The miR-210 Primed Endothelial Progenitor Cell Exosomes Alleviate Acute Ischemic Brain Injury


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Abstract

Background::Stem cell-released exosomes (EXs) have shown beneficial effects on regenerative diseases. Our previous study has revealed that EXs of endothelial progenitor cells (EPC-EXs) can elicit favorable effects on endothelial function. EXs may vary greatly in size, composition, and cargo uptake rate depending on the origins and stimulus; notably, EXs are promising vehicles for delivering microRNAs (miRs). Since miR-210 is known to protect cerebral endothelial cell mitochondria by reducing oxidative stress, here we study the effects of miR-210-loaded EPC-EXs (miR210-EPC-EXs) on ischemic brain damage in acute ischemic stroke (IS).

Methods::The miR210-EPC-EXs were generated from EPCs transfected with miR-210 mimic. Middle cerebral artery occlusion (MCAO) surgery was performed to induce acute IS in C57BL/6 mice. EPC-EXs or miR210-EPC-EXs were administrated via tail vein injection 2 hrs after IS. To explore the potential mechanisms, inhibitors of the vascular endothelial growth factor receptor 2 (VEGFR2)/PI3 kinase (PI3K) or tyrosine receptor kinase B (TrkB)/PI3k pathways were used. The brain tissue was collected after treatments for infarct size, cell apoptosis, oxidative stress, and protein expression (VEGFR2, TrkB) analyses on day two. The neurological deficit score (NDS) was evaluated before collecting the samples.

Results::As compared to EPC-EXs, miR210-EPC-EXs profoundly reduced the infarct volume and improved the NDS on day two post-IS. 2) Fewer apoptosis cells were detected in the peri-infarct brain of mice treated with miR210-EPC-EXs than in EPC-EXs-treated mice. Meanwhile, the oxidative stress was profoundly reduced by miR210-EPC-EXs. 3) The ratios of p-PI3k/PI3k, p- VEGFR2/VEGFR2, and p-TrkB/TrkB in the ipsilateral brain were raised by miR210-EPC-EXs treatment. These effects could be significantly blocked or partially inhibited by PI3k, VEGFR2, or TrkB pathway inhibitors.

Conclusion::These findings suggest that miR210-EPC-EXs protect the brain from acute ischemia- induced cell apoptosis and oxidative stress partially through the VEGFR2/PI3k and TrkB/PI3k signal pathways.

About the authors

Jinju Wang

Department of Biomedical Sciences, Joan C Edwards School of Medicine, Marshall University

Email: info@benthamscience.net

Shuzhen Chen

Department of Biomedical Sciences, Joan C Edwards School of Medicine, Marshall University

Email: info@benthamscience.net

Harshal Sawant

Department of Biomedical Sciences, Joan C Edwards School of Medicine, Marshall University

Email: info@benthamscience.net

Yanfang Chen

Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University

Email: info@benthamscience.net

Ji Bihl

Department of Biomedical Sciences, Joan C Edwards School of Medicine, Marshall University

