A Review of Pharmacological and Cell-based Therapies in Spinal Cord Injury

Journal of Cell and Molecular Research

مقاله 4، دوره 14، شماره 2 - شماره پیاپی 28، تیر 2023، صفحه 91-100   

نوع مقاله: Review / Mini-Review

شناسه دیجیتال (DOI): 10.22067/jcmr.2023.81950.1065

نویسندگان

Shiva Amanollahi؛ Hossein Kazemi Mehrjerdi^*

Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran

چکیده

Spinal cord injury (SCI) is a severe central nervous system trauma (CNS) that has two primary and secondary phases. The initial phase, which is irreversible, causes nerve tissue destruction and bleeding. Various factors in the second phase together aggravate the primary damage. One of the important factors of the second phase is the cascading of inflammatory factors, which, contribute to the further destruction of nerve tissue. In addition to surgical treatments, drug and cell-based or extracellular vesicles therapy, by modulating the immune system and reducing inflammatory factors at the lesion site, prevent further destruction of nerve tissue and help improve the patient's neurological and motor function. Researchers have provided many chemical and herbal medicines to reduce complications caused by spinal cord injury, many of which are currently being used and are also known as drugs of choice. However, sometimes the long-term use of these drugs causes side effects. Today, the new approach of cell therapy and the use of extracellular vesicles (EVs) is being investigated, which has minimized the side effects of drug treatments and helped to improve the function of nerve cells. Mesenchymal stem cells (MSCs), have a high ability to differentiate into different cells and to modulate the immune system by secreting paracrine factors. But since they cannot cross the blood-brain barrier (BBB), researchers solved this problem by extracting extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs), which also contain all paracrine factors. In this study, a brief overview of drug treatments, stem cells, and extracellular vesicular therapy in the treatment of spinal cord injury has been discussed.

کلیدواژه‌ها

Spinal cord injury؛ SCI therapies؛ Stem cell؛ Extracellular vesicle؛ Neuroimmunology

مراجع

Alizadeh, A., Dyck, S.M. and Karimi-Abdolrezaee, S., 2019. Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms. Frontiers in neurology, 10:282.

Anderson, D.K., Demediuk, P., Saunders, R.D., Dugan, L.L., Means, E.D. and Horrocks, L.A. (1985). Spinal cord injury and protection. Annals of emergency medicine, 14(8): 816-821.

Anjum, A., Yazid, M.D.I., Fauzi Daud, M., Idris, J., Ng, A.M.H., Selvi Naicker, A., Ismail, O.H.R., Athi Kumar, R.K. and Lokanathan, Y. (2020). Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. International journal of molecular sciences, 21(20): 7533.

Badner, A., Siddiqui, A.M. and Fehlings, M.G. (2017). Spinal cord injuries: how could cell therapy help?. Expert opinion on biological therapy, 17(5): 529-541.

Bagher, Z., Azami, M., Ebrahimi-Barough, S., Mirzadeh, H., Solouk, A., Soleimani, M., Ai, J., Nourani, M.R. and Joghataei, M.T. (2016). Differentiation of Wharton’s jelly-derived mesenchymal stem cells into motor neuron-like cells on three-dimensional collagen-grafted nanofibers. Molecular neurobiology, 53: 2397-2408.

Bagher, Z., Ebrahimi-Barough, S., Azami, M., Mirzadeh, H., Soleimani, M., Ai, J., Nourani, M.R. and Joghataei, M.T. (2015). Induction of human umbilical Wharton’s jelly-derived mesenchymal stem cells toward motor neuron-like cells. In Vitro Cellular & Developmental Biology-Animal, 51: 987-994.

Berebichez-Fridman, R. and Montero-Olvera, P.R. (2018). Sources and clinical applications of mesenchymal stem cells: state-of-the-art review. Sultan Qaboos University Medical Journal, 18(3): e264.

Bomstein, Y., Marder, J.B., Vitner, K., Smirnov, I., Lisaey, G., Butovsky, O., Fulga, V. and Yoles, E. (2003). Features of skin-coincubated macrophages that promote recovery from spinal cord injury. Journal of neuroimmunology, 142(1-2): 10-16.

