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Current Neurovascular Research

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ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

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Research Article

Bone Marrow Mesenchymal Stem Cell Exosomal miR-345-3p Ameliorates Cerebral Ischemia-reperfusion Injury by Targeting TRAF6

Author(s): Dan Hou, Lei Zhang, Yujie Hu, Guoshuai Yang* and Dan Yu*

Volume 20, Issue 4, 2023

Published on: 06 October, 2023

Page: [493 - 504] Pages: 12

DOI: 10.2174/1567202620666230905121102

Price: $65

Abstract

Introduction: The purpose of this study was to investigate the effects of bone marrow mesenchymal stem cells (BMSCs) exosomal miR-345-3p and tumor necrosis factor receptorassociated factor 6 (TRAF6) on cerebral ischemia reperfusion (CIR) injury. Exosomes (Exos) derived from BMSCs were isolated and identified. PC12 (rat pheochromocytoma) cells were used to establish an oxygen and glucose deprivation/reoxygenation (OGD/R) model.

Methods: Cell counting kit-8, TUNEL staining, lactate dehydrogenase staining, RT-qPCR, and western blotting were utilized for analyzing the functions of miR-345-3p about PC12 cells. Dualluciferase reporter experiment was then to confirm the link between miR-345-3p and TRAF6. Finally, using male SD rats, the middle cerebral artery occlusion (MCAO) model was constructed. Regulation of I/R damage in MCAO rats of miR-345-3p and TRAF6 were further explored in the changes of modified neurological severity score, cerebral infarction pictures, relative infarct volume, and histopathological changes. After OGD/R treatment, neuronal apoptosis was dramatically increased. After treatment with exosomal miR-345-3p, OGD/R-induced neuroapoptosis was dramatically inhibited. Exosomal miR-345-3p inhibited OGD/R-induced neuroapoptosis by downregulating the expression of TRAF6. However, the miR-345-3p inhibitor aggravated the changes caused by OGD/R.

Results: The corresponding regulations of miR-345-3p were reversed with TRAF6 overexpression. The animal experiments in vivo further verified that miR-345-3p ameliorated brain I/R injury in MCAO rats by targeting TRAF6.

Conclusion: This study found that BMSCs-exosomal miR-345-3p protected against CIR injury by decreasing TRAF6.

