Volume 24, Issue 6 (11-2020)                   IBJ 2020, 24(6): 347-360 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Seifali E, Hassanzadeh G, Mahdavipour M, Mortezaee K, Moini A, Satarian L, et al . Extracellular Vesicles Derived from Human Umbilical Cord Perivascular Cells Improve Functional Recovery in Brain Ischemic Rat via the Inhibition of Apoptosis. IBJ 2020; 24 (6) :347-360
URL: http://ibj.pasteur.ac.ir/article-1-3197-en.html
Extracellular Vesicles Derived from Human Umbilical Cord Perivascular Cells Improve Functional Recovery in Brain Ischemic Rat via the Inhibition of Apoptosis
Elham Seifali , Gholamreza Hassanzadeh , Marzieh Mahdavipour , Keywan Mortezaee , Ashraf Moini , Leila Satarian , Faezeh Shekari , Abdoreza Nazari , Shabnam Movassaghi , Mohammad Akbari *
Abstract:  
Background: Ischemic stroke, as a health problem caused by the reduced blood supply to the brain, can lead to the neuronal death. The number of reliable therapies for stroke is limited. Mesenchymal stem cells (MSCs) exhibit therapeutic achievement. A major limitation of MSC application in cell therapy is the short survival span. MSCs affect target tissues through the secretion of many paracrine agents including extracellular vesicles (EVs). This study aimed to investigate the effect of human umbilical cord perivascular cells (HUCPVCs)-derived EVs on apoptosis, functional recovery, and neuroprotection. Methods: Ischemia was induced by middle cerebral artery occlusion (MCAO) in male Wistar rats. Animals were classified into sham, MCAO, MCAO + HUCPVC, and MCAO + EV groups. Treatments began at two hours after ischemia. Expressions of apoptotic-related proteins (BAX/BCl-2 [B-cell lymphoma-2] and caspase-3 and -9), the amount of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, neuronal density (microtubule-associated protein 2 [MAP2]), and dead neurons (Nissl staining) were assessed on day seven post MCAO. Results: Administration of EVs improved the sensorimotor function (p < 0.001) and reduced the apoptotic rate of Bax/Bcl-2 ratio (p < 0.001), as well as caspases and TUNEL-positive cells (p < 0.001) in comparison to the MCAO group. EV treatment also reduced the number of dead neurons and increased the number of MAP2+ cells in the ischemic boundary zone (p < 0.001), as compared to the MCAO group. Conclusion:  Our findings showed that HUCPVCs-derived EVs are more effective than their mother’s cells in improving neural function, possibly via the regulation of apoptosis in the ischemic rats. The strategy of cell-free extracts is, thus, helpful in removing the predicaments surrounding cell therapy in targeting brain diseases.
Keywords: Apoptosis, Extracellular vesicles, Ischemia, Middle cerebral artery
Full-Text [PDF 1496 kb]      
Type of Study: Full Length/Original Article | Subject: Related Fields
References
1. Gu N, Dong Y, Tian Y, Di Z, Liu Z, Chang M, Jia X, Qian Y, Zhang W. Anti-apoptotic and angiogenic effects of intelectin-1 in rat cerebral ischemia. Brain research bulletin 2017; 130: 27-35. [DOI:10.1016/j.brainresbull.2016.12.006]
2. Li Y, Cheng Q, Hu G, Deng T, Wang Q, Zhou J, Su X. Extracellular vesicles in mesenchymal stromal cells: A novel therapeutic strategy for stroke. Experimental and therapeutic medicine 2018; 15(5): 4067-4079. [DOI:10.3892/etm.2018.5993]
3. Radak D, Katsiki N, Resanovic I, Jovanovic A, Sudar-Milovanovic E, Zafirovic S, A Mousad S, R Isenovic E. Apoptosis and acute brain ischemia in ischemic stroke. Current vascular pharmacology 2017; 15(2): 115-122. [DOI:10.2174/1570161115666161104095522]
4. Bretón RR, Rodríguez JCG. Excitotoxicity and oxidative stress in acute ischemic stroke, Acute Ischemic Stroke. Reterieved from: https://www. intechopen.com/books/acute-ischemic-stroke/ excito-toxicity-and-oxidative-stress-in-acute-ischemic-stroke.