Author for correspondence.
Email: info@benthamscience.net

References

  1. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365(11): 993-1003. doi: 10.1056/NEJMoa1105335 PMID: 21899409
  2. Gervois P, Wolfs E, Ratajczak J, et al. Stem cell‐based therapies for ischemic stroke: Preclinical results and the potential of imaging‐assisted evaluation of donor cell fate and mechanisms of brain regeneration. Med Res Rev 2016; 36(6): 1080-126. doi: 10.1002/med.21400 PMID: 27439773
  3. Liao S, Luo C, Cao B, et al. Endothelial progenitor cells for ischemic stroke: Update on basic research and application. Stem Cells Int 2017; 2017: 1-12. doi: 10.1155/2017/2193432 PMID: 28900446
  4. Chen J, Xiao X, Chen S, et al. Angiotensin-converting enzyme 2 priming enhances the function of endothelial progenitor cells and their therapeutic efficacy. Hypertension 2013; 61(3): 681-9. doi: 10.1161/HYPERTENSIONAHA.111.00202 PMID: 23266545
  5. Chen J, Chen J, Chen S, et al. Transfusion of CXCR4-primed endothelial progenitor cells reduces cerebral ischemic damage and promotes repair in db/db diabetic mice. PLoS One 2012; 7(11): e50105. doi: 10.1371/journal.pone.0050105 PMID: 23185548
  6. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6): 654-9. doi: 10.1038/ncb1596 PMID: 17486113
  7. Lopez-Verrilli MA, Court FA. Exosomes: Mediators of communication in eukaryotes. Biol Res 2013; 46(1): 5-11. doi: 10.4067/S0716-97602013000100001 PMID: 23760408
  8. Hofer HR, Tuan RS. Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther 2016; 7(1): 131. doi: 10.1186/s13287-016-0394-0 PMID: 27612948
  9. Zhang ZG, Chopp M. Exosomes in stroke pathogenesis and therapy. J Clin Invest 2016; 126(4): 1190-7. doi: 10.1172/JCI81133 PMID: 27035810
  10. Wang J, Chen S, Zhang W, Chen Y, Bihl JC. Exosomes from miRNA-126-modified endothelial progenitor cells alleviate brain injury and promote functional recovery after stroke. CNS Neurosci Ther 2020; 26(12): 1255-65. doi: 10.1111/cns.13455 PMID: 33009888
  11. Martins HC, Schratt G. MicroRNA-dependent control of neuroplasticity in affective disorders. Transl Psychiatry 2021; 11(1): 263. doi: 10.1038/s41398-021-01379-7 PMID: 33941769
  12. Li JS, Yao ZX. MicroRNAs: Novel regulators of oligodendrocyte differentiation and potential therapeutic targets in demyelination-related diseases. Mol Neurobiol 2012; 45(1): 200-12. doi: 10.1007/s12035-011-8231-z PMID: 22218763
  13. Rahmati S, Shojaei F, Shojaeian A, Rezakhani L, Dehkordi MB. An overview of current knowledge in biological functions and potential theragnostic applications of exosomes. Chem Phys Lipids 2020; 226: 104836. doi: 10.1016/j.chemphyslip.2019.104836 PMID: 31678051
  14. Fish JE, Santoro MM, Morton SU, et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 2008; 15(2): 272-84. doi: 10.1016/j.devcel.2008.07.008 PMID: 18694566
  15. Shultz JC, Goehe RW, Wijesinghe DS, et al. Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a. Cancer Res 2010; 70(22): 9185-96. doi: 10.1158/0008-5472.CAN-10-1545 PMID: 21045158
  16. Xin M, Deng X. Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem 2005; 280(11): 10781-9. doi: 10.1074/jbc.M500084200 PMID: 15642728
  17. Chan YC, Banerjee J, Choi SY, Sen CK. miR-210: The master hypoxamir. Microcirculation 2012; 19(3): 215-23. doi: 10.1111/j.1549-8719.2011.00154.x PMID: 22171547
  18. Mutharasan RK, Nagpal V, Ichikawa Y, Ardehali H. microRNA-210 is upregulated in hypoxic cardiomyocytes through Akt- and p53-dependent pathways and exerts cytoprotective effects. Am J Physiol Heart Circ Physiol 2011; 301(4): H1519-30. doi: 10.1152/ajpheart.01080.2010 PMID: 21841015