« Previous Next »
[1]
Xiao Y, Geng F, Wang G, Li X, Zhu J, Zhu W. Bone marrow-derived mesenchymal stem cells-derived exosomes prevent oligodendrocyte apoptosis through exosomal miR-134 by targeting caspase-8. J Cell Biochem 2018; 120(2): 2109-18.
[PMID: 30191592]
[2]
Shin TH, Lee DY, Basith S. et al. Metabolome changes in cerebral ischemia. Cells 2020; 9(7): 1630.
[http://dx.doi.org/10.3390/cells9071630] [PMID: 32645907]
[3]
Liang Q, Yang J, He J. et al. Stigmasterol alleviates cerebral ischemia/reperfusion injury by attenuating inflammation and improving antioxidant defenses in rats. Biosci Rep 2020; 40(4): BSR20192133.
[http://dx.doi.org/10.1042/BSR20192133] [PMID: 32149332]
[4]
Yang Z, Weian C, Susu H, Hanmin W. Protective effects of mangiferin on cerebral ischemia–reperfusion injury and its mechanisms. Eur J Pharmacol 2016; 771: 145-51.
[http://dx.doi.org/10.1016/j.ejphar.2015.12.003] [PMID: 26656757]
[5]
Xu Y, Gao X, Wang L, Yang M, Xie R. Bakuchiol ameliorates cerebral ischemia-reperfusion injury by modulating NLRP3 inflammasome and Nrf2 signaling. Respir Physiol Neurobiol 2021; 292: 103707.
[http://dx.doi.org/10.1016/j.resp.2021.103707] [PMID: 34087492]
[6]
Catanese L, Tarsia J, Fisher M. Acute ischemic stroke therapy overview. Circ Res 2017; 120(3): 541-58.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.309278] [PMID: 28154103]
[7]
Li H, Ghazanfari R, Zacharaki D, Lim HC, Scheding S. Isolation and characterization of primary bone marrow mesenchymal stromal cells. Ann N Y Acad Sci 2016; 1370(1): 109-18.
[http://dx.doi.org/10.1111/nyas.13102] [PMID: 27270495]
[8]
Wang J, Sun R, Li Z, Pan Y. Combined bone marrow stromal cells and oxiracetam treatments ameliorates acute cerebral ischemia/reperfusion injury through TRPC6. Acta Biochim Biophys Sin 2019; 51(8): 767-77.
[http://dx.doi.org/10.1093/abbs/gmz059] [PMID: 31236585]
[9]
Zeng Q, Zhou Y, Liang D. et al. Exosomes secreted from bone marrow mesenchymal stem cells attenuate oxygen-glucose deprivation/reoxygenation-induced pyroptosis in PC12 cells by promoting ampk-dependent autophagic flux. Front Cell Neurosci 2020; 14: 182.
[http://dx.doi.org/10.3389/fncel.2020.00182] [PMID: 32765221]
[10]
Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem 2019; 88(1): 487-514.
[http://dx.doi.org/10.1146/annurev-biochem-013118-111902] [PMID: 31220978]
[11]
Yu H, Xu Z, Qu G. et al. Hypoxic preconditioning enhances the efficacy of mesenchymal stem cells-derived conditioned medium in switching microglia toward anti-inflammatory polarization in ischemia/reperfusion. Cell Mol Neurobiol 2021; 41(3): 505-24.
[http://dx.doi.org/10.1007/s10571-020-00868-5] [PMID: 32424775]
[12]
Wang C, Zhu G, He W. et al. BMSCs protect against renal ischemia‐reperfusion injury by secreting exosomes loaded with miR‐199a‐5p that target BIP to inhibit endoplasmic reticulum stress at the very early reperfusion stages. FASEB J 2019; 33(4): 5440-56.
[http://dx.doi.org/10.1096/fj.201801821R] [PMID: 30640521]
[13]
Zhu G, Pei L, Lin F. et al. Exosomes from human‐bone‐marrow‐derived mesenchymal stem cells protect against renal ischemia/reperfusion injury via transferring miR‐199a‐3p. J Cell Physiol 2019; 234(12): 23736-49.
[http://dx.doi.org/10.1002/jcp.28941] [PMID: 31180587]
[14]
Chen Q, Liu Y, Ding X. et al. Bone marrow mesenchymal stem cell-secreted exosomes carrying microRNA-125b protect against myocardial ischemia reperfusion injury via targeting SIRT7. Mol Cell Biochem 2020; 465(1-2): 103-14.
