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Exosome-Encapsulated microRNA-140-5p Alleviates Neuronal Injury Following Subarachnoid Hemorrhage by Regulating IGFBP5-Mediated PI3K/AKT Signaling Pathway

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Abstract 

Recent literature has highlighted the therapeutic implication of exosomes (Exos) released by adipose tissue-originated stromal cells (ADSCs) in regenerative medicine. Herein, the current study sought to examine the potential protective effects of ADSC-Exos on neuronal injury following subarachnoid hemorrhage (SAH) by delivering miR-140-5p. Firstly, isolated primary neurons were co-cultured together with well-identified ADSC-Exos. TDP-43-treated neurons were subsequently treated with PKH67-ADSC-Exos and Cy3-miR-140-5p to assess whether ADSC-Exos could transmit miR-140-5p to the recipient neurons to affect their behaviors. Moreover, a luciferase assay was carried out to identify the presumable binding of miR-140-5p to IGFBP5. IGFBP5 rescue experimentation was also performed to testify whether IGFBP5 conferred the impact of miR-140-5p on neuronal damage. The role of PI3K/AKT signaling pathway was further analyzed with the application of its inhibitor miltefosine. Lastly, SAH rat models were developed for in vivo validation. It was found that ADSC-Exos conferred protection against TDP-43-caused neuronal injury by augmenting viability and suppressing cell apoptosis. In addition, miR-140-5p was transmitted from ADSC-Exos to neurons and post-transcriptionally downregulated the expression of IGFBP5. As a result, by means of suppressing IGFBP5 and activating the PI3K/AKT signaling pathway, miR-140-5p from ADSC-Exos induced a neuroprotective effect. Furthermore, in vivo findings substantiated the aforementioned protective role of ADSC-Exos-miR-140-5p, contributing to protection against SAH-caused neurological dysfunction. Collectively, our findings indicated that ADSC-Exos-miR-140-5p could inhibit TDP-43-induced neuronal injury and attenuate neurological dysfunction of SAH rats by inhibiting IGFBP5 and activating the PI3K/Akt signaling pathway.

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Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

SAH:

Subarachnoid hemorrhage

TDP-43:

Transactive response DNA-binding protein 43

ADSCs:

Adipose tissue-derived stromal cells

IGFBP5:

Insulin-like growth factor binding protein 5

IGF-I:

Insulin-like growth factor I

PI3K:

Phosphatidylinositol 3-kinase

AKT:

Protein kinase B

mTOR:

Mammalian target of rapamycin

HBSS:

Hanks’ balanced saline solution

NC:

Negative control

BSA:

Bovine serum albumin

MAP-2:

Microtubule-associated protein 2

FITC:

Fluorescein isothiocyanate

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

ECL:

Enhanced chemiluminescence

FACS:

Fluorescence-activated cell sorting

ANOVA:

Analysis of variance

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Funding

This study is supported by the National Natural Science Foundation of China (81870944; 81771233); the Specific Research Projects for Capital Health Development (2018–2-2041); the Beijing Science and Technology Planning Project (Z181100009618035); the Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20190501); and the Research and Promotion Program of Appropriate Techniques for Intervention of Chinese High-Risk Stroke People (GN-2020R0007).

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Authors and Affiliations

  1. Department of Neurosurgery, the Third Xiangya Hospital of Central South University, Changsha, 410013, People’s Republic of China

    Pinyan Wang, Jiajia Duan, Fei Liu & Aihua Liu

  2. Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China

    Yanan Xue

  3. Department of Neurosurgery, Xiangya Hospital Central South University, Changsha, 410008, People’s Republic of China

    Yuchun Zuo

  4. Biological Science, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, 321004, People’s Republic of China

    Yinan Xue

  5. Department of Neurosurgery, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA

    John H. Zhang

  6. Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, People’s Republic of China

    Fei Liu

  7. Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China

    Aihua Liu

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  1. Pinyan Wang
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Contributions

Pinyan Wang and Yanan Xue designed the study. Yuchun Zuo and Yinan Xue collated the data, Pinyan Wang, John H Zhang, and Jiajia Duan carried out data analyses and produced the initial draft of the manuscript. Fei Liu and Aihua Liu contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding authors

Correspondence to Fei Liu or Aihua Liu.

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Animal experimentation conformed to the animal ethics protocol ratified by Animal Ethics Committee of Central South University (No: 2019sydw0153). Extensive efforts were undertaken to minimize both the numbers and the respective suffering of the experimental animals.

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Wang, P., Xue, Y., Zuo, Y. et al. Exosome-Encapsulated microRNA-140-5p Alleviates Neuronal Injury Following Subarachnoid Hemorrhage by Regulating IGFBP5-Mediated PI3K/AKT Signaling Pathway. Mol Neurobiol 59, 7212–7228 (2022). https://doi.org/10.1007/s12035-022-03007-x

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