Bracken, M.B., Collins, W.F., Freeman, D.F., Shepard, M.J., Wagner, F.W., Silten, R.M., Hellenbrand, K.G., Ransohoff, J., Hunt, W.E., Perot, P.L. and Grossman, R.G. (1984). Efficacy of methylprednisolone in acute spinal cord injury. Jama, 251(1): 45-52.

Bracken, M.B., Shepard, M.J., Collins, W.F., Holford, T.R., Young, W., Baskin, D.S., Eisenberg, H.M., Flamm, E., Leo-Summers, L., Maroon, J. and Marshall, L.F. (1990). A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: results of the Second National Acute Spinal Cord Injury Study. New England Journal of Medicine, 322(20): 1405-1411.

Bracken, M.B., Shepard, M.J., Holford, T.R., Leo-Summers, L., Aldrich, E.F., Fazl, M., Fehlings, M., Herr, D.L., Hitchon, P.W., Marshall, L.F. and Nockels, R.P. (1997). Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the third national acute spinal cord injury randomized controlled trial. Jama, 277(20): 1597-1604.

Bradbury, E.J., Moon, L.D., Popat, R.J., King, V.R., Bennett, G.S., Patel, P.N., Fawcett, J.W. and McMahon, S.B. (2002). Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature, 416(6881): 636-640.

Casha, S., Zygun, D., McGowan, M.D., Bains, I., Yong, V.W. and John Hurlbert, R. (2012). Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain, 135(4): 1224-1236.

Chaves, R.H.D.F., Souza, C.C.D., Furlaneto, I.P., Teixeira, R.K.C., Oliveira, C.P.D., Rodrigues, E.D.M., Santos, D.A.S.D., Silva, R.C., Penha, N.E.A.D. and Lima, A.R.D. (2018). Influence of tramadol on functional recovery of acute spinal cord injury in rats. Acta Cirúrgica Brasileira, 33: 1087-1094.

Chiang, C.Y. and Chen, C. (2019). Toward characterizing extracellular vesicles at a single-particle level. Journal of biomedical science, 26(1): 1-10.

Chiba, K. (2005). FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacology & therapeutics, 108(3): 308-319.

Chukhchin, D.G., Bolotova, K., Sinelnikov, I., Churilov, D. and Novozhilov, E. (2020). Exosomes in the phloem and xylem of woody plants. Planta, 251: 1-14.

Clarke, W.E., Berry, M., Smith, C., Kent, A. and Logan, A. (2001). Coordination of fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-2 (FGF-2) trafficking to nuclei of reactive astrocytes around cerebral lesions in adult rats. Molecular and Cellular Neuroscience, 17(1): 17-30.

Colao, I.L., Corteling, R., Bracewell, D. and Wall, I. (2018). Manufacturing exosomes: a promising therapeutic platform. Trends in molecular medicine, 24(3): 242-256.

Didangelos, A., Iberl, M., Vinsland, E., Bartus, K. and Bradbury, E.J., 2014. Regulation of IL-10 by chondroitinase ABC promotes a distinct immune response following spinal cord injury. Journal of Neuroscience, 34(49): 16424-16432.

Domon, Y., Kitano, Y. and Makino, M. (2018). Analgesic effects of the novel α2δ ligand mirogabalin in a rat model of spinal cord injury. Die Pharmazie-An International Journal of Pharmaceutical Sciences, 73(11): 659-661.

Donovan, J. and Kirshblum, S. (2018). Clinical trials in traumatic spinal cord injury. Neurotherapeutics, 15(3): 654-668.

Evaniew, N., Noonan, V.K., Fallah, N., Kwon, B.K., Rivers, C.S., Ahn, H., Bailey, C.S., Christie, S.D., Fourney, D.R., Hurlbert, R.J. and Linassi, A.G. (2015). Methylprednisolone for the treatment of patients with acute spinal cord injuries: a propensity score-matched cohort study from a Canadian multi-center spinal cord injury registry. Journal of neurotrauma, 32(21): 1674-1683.

