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BMSC-Derived Exosomal Egr2 Ameliorates Ischemic Stroke by Directly Upregulating SIRT6 to Suppress Notch Signaling

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Abstract

Exosomes generated by BMSCs contribute to functional recovery in ischemic stroke. However, the regulatory mechanism is largely unknown. Exosomes were isolated from BMSCs. Tube formation, MTT, TUNEL, and flow cytometry assays were applied to examine cell angiogenesis, viability, and apoptosis. Protein and DNA interaction was evaluated by ChIP and luciferase assays. LDH release into the culture medium was examined. Infarction area was evaluated by TTC staining. Immunofluorescence staining was applied to examine CD31 expression. A mouse model of MCAO/R was established. BMSC-derived exosomes attenuated neuronal cell damage and facilitated angiogenesis of brain endothelial cells in response to OGD/R, but these effects were abolished by the knockdown of Egr2. Egr2 directly bound to the promoter of SIRT6 to promote its expression. The incompetency of Egr2-silencing exosomes was reversed by overexpression of SIRT6. Furthermore, SIRT6 inhibited Notch signaling via suppressing Notch1. Overexpression of SIRT6 and inhibition of Notch signaling improved cell injury and angiogenesis in OGD/R-treated cells. BMSC-derived exosomal Egr2 ameliorated MCAO/R-induced brain damage via upregulating SIRT6 to suppress Notch signaling in mice. BMSC-derived exosomes ameliorate OGD/R-induced injury and MCAO/R-caused cerebral damage in mice by delivering Egr2 to promote SIRT6 expression and subsequently suppress Notch signaling. Our study provides a potential exosome-based therapy for ischemic stroke.

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

Funding

This work was supported by the National Natural Science Foundation of China-Long non-coding RNA regulates the direction of neural stem cell differentiation (project number: 81760234) and Hainan Province Clinical Medical Center (project number: LCYX202107).

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  1. Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, Hainan Province, People’s Republic of China

    Rongjun Xiao, Qingsong Wang, Jun Peng, Zhengtao Yu, Jikun Zhang & Ying Xia

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  1. Rongjun Xiao
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Contributions

Rongjun Xiao: Conceptualization, writing—original draft preparation, investigation, validation, visualization, methodology.

Qingsong Wang: Methodology, data curation.

Jun Peng: Software.

Zhengtao Yu: Data curation.

Jikun Zhang: Software.

Ying Xia: Conceptualization, writing—original draft preparation, supervision, writing—reviewing and editing.

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Correspondence to Ying Xia.

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Xiao, R., Wang, Q., Peng, J. et al. BMSC-Derived Exosomal Egr2 Ameliorates Ischemic Stroke by Directly Upregulating SIRT6 to Suppress Notch Signaling. Mol Neurobiol 60, 1–17 (2023). https://doi.org/10.1007/s12035-022-03037-5

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