5. Li Y, Yang GY. Pathophysiology of Ischemic Stroke. Translational Research in Stroke. Translational Medicine Research.Singapore: Springer; 2017. [DOI:10.1007/978-981-10-5804-2_4]
6. Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nature reviews drug discovery 2017; 16(4): 273-284. [DOI:10.1038/nrd.2016.253]
7. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clinical cancer research 2009; 15(4): 1126-1132. [DOI:10.1158/1078-0432.CCR-08-0144]
8. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998; 281(5381): 1312-1316. [DOI:10.1126/science.281.5381.1312]
9. Schulz JB, Weller M, Moskowitz MA. Caspases as treatment targets in stroke and neurodegenerative diseases. Annals of neurology 1999; 45(4): 421-429. https://doi.org/10.1002/1531-8249(199904)45:4<421::AID-ANA2>3.0.CO;2-Q [DOI:10.1002/1531-8249(199904)45:43.0.CO;2-Q]
10. Sinden JD, Hicks C, Stroemer P, Vishnubhatla I, Corteling R. Human neural stem cell therapy for chronic ischemic stroke: charting progress from laboratory to patients. Stem cells development 2017; 26(13): 933-947 . [DOI:10.1089/scd.2017.0009]
11. Venkat P, Shen Y, Chopp M, Chen J. Cell-based and pharmacological neurorestorative therapies for ischemic stroke. Neuropharmacology 2018; 134(Pt B): 310-322. [DOI:10.1016/j.neuropharm.2017.08.036]
12. Monteforte A, Lam B, Sherman MB, Henderson K, Sligar AD, Spencer A, Tang B, Dunn AK, Baker AB. Glioblastoma exosomes for therapeutic angiogenesis in peripheral ischemia. Tissue engineering part A 2017; 23(21-22): 1251-1261. [DOI:10.1089/ten.tea.2016.0508]
13. Nawaz M, Fatima F, Vallabhaneni KC, Penfornis P, Valadi H, Ekström K, Kholia S, Whitt JD, Fernandes JD, Pochampally R, Squire JA, Camussi G. Extracellular vesicles: Evolving factors in stem cell biology. Stem cells international 2016; 2016:1073140. [DOI:10.1155/2016/1073140]
14. Teixeira FG, Carvalho MM, Neves-Carvalho A, Panchalingam KM, Behie LA, Pinto L, Sousa N, Salgado AJ. Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation. Stem cell reviews and reports 2015; 11(2): 288-297. [DOI:10.1007/s12015-014-9576-2]
15. Fraga JS, Silva NA, Lourenco AS, Goncalves V, Neves NM, Reis RL, Rodrigues AJ, Manadas B, Sousa N, Salgado AJ. Unveiling the effects of the secretome of mesenchymal progenitors from the umbilical cord in different neuronal cell populations. Biochimie 2013; 95(12): 2297-2303. [DOI:10.1016/j.biochi.2013.06.028]
16. S ELA, Mager I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nature reviews drug discovery 2013; 12(5): 347-357. [DOI:10.1038/nrd3978]
17. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK. Exosome secreted by MSC reduces myocardial ischemia/ reperfusion injury. Stem cell research 2010; 4(3): 214-222. [DOI:10.1016/j.scr.2009.12.003]
18. Eirin A, Zhu XY, Puranik AS, Woollard JR, Tang H, Dasari S, Lerman A, Van Wijnen AJ, Lerman LO. Integrated transcriptomic and proteomic analysis of the molecular cargo of extracellular vesicles derived from porcine adipose tissue-derived mesenchymal stem cells. PLoS one 2017; 12(3): e0174303. [DOI:10.1371/journal.pone.0174303]
19. Calió ML, Marinho DS, Ko GM, Ribeiro RR, Carbonel AF, Oyama LM, Ormanji M, Guirao TP, Calió PL, Reis LA. Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model. Free radical biology and medicine 2014; 70: 141-154. [DOI:10.1016/j.freeradbiomed.2014.01.024]
20. Joerger-Messerli MS, Oppliger B, Spinelli M, Thomi G, Di Salvo I, Schneider P, Schoeberlein A. Extracellular vesicles derived from Wharton's jelly mesenchymal stem cells prevent and resolve programmed cell death mediated by perinatal hypoxia-ischemia in neuronal cells. Cell transplantation 2018; 27(1): 168-180. [DOI:10.1177/0963689717738256]
