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Modulating Pro-inflammatory Cytokines, Tissue Damage Magnitude, and Motor Deficit in Spinal Cord Injury with Subventricular Zone-Derived Extracellular Vesicles

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Abstract

Background

The upregulation of TNF-α, IL-1β, IL-18, and IL-6 exacerbates the spinal cord injury by amplifying the neuroinflammation. Impeding the release and activation of these cytokines can stop the progression of lesion and promote healing. Modulating the inflammatory response with subventricular zone-derived extracellular vesicles (SVZ-EVs) is one highly promising approach.

Methods and materials

SVZ tissue was cultured and EVs were prepared, isolated, and injected intrathecal, in spinal cord-injured (SCI) rats. BBB locomotor scoring, qRT-PCR, Western Blot, H&E, and Nissl staining techniques were applied to record the outcomes.

Results

The intracisternally injected SVZ-EVs significantly decreased the gene and protein expression of TNF-α, IL-1β, IL-18, and IL-6, prevented extensive tissue damage, allowed healing, and improved the hind limb motor function in SCI models.

Conclusion

The results of the present study showed that SVZ-EVs therapy ameliorate inflammation, tissue damage, and motor deficit in traumatic spinal cord injury.

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References

  • Ahuja CS, Nori S, Tetreault L, Wilson J, Kwon B, Harrop J, Choi D, Fehlings MG (2017a) Traumatic spinal cord injury-repair and regeneration. Neurosurgery. 80(3S):S9–S22

    Article  PubMed  Google Scholar 

  • Ahuja CS, Wilson JR, Nori S, Kotter MRN, Druschel C, Curt A et al (2017b) Traumatic spinal cord injury. Nat Rev Dis Primers. 3:17018

    Article  PubMed  Google Scholar 

  • Aligholi H, Hassanzadeh G, Gorji A, Azari H (2016) A novel biopsy method for isolating neural stem cells from the subventricular zone of the adult rat brain for autologous transplantation in CNS injuries. Methods Mol Biol. 1462:711–731

    Article  CAS  PubMed  Google Scholar 

  • Amini Pishva A, Akbari M, Farahabadi A, Arabkheradmand A, Beyer C, Dashti N, Moradi F, Hassanzadeh G (2016) Effect of estrogen therapy on TNF-alpha and iNOS gene expression in spinal cord injury model. Acta Med Iran. 54(5):296–301

    PubMed  Google Scholar 

  • Azari H, Rahman M, Sharififar S, Reynolds BA (2010) Isolation and expansion of the adult mouse neural stem cells using the neurosphere assay. J Vis Exp. 45

  • Aziz I, Che Ramli MD, Mohd Zain NS, Sanusi J (2014) Behavioral and histopathological study of changes in spinal cord injured rats supplemented with spirulina platensis. Evid Based Complement Alternat Med. 2014:871657

    Article  PubMed  PubMed Central  Google Scholar 

  • Bauernfeind F, Hornung V (2013) Of inflammasomes and pathogens--sensing of microbes by the inflammasome. EMBO Mol Med. 5(6):814–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bazrafkan M, Nikmehr B, Shahverdi A, Hosseini SR, Hassani F, Poorhassan M et al (2017) Lipid peroxidation and its role in the expression of NLRP1a and NLRP3 genes in testicular tissue of male rats: a model of spinal cord injury. Iran Biomed J.

  • Cavaillon JM (2001) Pro- versus anti-inflammatory cytokines: myth or reality. Cell Mol Biol (Noisy-le-grand). 47(4):695–702

    CAS  Google Scholar 

  • Cave JW, Wang M, Baker H (2014) Adult subventricular zone neural stem cells as a potential source of dopaminergic replacement neurons. Front Neurosci. 8:16

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L (2018) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 9(6):7204–7218

    Article  PubMed  Google Scholar 

  • de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW (2008) A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci. 28(13):3404–3414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Farahabadi A, Akbari M, Amini Pishva A, Zendedel A, Arabkheradmand A, Beyer C, Dashti N, Hassanzadeh G (2016) Effect of progesterone therapy on TNF-alpha and iNOS gene expression in spinal cord injury model. Acta Med Iran. 54(6):345–351

    PubMed  Google Scholar 

  • Gabay C (2006) Interleukin-6 and chronic inflammation. Arthritis Res Ther 8(Suppl 2):S3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Garcia E, Aguilar-Cevallos J, Silva-Garcia R, Ibarra A (2016) Cytokine and growth factor activation in vivo and in vitro after spinal cord injury. Mediators Inflamm. 2016:9476020