  19. Jiang Y, Li L, Tan X, Liu B, Zhang Y, Li C. miR 210 mediates vagus nerve stimulation induced antioxidant stress and anti‐apoptosis reactions following cerebral ischemia/reperfusion injury in rats. J Neurochem 2015; 134(1): 173-81. doi: 10.1111/jnc.13097 PMID: 25783636
  20. Wang F, Xiong L, Huang X, et al. miR-210 suppresses BNIP3 to protect against the apoptosis of neural progenitor cells. Stem Cell Res 2013; 11(1): 657-67. doi: 10.1016/j.scr.2013.04.005 PMID: 23688833
  21. Ma X, Wang J, Li J, et al. Loading MiR-210 in endothelial progenitor cells derived exosomes boosts their beneficial effects on hypoxia/reoxygeneation-injured human endothelial cells via protecting mitochondrial function. Cell Physiol Biochem 2018; 46(2): 664-75. doi: 10.1159/000488635 PMID: 29621777
  22. Yerrapragada SM, Sawant H, Chen S, Bihl T, Wang J, Bihl JC. The protective effects of miR-210 modified endothelial progenitor cells released exosomes in hypoxia/reoxygenation injured neurons. Exp Neurol 2022; 358: 114211. doi: 10.1016/j.expneurol.2022.114211 PMID: 36027941
  23. Liu H, Wang J, Chen Y, et al. NPC-EXs alleviate endothelial oxidative stress and dysfunction through the miR-210 downstream Nox2 and VEGFR2 pathways. Oxid Med Cell Longev 2017; 2017: 1-11. doi: 10.1155/2017/9397631 PMID: 28630660
  24. Zeng L, Liu J, Wang Y, et al. MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia. Front Biosci 2011; 3(4): 1265-72. PMID: 21622133
  25. Zeng LL, He XS, Liu JR, Zheng CB, Wang YT, Yang GY. Lentivirus mediated overexpression of microRNA 210 improves long term outcomes after focal cerebral ischemia in mice. CNS Neurosci Ther 2016; 22(12): 961-9. doi: 10.1111/cns.12589 PMID: 27390218
  26. Wang J, Chen S, Ma X, et al. Effects of endothelial progenitor cell-derived microvesicles on hypoxia/reoxygenation-induced endothelial dysfunction and apoptosis. Oxid Med Cell Longev 2013; 2013: 1-9. doi: 10.1155/2013/572729 PMID: 24288585
  27. Ma C, Wang J, Liu H, et al. Moderate exercise enhances endothelial progenitor cell exosomes release and function. Med Sci Sports Exerc 2018; 50(10): 2024-32. doi: 10.1249/MSS.0000000000001672 PMID: 30222687
  28. Wang J, Liu H, Chen S, Zhang W, Chen Y, Yang Y. Moderate exercise has beneficial effects on mouse ischemic stroke by enhancing the functions of circulating endothelial progenitor cell-derived exosomes. Exp Neurol 2020; 330: 113325. doi: 10.1016/j.expneurol.2020.113325 PMID: 32325158
  29. Chen CW, Wang LL, Zaman S, et al. Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction. Cardiovasc Res 2018; 114(7): 1029-40. doi: 10.1093/cvr/cvy067 PMID: 29566124
  30. Jang SC, Kim OY, Yoon CM, et al. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano 2013; 7(9): 7698-710. doi: 10.1021/nn402232g PMID: 24004438
  31. Wang J, Chen S, Bihl J. Exosome-mediated transfer of ACE2 (Angiotensin-Converting Enzyme 2) from endothelial progenitor cells promotes survival and function of endothelial cell. Oxid Med Cell Longev 2020; 2020: 1-11. doi: 10.1155/2020/4213541 PMID: 32051731
  32. Wang J, Guo R, Yang Y, et al. The novel methods for analysis of exosomes released from endothelial cells and endothelial progenitor cells. Stem Cells Int 2016; 2016: 1-12. doi: 10.1155/2016/2639728 PMID: 27118976
  33. Zheng Y, Hou J, Liu J, et al. Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats. J Pharmacol Sci 2014; 124(3): 354-64. doi: 10.1254/jphs.13220FP PMID: 24646622
  34. Moon IJ, Kim DY, Rhee CS, Lee CH, Min YG. Role of angiogenic factors in airway remodeling in an allergic rhinitis murine model. Allergy Asthma Immunol Res 2012; 4(1): 37-45. doi: 10.4168/aair.2012.4.1.37 PMID: 22211169
  35. Miranda CO, Teixeira CA, Liz MA, et al. Systemic delivery of bone marrow-derived mesenchymal stromal cells diminishes neuropathology in a mouse model of Krabbe’s disease. Stem Cells 2011; 29(11): 1738-51. doi: 10.1002/stem.724 PMID: 21898691
