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MiR-124 and Small Molecules Synergistically Regulate the Generation of Neuronal Cells from Rat Cortical Reactive Astrocytes

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Abstract

Irreversible neuron loss caused by central nervous system injuries usually leads to persistent neurological dysfunction. Reactive astrocytes, because of their high proliferative capacity, proximity to neuronal lineage, and significant involvement in glial scarring, are ideal starting cells for neuronal regeneration. Having previously identified several small molecules as important regulators of astrocyte-to-neuron reprogramming, we established herein that miR-124, ruxolitinib, SB203580, and forskolin could co-regulate rat cortical reactive astrocyte-to-neuron conversion. The induced cells had reduced astroglial properties, displayed typical neuronal morphologies, and expressed neuronal markers, reflecting 25.9% of cholinergic neurons and 22.3% of glutamatergic neurons. Gene analysis revealed that induced neuron gene expression patterns were more similar to that of primary neurons than of initial reactive astrocytes. On the molecular level, miR-124-driven neuronal differentiation of reactive astrocytes was via targeting of the SOX9-NFIA-HES1 axis to inhibit HES1 expression. In conclusion, we present a novel approach to inducing endogenous rat cortical reactive astrocytes into neurons through co-regulation involving miR-124 and three small molecules. Thus, our research has potential implications for inhibiting glial scar formation and promoting neuronal regeneration after central nervous system injury or disease.

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Data and Materials Availability

The datasets used and/or analysed during the current study are available from the corresponding author (Guangfan Chi, guangfan130@jlu.edu.cn) on reasonable request.

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Acknowledgements

We thank Shanghai Sangon Biotech Co., Ltd., for RNA-seq analysis and Guangzhou RiboBio Co., Ltd., for designing the miR mimics and si-RNA. We also thank Editage for English language editing.

Funding

This work was supported by the National Natural Science Foundation of China (Grant numbers 81571199 and 81870974) and the Fundamental Research Funds for the Central Universities, JLU. The funding body had no role in the design of the study, the collection, analysis and interpretation of data and in the writing of the manuscript.

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Authors and Affiliations

  1. The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China

    Yangyang Zheng, Jinying Xu, Yifei Yu, Shuang Lv, Yulin Li, Chengshi Quan & Guangfan Chi

  2. China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun, 130031, Jilin, China

    Zhehao Huang & Lin Chen

  3. The First Hospital of Jilin University, No. 1 Xinmin Avenue, Changchun, 130021, Jilin, China

    Kun Hou

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  6. Shuang Lv
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  7. Lin Chen
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  8. Yulin Li
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  9. Chengshi Quan
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  10. Guangfan Chi
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Contributions

GC, CQ and YL conceived the study, designed the experiments, and together with YZ revised the manuscript. YZ performed the cellular and molecular experiments in vitro, with help from ZH and JX. KH, YY, SL and LC provided reagents and conducted the data analysis and interpretation. YZ wrote the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Yulin Li, Chengshi Quan or Guangfan Chi.

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The animal study has been reviewed and approved by the Ethics Committee of Jilin University (Ethical approval code: 2015-19).

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The authors have no relevant financial or non-financial interests to disclose.

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Zheng, Y., Huang, Z., Xu, J. et al. MiR-124 and Small Molecules Synergistically Regulate the Generation of Neuronal Cells from Rat Cortical Reactive Astrocytes. Mol Neurobiol 58, 2447–2464 (2021). https://doi.org/10.1007/s12035-021-02345-6

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