[http://dx.doi.org/10.1007/s11010-019-03671-z] [PMID: 31858380]
[15]
Yoshitaka T, Kawai A, Miyaki S. et al. Analysis of microRNAs expressions in chondrosarcoma. J Orthop Res 2013; 31(12): 1992-8.
[http://dx.doi.org/10.1002/jor.22457]
[16]
Tian T, Wang J, Zhou X. A review: microRNA detection methods. Org Biomol Chem 2015; 13(8): 2226-38.
[http://dx.doi.org/10.1039/C4OB02104E] [PMID: 25574760]
[17]
Fan ZX, Yang J. The role of microRNAs in regulating myocardial ischemia reperfusion injury. Saudi Med J 2015; 36(7): 787-93.
[http://dx.doi.org/10.15537/smj.2015.7.11089] [PMID: 26108581]
[18]
Li X, Bi T, Yang S. Exosomal microRNA-150-5p from bone marrow mesenchymal stromal cells mitigates cerebral ischemia/reperfusion injury via targeting toll-like receptor 5. Bioengineered 2022; 13(2): 3029-42.
[http://dx.doi.org/10.1080/21655979.2021.2012402] [PMID: 34898357]
[19]
Zhao Y, Gan Y, Xu G, Hua K, Liu D. Exosomes from MSCs overexpressing microRNA-223-3p attenuate cerebral ischemia through inhibiting microglial M1 polarization mediated inflammation. Life Sci 2020; 260: 118403.
[http://dx.doi.org/10.1016/j.lfs.2020.118403] [PMID: 32926923]
[20]
Wei Q, Tu Y, Zuo L. et al. MiR-345-3p attenuates apoptosis and inflammation caused by oxidized low-density lipoprotein by targeting TRAF6 via TAK1/p38/NF-kB signaling in endothelial cells. Life Sci 2020; 241: 117142.
[http://dx.doi.org/10.1016/j.lfs.2019.117142] [PMID: 31825793]
[21]
Li Y, Lv Y, Wang J. et al. LncRNA NORAD mediates the proliferation and apoptosis of diffuse large-b-cell lymphoma via regulation of miR-345-3p/TRAF6 axis. Arch Med Res 2022; 53(3): 271-9.
[http://dx.doi.org/10.1016/j.arcmed.2022.01.004] [PMID: 35164979]
[22]
Kobayashi T, Walsh MC, Choi Y. The role of TRAF6 in signal transduction and the immune response. Microbes Infect 2004; 6(14): 1333-8.
[http://dx.doi.org/10.1016/j.micinf.2004.09.001] [PMID: 15555541]
[23]
Wu H, Arron JR. TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. BioEssays 2003; 25(11): 1096-105.
[http://dx.doi.org/10.1002/bies.10352] [PMID: 14579250]
[24]
Gohda J, Matsumura T, Inoue J. Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol 2004; 173(5): 2913-7.
[25]
Yuan P, Liu Z, Liu M, Huang J, Li X, Zhou X. Up-regulated tumor necrosis factor-associated factor 6 level is correlated with apoptosis in the rat cerebral ischemia and reperfusion. Neurol Sci 2013; 34(7): 1133-8.
[http://dx.doi.org/10.1007/s10072-012-1199-2]
[26]
Bruneau S, Datta D, Flaxenburg JA, Pal S, Briscoe DM. TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor. Biochem Biophys Res Commun 2012; 419(1): 66-71.
[http://dx.doi.org/10.1016/j.bbrc.2012.01.128] [PMID: 22326918]
[27]
Song Z, Jin R, Yu S, Nanda A, Granger DN, Li G. Crucial role of CD40 signaling in vascular wall cells in neointimal formation and vascular remodeling after vascular interventions. Arterioscler Thromb Vasc Biol 2012; 32(1): 50-64.
[http://dx.doi.org/10.1161/ATVBAHA.111.238329] [PMID: 21998133]
[28]
Li N, Liu Y, Li JR, Zhang WX. Chrysin, which targets PLAU, protects PC12 cells from OGD/R-stimulated damage through repressing the NF-κB signaling pathway. Regen Ther 2022; 19: 69-76.
[http://dx.doi.org/10.1016/j.reth.2021.11.002] [PMID: 35097165]
[29]
Gan C, Ouyang F. Exosomes released from bone-marrow stem cells ameliorate hippocampal neuronal injury through transferring miR-455-3p. J Stroke Cerebrovasc Dis 2022; 31(8): 106142.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106142]
[30]