21. Liu W, Wang Y, Gong F, Rong Y, Luo Y, Tang P, Zhou Z, Zhou Z, Xu T, Jiang T. Exosomes derived from bone mesenchymal stem cells repair traumatic spinal cord injury by suppressing the activation of A1 neurotoxic reactive astrocytes. Journal of neurotrauma 2019; 36(3): 469-484. [DOI:10.1089/neu.2018.5835]
22. Zhao Y, Sun X, Cao W, Ma J, Sun L, Qian H, Zhu W, Xu W. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem cells international 2015; 2015: 761643. [DOI:10.1155/2015/761643]
23. Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, Xiong Y. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. Journal of neurosurgery 2015; 122(4): 856-867. [DOI:10.3171/2014.11.JNS14770]
24. Huang JH, Yin XM, Xu Y, Xu CC, Lin X, Ye FB, Cao Y, Lin FY. Systemic administration of exosomes released from mesenchymal stromal cells attenuates apoptosis, Inflammation, and promotes angiogenesis after spinal cord injury in rats. Journal of neurotrauma 2017; 34(24): 3388-3396. [DOI:10.1089/neu.2017.5063]
25. Zendedel A, Habib P, Dang J, Lammerding L, Hoffmann S, Beyer C, Slowik A. Omega-3 poly-unsaturated fatty acids ameliorate neuroinflammation and mitigate ischemic stroke damage through interactions with astrocytes and microglia. Journal of neuroimmunology 2015; 278: 200-211. [DOI:10.1016/j.jneuroim.2014.11.007]
26. Mokhtari T, Akbari M, Malek F, Kashani IR, Rastegar T, Noorbakhsh F, Ghazi-Khansari M, Attari F, Hassanzadeh G. Improvement of memory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. DARU journal of pharmaceutical sciences 2017; 25(1): 4. [DOI:10.1186/s40199-017-0169-x]
27. Mahdavipour M, Hassanzadeh G, Seifali E, Mortezaee K, Aligholi H, Shekari F, Sarkoohi P, Zeraatpisheh Z, Nazari A, Movassaghi S, Akbari M. Effects of neural stem cell‐derived extracellular vesicles on neuronal protection and functional recovery in the rat model of middle cerebral artery occlusion. Cell biochemistry andfunction 2020; 38(4): 373-383. [DOI:10.1002/cbf.3484]
28. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 7th Edition. Amesterdam: Elsevier; 2013.
29. Sarugaser R, Ennis J, Stanford WL, Davies JE. Isolation, propagation, and characterization of human umbilical cord perivascular cells (HUCPVCs). Stem cells in regenerative medicine 2009: 482: 269-279. [DOI:10.1007/978-1-59745-060-7_17]
30. Eom J, Feisst V, Ranjard L, Loomes K, Damani T, Jackson-Patel V, Locke M, Sheppard H, Narayan P, Dunbar PR. Visualization and quantification of mesenchymal cell adipogenic differentiation potential with a lineage specific marker. Journal of visualized experiments 2018; (133): 57153. [DOI:10.3791/57153]
31. Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP. Osteogenic differentiation of purified, culture‐expanded human mesenchymal stem cells in vitro. Journal of cellular biochemistry 1997; 64(2): 295-312. https://doi.org/10.1002/(SICI)1097-4644(199702)64:2<295::AID-JCB12>3.0.CO;2-I [DOI:10.1002/(SICI)1097-4644(199702)64:23.0.CO;2-I]
32. Sunkara V, Woo HK, Cho YK. Emerging techniques in the isolation and characterization of extracellular vesicles and their roles in cancer diagnostics and prognostics. The analyst 2016; 141(2): 371-381. [DOI:10.1039/C5AN01775K]
33. Weng Y, Sui Z, Shan Y, Hu Y, Chen Y, Zhang L, Zhang Y. Effective isolation of exosomes with polyethylene glycol from cell culture supernatant for in-depth proteome profiling. Analyst 2016; 141(15): 4640-4646. [DOI:10.1039/C6AN00892E]
34. Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR. A semiautomated method for measuring brain infarct volume. Journal of cerebral blood flow and metabolism 1990; 10(2): 290-293. [DOI:10.1038/jcbfm.1990.47]
