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MiR-17-5p Mediates the Effects of ACE2-Enriched Endothelial Progenitor Cell-Derived Exosomes on Ameliorating Cerebral Ischemic Injury in Aged Mice

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Abstract

Aging is one of the key mechanisms of vascular dysfunction and contributes to the initiation and progression of ischemic stroke (IS). Our previous study demonstrated that ACE2 priming enhanced the protective effects of exosomes derived from endothelial progenitor cells (EPC-EXs) on hypoxia-induced injury in aging endothelial cells (ECs). Here, we aimed to investigate whether ACE2-enriched EPC-EXs (ACE2-EPC-EXs) could attenuate brain ischemic injury by inhibiting cerebral EC damage through their carried miR-17-5p and the underlying molecular mechanisms. The enriched miRs in ACE2-EPC-EXs were screened using the miR sequencing method. EPC-EXs, ACE2-EPC-EXs, and ACE2-EPC-EXs with miR-17-5p deficiency (ACE2-EPC-EXsantagomiR-17-5p) were administered to transient middle cerebral artery occlusion (tMCAO)-operated aged mice or coincubated with hypoxia/reoxygenation (H/R)-treated aging ECs. The results showed that (1) the level of brain EPC-EXs and their carried ACE2 were significantly decreased in aged mice compared to in young mice, and (2) after tMCAO, aged mice displayed increases in brain cell senescence, infarct volume, and neurological deficit score (NDS) and a decrease in cerebral blood flow (CBF). (3) Compared with EPC-EXs, ACE2-EPC-EXs were enriched with miR-17-5p and more effective in increasing ACE2 and miR-17-5p expression in cerebral microvessels, accompanied by obvious increases in cerebral microvascular density (cMVD) and cerebral blood flow (CBF) and decreases in brain cell senescence, infarct volume, neurological deficit score (NDS), cerebral EC ROS production, and apoptosis in tMCAO-operated aged mice. Moreover, silencing of miR-17-5p partially abolished the beneficial effects of ACE2-EPC-EXs. (4) In H/R-treated aging ECs, ACE2-EPC-EXs were more effective than EPC-EXs in decreasing cell senescence, ROS production, and apoptosis and increasing cell viability and tube formation. In a mechanistic study, ACE2-EPC-EXs more effectively inhibited PTEN protein expression and increased the phosphorylation of PI3K and Akt, which were partially abolished by miR-17-5p knockdown. Altogether, our data suggest that ACE-EPC-EXs have better protective effects on ameliorating aged IS mouse brain neurovascular injury by inhibiting cell senescence, EC oxidative stress, apoptosis, and dysfunction by activating the miR-17-5p/PTEN/PI3K/Akt signaling pathway.

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Author Contribution

QP, YW, JL, XJ, YS, SL, YC, and XM performed experiments; QP, YW, and XM wrote the manuscript; QP, YW, JL, ZX, XJ, and XM contributed to manuscript preparation; All authors discussed the results, analyzed data and commented on the manuscript; QP, YC, and XM developed the concepts and designed the study. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC, nos. 82170407, 81870580); the Guangdong Basic and Applied Basic Research Foundation (2021A1515010982, 2020A1515010089, 2022A1515012414); the Finance fund for science and technology special competitive allocation project of Zhanjiang city (no. 2021A05244); the Guangdong Key Laboratory of Age-related Cardiac and Cerebral Diseases (Exosome Transformation Laboratory of Neurological Diseases) and Exosome Research Platform (no. CLP2021A003); the “Clinical Medicine” + Science and Technology Cooperation Project of the Affiliated Hospital of Guangdong Medical University (no. CLP2021B005); and the PhD initiation Project of the Affiliated Hospital of Guangdong Medical University (no. 2021023563).

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  1. Qunwen Pan and Yan Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Guangdong Key Laboratory of Age-related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China

    Qunwen Pan, Yan Wang, Jinhua Liu, Xiaojuan Jin, Zhi Xiang, Suqing Li, Yumeng Shi, Wangtao Zhong & Xiaotang Ma

  2. Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, China

    Yan Wang

  3. Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA

    Yanfang Chen

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Supplementary materials 1:

Fig.S1 Characterization of EPC-EXs. (A) Immunofluorescence images of GFP marker expression in EPCs after lentivirus infection. Scale bar, 50 μm. (B) EXs specific marker CD63 and TSG101 were measured by western blotting. (C) The numbers and size of EPC-EXs were detected by NTA. (D) The morphology of EPC-EXs was detected by TEM. Scale bar, 200 μm. (ZIP 12634 kb). Fig. S2 EPC-EXs distribution and metabolism in cerebral infarct area after tail vein injection. (A) Images showing PKH26 labeled EPC-EXs (red) merged into cerebral neurons (NEUN, green) and astrocytes (GFAP, green). Scale bar, 30 μm. (B) The metabolism of EPC-EXs (PKH26, red) in cerebral ECs (CD31, green) and infarct area were detected by immunofluorescence staining. Scale bar, 30 μm.

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Pan, Q., Wang, Y., Liu, J. et al. MiR-17-5p Mediates the Effects of ACE2-Enriched Endothelial Progenitor Cell-Derived Exosomes on Ameliorating Cerebral Ischemic Injury in Aged Mice. Mol Neurobiol 60, 3534–3552 (2023). https://doi.org/10.1007/s12035-023-03280-4

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