Zhang G, Ge M, Han Z. et al. Wnt/β-catenin signaling pathway contributes to isoflurane postconditioning against cerebral ischemia-reperfusion injury and is possibly related to the transforming growth factorβ1/Smad3 signaling pathway. Biomed Pharmacother 2019; 110: 420-30.
[http://dx.doi.org/10.1016/j.biopha.2018.11.143] [PMID: 30530044]
[31]
Zhang D, Cai G, Liu K. et al. Microglia exosomal miRNA-137 attenuates ischemic brain injury through targeting Notch1. Aging 2021; 13(3): 4079-95.
[http://dx.doi.org/10.18632/aging.202373] [PMID: 33461167]
[32]
Li X, Zheng L, Xia Q. et al. A novel cell-penetrating peptide protects against neuron apoptosis after cerebral ischemia by inhibiting the nuclear translocation of annexin A1. Cell Death Differ 2019; 26(2): 260-75.
[http://dx.doi.org/10.1038/s41418-018-0116-5] [PMID: 29769639]
[33]
Fard N, Saffari A, Emami G, Hofer S, Kauczor HU, Mehrabi A. Acute respiratory distress syndrome induction by pulmonary ischemia–reperfusion injury in large animal models. J Surg Res 2014; 189(2): 274-84.
[http://dx.doi.org/10.1016/j.jss.2014.02.034] [PMID: 24768138]
[34]
Zhu L, Zhou X, Li S. et al. miR 183 5p attenuates cerebral ischemia injury by negatively regulating PTEN. Mol Med Rep 2020; 22(5): 3944-54.
[http://dx.doi.org/10.3892/mmr.2020.11493] [PMID: 32901892]
[35]
Deng S, Zeng Y, Xiang J, Lin S, Shen J. Icariin protects bone marrow mesenchymal stem cells in aplastic anemia by targeting MAPK pathway. Mol Biol Rep 2022; 49(9): 8317-24.
[http://dx.doi.org/10.1007/s11033-022-07645-1] [PMID: 35708859]
[36]
Salunkhe S. Dheeraj, Basak M, Chitkara D, Mittal A. Surface functionalization of exosomes for target-specific delivery and in vivo imaging & tracking: Strategies and significance. J Control Release 2020; 326: 599-614.
[http://dx.doi.org/10.1016/j.jconrel.2020.07.042] [PMID: 32730952]
[37]
Yue Y, Zhao H, Yue Y, Zhang Y, Wei W. Downregulation of microrna-421 relieves cerebral ischemia/reperfusion injuries: Involvement of anti-apoptotic and antioxidant activities. Neuromolecular Med 2020; 22(3): 411-9.
[http://dx.doi.org/10.1007/s12017-020-08600-8] [PMID: 32385800]
[38]
Xie Q, Zeng J, Zheng Y. et al. Mitochondrial transplantation attenuates cerebral ischemia-reperfusion injury: Possible involvement of mitochondrial component separation. Oxid Med Cell Longev 2021; 2021: 1006636.
[http://dx.doi.org/10.1155/2021/1006636] [PMID: 34849186]
[39]
Liu X, Zhang M, Liu H. et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate cerebral ischemia-reperfusion injury-induced neuroinflammation and pyroptosis by modulating microglia M1/M2 phenotypes. Exp Neurol 2021; 341: 113700.
[http://dx.doi.org/10.1016/j.expneurol.2021.113700] [PMID: 33741350]
[40]
Li L, Yue S, Han R. et al. Storax protected primary cortical neurons from oxygen-glucose deprivation/reoxygenation injury via inhibiting the TLR4/TRAF6/NF-κB signaling pathway. Brain Res 2022; 1792: 148021.
[http://dx.doi.org/10.1016/j.brainres.2022.148021] [PMID: 35878660]
[41]
Li T, Qin JJ, Yang X. et al. The ubiquitin E3 ligase TRAF6 exacerbates ischemic stroke by ubiquitinating and activating rac1. J Neurosci 2017; 37(50): 12123-40.
[http://dx.doi.org/10.1523/JNEUROSCI.1751-17.2017] [PMID: 29114077]
[42]
Wu D, Lee YCG, Liu HC. et al. Identification of TLR downstream pathways in stroke patients. Clin Biochem 2013; 46(12): 1058-64.
[http://dx.doi.org/10.1016/j.clinbiochem.2013.05.059] [PMID: 23726813]

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