    PubMed  PubMed Central  Google Scholar 

  • Gazdic M, Volarevic V, Harrell CR, Fellabaum C, Jovicic N, Arsenijevic N et al (2018) Stem cells therapy for spinal cord injury. Int J Mol Sci 19(4)

    Article  PubMed Central  CAS  Google Scholar 

  • Gholaminejhad M, Arabzadeh S, Akbari M, Mohamadi Y, Hassanzadeh G (2017) Anti-oxidative and neuroprotective effects of flaxseed on experimental unilateral spinal cord injury in rat. J Contemp Med Sci. 3(10):213–217

    Article  CAS  Google Scholar 

  • Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T (2010) Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford). 49(7):1215–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jo EK, Kim JK, Shin DM, Sasakawa C (2016) Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 13(2):148–159

    Article  CAS  PubMed  Google Scholar 

  • Konoshenko MY, Lekchnov EA, Vlassov AV, Laktionov PP (2018) Isolation of extracellular vesicles: general methodologies and latest trends. Biomed Res Int. 2018:8545347

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lai CP, Breakefield XO (2012) Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front Physiol. 3:228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee K, Na W, Lee JY, Na J, Cho H, Wu H, Yune TY, Kim WS, Ju BG (2012) Molecular mechanism of Jmjd3-mediated interleukin-6 gene regulation in endothelial cells underlying spinal cord injury. J Neurochem. 122(2):272–282

    Article  CAS  PubMed  Google Scholar 

  • Li X, Chen S, Mao L, Li D, Xu C, Tian H et al (2019) Zinc improves functional recovery by regulating the secretion of granulocyte colony stimulating factor from microglia/macrophages after spinal cord injury. Front Mol Neurosci. 12:18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 − ΔΔCT method. Methods. 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  • Lu Y, Zhou Y, Zhang R, Wen L, Wu K, Li Y et al (2019) Bone mesenchymal stem cell-derived extracellular vesicles promote recovery following spinal cord injury via improvement of the integrity of the blood-spinal cord barrier. Front Neurosci. 13:209

    Article  PubMed  PubMed Central  Google Scholar 

  • Mohamadi Y, Noori Moghahi SMH, Mousavi M, Borhani-Haghighi M, Abolhassani F, Kashani IR, Hassanzadeh G (2019) Intrathecal transplantation of Wharton's jelly mesenchymal stem cells suppresses the NLRP1 inflammasome in the rat model of spinal cord injury. J Chem Neuroanat. 97:1–8

    Article  CAS  PubMed  Google Scholar 

  • Mousavi M, Hedayatpour A, Mortezaee K, Mohamadi Y, Abolhassani F, Hassanzadeh G (2019) Schwann cell transplantation exerts neuroprotective roles in rat model of spinal cord injury by combating inflammasome activation and improving motor recovery and remyelination. Metab Brain Dis

  • Okano H, Sawamoto K (2008) Neural stem cells: involvement in adult neurogenesis and CNS repair. Philos Trans R Soc Lond B Biol Sci. 363(1500):2111–2122

    Article  PubMed  PubMed Central  Google Scholar 

  • Pan JZ, Ni L, Sodhi A, Aguanno A, Young W, Hart RP (2002) Cytokine activity contributes to induction of inflammatory cytokine mRNAs in spinal cord following contusion. J Neurosci Res. 68(3):315–322

    Article  CAS  PubMed  Google Scholar 

  • Paterniti I, Esposito E, Cuzzocrea S. Role of the neuroinflammation in the degree of spinal cord injury: new therapeutic strategies. 2016. In: Recovery of Motor Function Following Spinal Cord Injury [Internet]. IntechOpen. Available from: https://doi.org/10.5772/63222.

    Google Scholar 

  • Poon PC, Gupta D, Shoichet MS, Tator CH (2007) Clip compression model is useful for thoracic spinal cord injuries: histologic and functional correlates. Spine (Phila Pa 1976). 32(25):2853–2859

    Article  Google Scholar 

  • Properzi F, Logozzi M, Fais S (2013) Exosomes: the future of biomarkers in medicine. Biomark Med. 7(5):769–778

    Article  CAS  PubMed  Google Scholar 

  • Rajendran L, Bali J, Barr MM, Court FA, Kramer-Albers EM, Picou F et al (2014) Emerging roles of extracellular vesicles in the nervous system. J Neurosci. 34(46):15482–15489

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ramadan WS, Abdel-Hamid GA, Al-Karim S, Abbas AT (2017) Histological, immunohistochemical and ultrastructural study of secondary compressed spinal cord injury in a rat model. Folia Histochem Cyto. 55(1):11–20

