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Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Brain Damage Following Subarachnoid Hemorrhage via the Interaction of miR-140-5p and HDAC7

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Abstract

Subarachnoid hemorrhage (SAH) triggers severe neuroinflammation and cognitive impairment, where microglial M1 polarization exacerbates the injury and M2 polarization mitigates damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), carrying microRNA (miR)-140-5p, offer therapeutic promise by targeting the cAMP/PKA/CREB pathway and modulating microglial responses, demonstrating a novel approach for addressing SAH-induced brain injury. This research explored the role of miR-140-5p delivered by MSC-EVs in mitigating brain damage following SAH. Serum from SAH patients and healthy individuals was analyzed for miR-140-5p and cAMP levels. The association between miR-140-5p levels, brain injury severity, and patient survival was examined, along with the target relationship between miR-140-5p and histone deacetylases 7 (HDAC7). MSC-EVs were characterized for their ability to cross the blood-brain barrier and modulate the HDAC7/AKAP12/cAMP/PKA/CREB axis, reducing M1 polarization and inflammation. The therapeutic effect of MSC-EV-miR-140-5p was demonstrated in an SAH mouse model, showing reduced neuronal apoptosis and improved neurological function. This study highlights the potential of MSC-EV-miR-140-5p in mitigating SAH-induced neuroinflammation and brain injury, providing a foundation for developing MSC-EV-based treatments for SAH.

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Data Availability

The data that supports the findings of this study are available on request from the corresponding author upon reasonable request.

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Funding

This study was supported by Zhenjiang City Social Development Subject (SH2022034), Jichuan Pharmaceutical Horizontal Project (JC-2023-003) and Zhenjiang Jinshan Healer (2021-JSYZ-22).

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  1. Yu Qian and Bo Chen are regarded as co-first authors.

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  1. Department of Neurosurgery, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212000, P.R. China

    Yu Qian, Bo Chen, Eryi Sun, Xinyu Lu, Zheng Li & Runpei Wang

  2. Department of Neurosurgery, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, West Huanghe Road, Huaiyin District, Huai’an, Jiangsu Province, 223300, P.R. China

    Dazhao Fang

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Yu Qian conceived and designed research. Bo Chen performed experiments. Eryi Sun interpreted results of experiments. Xinyu Lu analyzed data. Zheng Li prepared figures. Runpei Wang drafted paper. Dazhao Fang edited and revised manuscript. All authors read and approved final version of manuscript.

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Correspondence to Dazhao Fang.

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The collection of human blood samples in this study complies with the ethical standards of the Declaration of Helsinki and has been approved by the Ethics Committee of The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University. Written informed consent was obtained from all participants or their direct relatives. All animal experiments were conducted in accordance with ethical standards and received approval from the Animal Ethics Committee of The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, following the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.

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Qian, Y., Chen, B., Sun, E. et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Brain Damage Following Subarachnoid Hemorrhage via the Interaction of miR-140-5p and HDAC7. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04118-3

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