35. Zhang A, Bai Y, Hu Y, Zhang F, Wu Y, Wang Y, Zheng P, He Q. The effects of exercise intensity on p-NR2B expression in cerebral ischemic rats. Canadian journal of neurological sciences 2012; 39(5): 613-618. [DOI:10.1017/S0317167100015341]
36. Bouet V, Boulouard M, Toutain J, Divoux D, Bernaudin M, Schumann-Bard P, Freret T. The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice. Nature protocols 2009; 4(10): 1560-1564. [DOI:10.1038/nprot.2009.125]
37. Borlongan CV, Hida H, Nishino H. Early assessment of motor dysfunctions aids in successful occlusion of the middle cerebral artery. Neuroreport 1998; 9(16): 3615-3621. [DOI:10.1097/00001756-199811160-00012]
38. Pan Y, Zhang H, Acharya AB, Patrick PH, Oliver D, Morley JE. Effect of testosterone on functional recovery in a castrate male rat stroke model. Brain research 2005; 1043(1-2): 195-204. [DOI:10.1016/j.brainres.2005.02.078]
39. Enayati A, Yassa N, Mazaheri Z, Rajaei M, Pourabouk M, Ghorghanlu S, Basiri S, Khori V. Cardioprotective and anti-apoptotic effects of Potentilla reptans L. Root via Nrf2 pathway in an isolated rat heart ischemia/reperfusion model. Life sciences 2018; 215: 216-226. [DOI:10.1016/j.lfs.2018.11.021]
40. Fuhrich DG, Lessey BA, Savaris RF. Comparison of HSCORE assessment of endometrial beta integrin subunit expression with digital HSCORE using computerized image analysis (ImageJ). Analytical and quantitative cytopathology and histopathology 2013; 35(4): 210-216.
41. Haines DM, Chelack BJ. Technical considerations for developing enzyme immunohistochemical staining procedures on formalin-fixed paraffin-embedded tissues for diagnostic pathology. Journal of veterinary diagnostic investigation 1991; 3(1): 101-112. [DOI:10.1177/104063879100300128]
42. Zhu H, Zhang Y, Shi Z, Lu D, Li T, Ding Y, Ruan Y, Xu A. The neuroprotection of liraglutide against ischaemia-induced apoptosis through the activation of the PI3K/AKT and MAPK pathways. Scientific reports 2016; 6: 26859. [DOI:10.1038/srep26859]
43. Sugiyama Y, Sato Y, Kitase Y, Suzuki T, Kondo T, Mikrogeorgiou A, Horinouchi A, Maruyama S, Shimoyama Y, Tsuji M, Suzuki S, Yamamoto T, Hayakawa M. Intravenous administration of bone marrow-derived mesenchymal stem cell, but not adipose tissue-derived stem cell, ameliorated the neonatal hypoxic-Ischemic brain Injury by changingcerebral inflammatory state in rat. Frontiers in neurology 2018; 9: 757. [DOI:10.3389/fneur.2018.00757]
44. Sabbaghziarani F, Mortezaee K, Akbari M, Kashani IR, Soleimani M, Moini A, Ataeinejad N, Zendedel A, Hassanzadeh G. Retinoic acid-pretreated Wharton's jelly mesenchymal stem cells in combination with triiodothyronine improve expression of neurotrophic factors in the subventricular zone of the rat ischemic brain injury. Metabolic brain disease 2017; 32(1): 185-193. [DOI:10.1007/s11011-016-9897-8]
45. Wiklander OP, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, Mager I, Vader P, Lee Y, Sork H, Seow Y, Heldring N, Alvarez-Erviti L, Smith CI, Le Blanc K, Macchiarini P, Jungebluth P, Wood MJ, Andaloussi SE. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. Journal of extracellular vesicles 2015; 4: 26316. [DOI:10.3402/jev.v4.26316]
46. Hirshman BR, Kras RT, Akers JC, Carter BS, Chen CC. Extracellular Vesicles in Molecular Diagnostics: An Overview with a Focus on CNS diseases. Advances in clinical chemistry 2016; 76: 37-53. [DOI:10.1016/bs.acc.2016.05.005]
47. Maumus M, Jorgensen C, Noel D. Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie 2013; 95(12): 2229-2234. [DOI:10.1016/j.biochi.2013.04.017]
48. 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. Journal of cerebral blood flow and metabolism 2013; 33(11): 1711-1715. [DOI:10.1038/jcbfm.2013.152]
