Conception and design, H. F. Z., S. L., L. H., and Z. Y. L.; acquisition of data, H. F. Z., X. B. H., and S. L.; analysis and interpretation of data, H. F. Z. and F. T.; drafting the article, H. F. Z.; revising it critically for important intellectual content, H. F. Z., W. Y. D. S. H. D., R. Q. H., and Z. Y. L.; all authors approved the final version to be published.

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Correspondence to Zhiyuan Li.

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Zhao, H., Li, S., He, L. et al. Ameliorating Effect of Umbilical Cord Mesenchymal Stem Cells in a Human Induced Pluripotent Stem Cell Model of Dravet Syndrome. Mol Neurobiol 59, 748–761 (2022). https://doi.org/10.1007/s12035-021-02633-1

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