Ezquer, F.E., Ezquer, M.E., Vicencio, J.M. and Calligaris, S.D. (2017). Two complementary strategies to improve cell engraftment in mesenchymal stem cell-based therapy: Increasing transplanted cell resistance and increasing tissue receptivity. Cell adhesion & migration, 11(1): 110-119.

Feigin, V.L., Nichols, E., Alam, T., Bannick, M.S., Beghi, E., Blake, N., Culpepper, W.J., Dorsey, E.R., Elbaz, A., Ellenbogen, R.G. and Fisher, J.L. (2019). Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology, 18(5): 459-480.

Fry, E.J., Chagnon, M.J., López‐Vales, R., Tremblay, M.L. and David, S. (2010). Corticospinal tract regeneration after spinal cord injury in receptor protein tyrosine phosphatase sigma deficient mice. Glia, 58(4): 423-433.

Fu, X., Liu, G., Halim, A., Ju, Y., Luo, Q. and Song, G. (2019). Mesenchymal stem cell migration and tissue repair. Cells, 8(8): 784.

Galandiuk, S., Raque, G., Appel, S. and Polk Jr, H.C. (1993). The two-edged sword of large-dose steroids for spinal cord trauma. Annals of surgery, 218(4): 419.

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

Ghirnikar, R.S., Lee, Y.L. and Eng, L.F. (2001). Chemokine antagonist infusion promotes axonal sparing after spinal cord contusion injury in rat. Journal of neuroscience research, 64(6): 582-589.

Giacoppo, S., Bramanti, P. and Mazzon, E. (2017). The transplantation of mesenchymal stem cells derived from unconventional sources: an innovative approach to multiple sclerosis therapy. Archivum immunologiae et therapiae experimentalis, 65: 363-379.

Glaser, J., Gonzalez, R., Sadr, E. and Keirstead, H.S. (2006). Neutralization of the chemokine CXCL10 reduces apoptosis and increases axon sprouting after spinal cord injury. Journal of neuroscience research, 84(4): 724-734.

Gonzalez, R., Hickey, M.J., Espinosa, J.M., Nistor, G., Lane, T.E. and Keirstead, H.S. (2007). Therapeutic neutralization of CXCL10 decreases secondary degeneration and functional deficit after spinal cord injury in mice. Regenerative medicine. 2: 771-783.

Gris, D., Marsh, D.R., Oatway, M.A., Chen, Y., Hamilton, E.F., Dekaban, G.A. and Weaver, L.C. (2004). Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. Journal of Neuroscience, 24(16): 4043-4051.

Guo, S., Perets, N., Betzer, O., Ben-Shaul, S., Sheinin, A., Michaelevski, I., Popovtzer, R., Offen, D. and Levenberg, S. (2019). Intranasal delivery of mesenchymal stem cell derived exosomes loaded with phosphatase and tensin homolog siRNA repairs complete spinal cord injury. ACS nano, 13(9): 10015-10028.

Hall, E.D. and Braughler, J.M. (1982). Glucocorticoid mechanisms in acute spinal cord injury: a review and therapeutic rationale. Surgical neurology, 18(5): 320-327.

He, W., Zhang, X., Li, X., Ju, D., Mao, T., Lu, Y., Gu, Y., Qi, L., Wang, Q., Wu, Q. and Dong, C. (2022). A decellularized spinal cord extracellular matrix-gel/GelMA hydrogel three-dimensional composite scaffold promotes recovery from spinal cord injury via synergism with human menstrual blood-derived stem cells. Journal of Materials Chemistry B, 10(30): 5753-5764.

Hematti, P. (2008). Role of mesenchymal stromal cells in solid organ transplantation. Transplantation reviews, 22(4): 262-273.

Hurlbert, R.J., Hadley, M.N., Walters, B.C., Aarabi, B., Dhall, S.S., Gelb, D.E., Rozzelle, C.J., Ryken, T.C. and Theodore, N. (2013). Pharmacological therapy for acute spinal cord injury. Neurosurgery, 72(suppl_3): 93-105.

Hurtado, A., Marcillo, A., Frydel, B., Bunge, M.B., Bramlett, H.M. and Dietrich, W.D. (2012). Anti-CD11d monoclonal antibody treatment for rat spinal cord compression injury. Experimental neurology, 233(2): 606-611.