49. Xin H, Katakowski M, Wang F, Qian JY, Liu XS, Ali MM, Buller B, Zhang ZG, Chopp M. MicroRNA-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke 2017; 48(3): 747-753. [DOI:10.1161/STROKEAHA.116.015204]
50. Phinney DG, Pittenger MF. Concise review: MSC‐derived exosomes for cell‐free therapy. Stem cells 2017; 35(4): 851-858. [DOI:10.1002/stem.2575]
51. Lee JY, Kim E, Choi S-M, Kim D-W, Kim KP, Lee I, Kim H-S. Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke. Scientific reports 2016; 6: 33038. [DOI:10.1038/srep33038]
52. Doeppner TR, Herz J, Görgens A, Schlechter J, Ludwig A-K, Radtke S, de Miroschedji K, Horn PA, Giebel B, Hermann DM. Extracellular vesicles improve post‐stroke neuroregeneration and prevent postischemic immunosuppression. Stem cells translational medicine 2015; 4(10): 1131-1143. [DOI:10.5966/sctm.2015-0078]
53. Xiao B, Chai Y, Lv S, Ye M, Wu M, Xie L, Fan Y, Zhu X, Gao Z. Endothelial cell-derived exosomes protect SH-SY5Y nerve cells against ischemia/reperfusion injury. International journal of molecular medicine 2017; 40(4): 1201-1209. [DOI:10.3892/ijmm.2017.3106]
54. Hedayatpour A, Shiasi M, Famitafreshi H, Abolhassani F, Ebrahimnia P, Mokhtari T, Hassanzaeh G, Karimian M, Nazparvar B, Marefati N, Tarzjani MD. Co-administration ofprogesterone and melatonin attenuates ischemia-induced hippocampal damage in Rats. Journal of molecular neuroscience 2018; 66(2): 251-260. [DOI:10.1007/s12031-018-1163-6]
55. Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke 2009; 40(5): e331-e339. [DOI:10.1161/STROKEAHA.108.531632]
56. Pena-Blanco A, Garcia-Saez AJ. Bax, Bak and beyond-mitochondrial performance in apoptosis. The FEBS journal 2018; 285(3): 416-431. [DOI:10.1111/febs.14186]
57. Liu QS, Deng R, Li S, Li X, Li K, Kebaituli G, Li X, Liu R. Ellagic acid protects against neuron damage in ischemic stroke through regulating the ratio of Bcl-2/Bax expression. Applied physiology, nutrition, and metabolism 2017; 42(8): 855-860. [DOI:10.1139/apnm-2016-0651]
58. Aboutaleb N, Shamsaei N, Rajabi H, Khaksari M, Erfani S, Nikbakht F, Motamedi P, Shahbazi A. Protection of Hippocampal CA1 neurons against ischemia/reperfusion injury by exercise preconditioning via modulation of Bax/Bcl-2 ratio and prevention of caspase-3 activation. Basic and clinical neuroscience 2016; 7(1): 21-29.
59. Wang C, Liu M, Pan Y, Bai B, Chen J. Global gene expression profile of cerebral ischemia-reperfusion injury in rat MCAO model. Oncotarget 2017; 8(43): 74607-74622. [DOI:10.18632/oncotarget.20253]
60. Julien O, Wells JA. Caspases and thir substrates. Cell death and differentiation 2017; 24(8): 1380-1389. [DOI:10.1038/cdd.2017.44]
61. Wang L, Pei S, Han L, Guo B, Li Y, Duan R, Yao Y, Xue B, Chen X, Jia Y. Mesenchymal stem cell-derived exosomes reduce A1 astrocytes via downregulation of phosphorylated NFκB P65 subunit in spinal cord injury. Cellular Physiology and biochemistry 2018; 50(4): 1535-1559. [DOI:10.1159/000494652]
62. Lu Y, Zhou Y, Zhang R, Wen L, Wu K, Li Y, Yao Y, Duan R, Jia Y. Bone Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote recovery Following Spinal Cord Injury via Improvement of the Integrity of the Blood-Spinal Cord Barrier. Frontiers in neuroscience 2019; 13: 209. [DOI:10.3389/fnins.2019.00209]
63. Li Y, Jiang N, Powers C, Chopp M. Neuronal damage and plasticity identified by microtubule-associated protein 2, growth-associated protein 43, and cyclin D1 immunoreactivity after focal cerebral ischemia in rats. Stroke 1998; 29:(9): 1972-1979. [DOI:10.1161/01.STR.29.9.1972]
Add your comments about this article : Your username or Email:
CAPTCHA
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2024 CC BY-NC 4.0 | Iranian Biomedical Journal

Designed & Developed by : Yektaweb