  36. Milde S, Brown GC. Knockout of the P2Y6 Receptor Prevents Peri-Infarct Neuronal Loss after Transient, Focal Ischemia in Mouse Brain. Int J Mol Sci 2022; 23(4): 2304. doi: 10.3390/ijms23042304 PMID: 35216419
  37. Zhang W, Zhao J, Wang R, et al. Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain. CNS Neurosci Ther 2019; 25(12): 1329-42. doi: 10.1111/cns.13256 PMID: 31697040
  38. Wang J, Zhong Y, Ma X, et al. Analyses of endothelial cells and endothelial progenitor cells released microvesicles by using microbead and Q-dot based nanoparticle tracking analysis. Sci Rep 2016; 6(1): 24679. doi: 10.1038/srep24679 PMID: 27094208
  39. Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal stem cells for neurological disorders. Adv Sci 2021; 8(7): 2002944. doi: 10.1002/advs.202002944 PMID: 33854883
  40. Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and regenerative effects of mesenchymal stem cells and extracellular vesicles: Therapeutic outlook for inflammatory and degenerative diseases. Front Immunol 2021; 11: 591065. doi: 10.3389/fimmu.2020.591065 PMID: 33613514
  41. Hade MD, Suire CN, Suo Z. Mesenchymal stem cell-derived exosomes: Applications in regenerative medicine. Cells 2021; 10(8): 1959. doi: 10.3390/cells10081959 PMID: 34440728
  42. Venkat P, Zacharek A, Landschoot-Ward J, et al. Exosomes derived from bone marrow mesenchymal stem cells harvested from type two diabetes rats promotes neurorestorative effects after stroke in type two diabetes rats. Exp Neurol 2020; 334: 113456. doi: 10.1016/j.expneurol.2020.113456 PMID: 32889008
  43. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 2013; 33(11): 1711-5. doi: 10.1038/jcbfm.2013.152 PMID: 23963371
  44. Zhou Y, Li P, Goodwin AJ, et al. Exosomes from endothelial progenitor cells improve the outcome of a murine model of sepsis. Mol Ther 2018; 26(5): 1375-84. doi: 10.1016/j.ymthe.2018.02.020 PMID: 29599080
  45. Li Y, Wang J, Chen S, et al. miR-137 boosts the neuroprotective effect of endothelial progenitor cell-derived exosomes in oxyhemoglobin-treated SH-SY5Y cells partially via COX2/PGE2 pathway. Stem Cell Res Ther 2020; 11(1): 330. doi: 10.1186/s13287-020-01836-y PMID: 33100224
  46. Xia J, Song X, Meng J, Lou D. Endothelial progenitor cells-derived exosomes transfer microRNA-30e-5p to regulate Erastin-induced ferroptosis in human umbilical vein endothelial cells via the specificity protein 1/adenosine monophosphate-activated protein kinase axis. Bioengineered 2022; 13(2): 3566-80. doi: 10.1080/21655979.2022.2025519 PMID: 35068337
  47. Xia L, Wang X, Yao W, Wang M, Zhu J. Lipopolysaccharide increases exosomes secretion from endothelial progenitor cells by toll‐like receptor 4 dependent mechanism. Biol Cell 2022; 114(5): 127-37. doi: 10.1111/boc.202100086 PMID: 35235701
  48. Wiklander OPB, Nordin JZ, O’Loughlin A, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 2015; 4(1): 26316. doi: 10.3402/jev.v4.26316 PMID: 25899407
  49. Choi H, Choi Y, Yim HY, Mirzaaghasi A, Yoo JK, Choi C. Biodistribution of exosomes and engineering strategies for targeted delivery of therapeutic exosomes. Tissue Eng Regen Med 2021; 18(4): 499-511. doi: 10.1007/s13770-021-00361-0 PMID: 34260047
  50. Li WL, Fraser JL, Yu SP, Zhu J, Jiang YJ, Wei L. The role of VEGF/VEGFR2 signaling in peripheral stimulation-induced cerebral neurovascular regeneration after ischemic stroke in mice. Exp Brain Res 2011; 214(4): 503-13. doi: 10.1007/s00221-011-2849-y PMID: 21922279
  51. Sheng S, Huang J, Ren Y, et al. Neuroprotection against hypoxic/ischemic injury: δ-Opioid receptors and BDNF-TrkB pathway. Cell Physiol Biochem 2018; 47(1): 302-15. doi: 10.1159/000489808 PMID: 29768254

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