Jia, Y., Lu, T., Chen, Q., Pu, X., Ji, L., Yang, J. and Luo, C. (2021). Exosomes secreted from sonic hedgehog-modified bone mesenchymal stem cells facilitate the repair of rat spinal cord injuries. Acta Neurochirurgica, 163: 2297-2306.

Kang, Y., Ding, H., Zhou, H., Wei, Z., Liu, L., Pan, D. and Feng, S. (2018). Epidemiology of worldwide spinal cord injury: a literature review. Journal of Neurorestoratology, 6(1): 3.

Kang, C.B., Hong, Y., Dhe-Paganon, S. and Yoon, H.S. (2008). FKBP family proteins: immunophilins with versatile biological functions. Neurosignals, 16(4): 318-325.

Kang, J. and Guo, Y. (2022). Human umbilical cord mesenchymal stem cells derived exosomes promote neurological function recovery in a rat spinal cord injury model. Neurochemical Research, 47(6): 1532-1540.

Kawakami, M. (2013). Molecular dissection of cyclosporin a’s neuroprotective effect reveals potential therapeutics for ischemic brain injury. Brain sciences, 3(3): 1325-1356.

Khodabakhshi Rad, A., Kazemi Mehrjerdi, H., Pedram, M.S., Azizzadeh, M. and Amanollahi, S. (2022). Clinical Evaluation of the effect of Methylprednisolone Sodium Succinate and Meloxicam in Experimental Acute Spinal Cord Injury. Iranian Journal of Veterinary Medicine.

Kim, J.W., Ha, K.Y., Molon, J.N. and Kim, Y.H. (2013). Bone marrow–derived mesenchymal stem cell transplantation for chronic spinal cord injury in rats: comparative study between intralesional and intravenous transplantation. Spine, 38(17): E1065-E1074.

Kitamura, K., Iwanami, A., Nakamura, M., Yamane, J., Watanabe, K., Suzuki, Y., Miyazawa, D., Shibata, S., Funakoshi, H., Miyatake, S. and Coffin, R.S. (2007). Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury. Journal of neuroscience research, 85(11): 2332-2342.

Kitamura, K., Fujiyoshi, K., Yamane, J.I., Toyota, F., Hikishima, K., Nomura, T., Funakoshi, H., Nakamura, T., Aoki, M., Toyama, Y. and Okano, H. (2011). Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury. PloS one, 6(11): e27706.

Koshinaga, M., Sanon, H.R. and Whittemore, S.R. (1993). Altered acidic and basic fibroblast growth factor expression following spinal cord injury. Experimental neurology, 120(1):32-48.

Knoller, N., Auerbach, G., Fulga, V., Zelig, G., Attias, J., Bakimer, R., Marder, J.B., Yoles, E., Belkin, M., Schwartz, M. and Hadani, M. (2005). Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. Journal of Neurosurgery: Spine, 3(3): 173-181.

Kuo, H.S., Tsai, M.J., Huang, M.C., Chiu, C.W., Tsai, C.Y., Lee, M.J., Huang, W.C., Lin, Y.L., Kuo, W.C. and Cheng, H. (2011). Acid fibroblast growth factor and peripheral nerve grafts regulate Th2 cytokine expression, macrophage activation, polyamine synthesis, and neurotrophin expression in transected rat spinal cords. Journal of Neuroscience, 31(11): 4137-4147.

Kuo, H.S., Tsai, M.J., Huang, M.C., Chiu, C.W., Tsai, C.Y., Lee, M.J., Huang, W.C., Lin, Y.L., Kuo, W.C. and Cheng, H. (2011). Acid fibroblast growth factor and peripheral nerve grafts regulate Th2 cytokine expression, macrophage activation, polyamine synthesis, and neurotrophin expression in transected rat spinal cords. Journal of Neuroscience, 31(11): 4137-4147.

Kwon, B.K., Tetzlaff, W., Grauer, J.N., Beiner, J. and Vaccaro, A.R. (2004). Pathophysiology and pharmacologic treatment of acute spinal cord injury. The spine journal, 4(4): 451-464.