    Article  CAS  Google Scholar 

  • Rice T, Larsen JEA, Li H, Nuttall RK, Larsen PH, Casha S et al (2017) Neuroprotection by minocycline in murine traumatic spinal cord injury: analyses of matrix metalloproteinases. Neuroimmunol Neuroinflammation. 4:243–253

    Article  CAS  Google Scholar 

  • Rong Y, Liu W, Wang J, Fan J, Luo Y, Li L, Kong F, Chen J, Tang P, Cai W (2019) Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death Dis. 10(5):340

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ruppert KA, Nguyen TT, Prabhakara KS, Toledano Furman NE, Srivastava AK, Harting MT, Cox CS Jr, Olson SD (2018) Human mesenchymal stromal cell-derived extracellular vesicles modify microglial response and improve clinical outcomes in experimental spinal cord injury. Sci Rep. 8(1):480

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sanchez-Ventura J, Amo-Aparicio J, Navarro X, Penas C (2019) BET protein inhibition regulates cytokine production and promotes neuroprotection after spinal cord injury. J Neuroinflammation. 16(1):124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sankavaram SR, Hakim R, Covacu R, Frostell A, Neumann S, Svensson M, Brundin L (2019) Adult neural progenitor cells transplanted into spinal cord injury differentiate into oligodendrocytes, enhance myelination, and contribute to recovery. Stem Cell Reports. 12(5):950–966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao Y, Shen Y, Chen T, Xu F, Chen X, Zheng S (2016) The functions and clinical applications of tumor-derived exosomes. Oncotarget. 7(37):60736–60751

    Article  PubMed  PubMed Central  Google Scholar 

  • Silva NA, Sousa N, Reis RL, Salgado AJ (2014) From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol. 114:25–57

    Article  PubMed  Google Scholar 

  • Suárez-Meade P, Ibarra A Protective role of the immune system in spinal cord injury: immunomodulation with altered peptide ligands. 2016. In: Recovery of Motor Function Following Spinal Cord Injury [Internet]. intechopen; [61-80]. Available from:. https://doi.org/10.5772/63221

    Google Scholar 

  • Tan Y, Yu L, Zhang C, Chen K, Lu J, Tan L (2018) miRNA-146a attenuates inflammation in an in vitro spinal cord injury model via inhibition of TLR4 signaling. Exp Ther Med. 16(4):3703–3709

    PubMed  PubMed Central  Google Scholar 

  • Venereau E, Ceriotti C, Bianchi ME (2015) DAMPs from cell death to new life. Front Immunol. 6:422

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Westerlund U, Svensson M, Moe MC, Varghese M, Gustavsson B, Wallstedt L et al (2005) Endoscopically harvested stem cells: a putative method in future autotransplantation. Neurosurgery 57(4):779–784 discussion -84

    Article  PubMed  Google Scholar 

  • Yu B, Zhang X, Li X (2014) Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 15(3):4142–4157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zendedel A, Johann S, Mehrabi S, Joghataei MT, Hassanzadeh G, Kipp M, Beyer C (2016) Activation and regulation of NLRP3 inflammasome by intrathecal application of SDF-1a in a spinal cord injury model. Mol Neurobiol. 53(5):3063–3075

    Article  CAS  PubMed  Google Scholar 

  • Zendedel A, Monnink F, Hassanzadeh G, Zaminy A, Ansar MM, Habib P et al (2017) Estrogen attenuates local inflammasome expression and activation after spinal cord injury. Mol Neurobiol

  • Zhang N, Yin Y, Xu SJ, Wu YP, Chen WS (2012) Inflammation & apoptosis in spinal cord injury. Indian J Med Res. 135:287–296

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Sahar Ijaz, Ibrahim Mohammed, Morteza Gholaminejhad, Mohammad Akbari & Gholamreza Hassanzadeh

  2. CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China

    Tahmineh Mokhtari

  3. Department of Psychology, University of Chinese Academy of Sciences, Beijing, China

    Tahmineh Mokhtari

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  1. Sahar Ijaz
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  2. Ibrahim Mohammed
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  3. Morteza Gholaminejhad
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  4. Tahmineh Mokhtari
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  5. Mohammad Akbari
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  6. Gholamreza Hassanzadeh
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Correspondence to Gholamreza Hassanzadeh.

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Ijaz, S., Mohammed, I., Gholaminejhad, M. et al. Modulating Pro-inflammatory Cytokines, Tissue Damage Magnitude, and Motor Deficit in Spinal Cord Injury with Subventricular Zone-Derived Extracellular Vesicles. J Mol Neurosci 70, 458–466 (2020). https://doi.org/10.1007/s12031-019-01437-2

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