75. Lai, P., Chen, X., Guo, L., Wang, Y., Liu, X., Liu, Y., Zhou, T., Huang, T., Geng, S., Luo, C. and Huang, X. (2018). A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD. Journal of hematology & oncology, 11(1): 1-15.

Lambrechts, M.J. and Cook, J.L. (2021). Nonsteroidal anti-inflammatory drugs and their neuroprotective role after an acute spinal cord injury: a systematic review of animal models. Global Spine Journal, 11(3): 365-377.

Lee, K.D., Chow, W.N., Sato-Bigbee, C., Graf, M.R., Graham, R.S., Colello, R.J., Young, H.F. and Mathern, B.E. (2009). FTY720 reduces inflammation and promotes functional recovery after spinal cord injury. Journal of neurotrauma, 26(12): 2335-2344.

Lee, S.H. (2018). The advantages and limitations of mesenchymal stem cells in clinical application for treating human diseases. Osteoporosis and sarcopenia, 4(4): 150.

Li, L., Zhang, Y., Mu, J., Chen, J., Zhang, C., Cao, H. and Gao, J. (2020). Transplantation of human mesenchymal stem-cell-derived exosomes immobilized in an adhesive hydrogel for effective treatment of spinal cord injury. Nano letters, 20(6): 4298-4305.

Liu, J., Farmer Jr, J.D., Lane, W.S., Friedman, J., Weissman, I. and Schreiber, S.L. (1991). Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell, 66(4): 807-815.

Liu, C., Hu, F., Jiao, G., Guo, Y., Zhou, P., Zhang, Y., Zhang, Z., Yi, J., You, Y., Li, Z. and Wang, H. (2022). Dental pulp stem cell-derived exosomes suppress M1 macrophage polarization through the ROS-MAPK-NFκB P65 signaling pathway after spinal cord injury. Journal of Nanobiotechnology, 20(1): 1-19.

Ma, Z., Lu, Y., Yang, Y., Wang, J. and Kang, X. (2019). Research progress and prospects of tissue engineering scaffolds for spinal cord injury repair and protection. Regenerative Medicine, 14(9): 887-898.

Mabon, P.J., Weaver, L.C. and Dekaban, G.A. (2000). Inhibition of monocyte/macrophage migration to a spinal cord injury site by an antibody to the integrin αD: a potential new anti-inflammatory treatment. Experimental neurology, 166(1): 52-64.

Matsumoto, T., Tamaki, T., Kawakami, M., Yoshida, M., Ando, M. and Yamada, H. (2001). Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury. Spine, 26: 426-430.

Mendt, M., Rezvani, K. and Shpall, E. (2019). Mesenchymal stem cell-derived exosomes for clinical use. Bone marrow transplantation, 54(Suppl 2): 789-792.

M Healy, L. and P Antel, J. (2016). Sphingosine-1-phosphate receptors in the central nervous and immune systems. Current drug targets, 17(16): 1841-1850.

Musiał-Wysocka, A., Kot, M. and Majka, M. (2019). The pros and cons of mesenchymal stem cell-based therapies. Cell transplantation, 28(7): 801-812.

Navajas, R., Corrales, F.J. and Paradela, A. (2019). Serum exosome isolation by size-exclusion chromatography for the discovery and validation of preeclampsia-associated biomarkers. Proteomics for Biomarker Discovery: Methods and Protocols: 39-50.

Norimatsu, Y., Ohmori, T., Kimura, A., Madoiwa, S., Mimuro, J., Seichi, A., Yatomi, Y., Hoshino, Y. and Sakata, Y. (2012). FTY720 improves functional recovery after spinal cord injury by primarily nonimmunomodulatory mechanisms. The American journal of pathology, 180(4): 1625-1635.

Nooshabadi, V.T., Khanmohamadi, M., Valipour, E., Mahdipour, S., Salati, A., Malekshahi, Z.V., Shafei, S., Amini, E., Farzamfar, S. and Ai, J. (2020). Impact of exosome‐loaded chitosan hydrogel in wound repair and layered dermal reconstitution in mice animal model. Journal of Biomedical Materials Research Part A, 108(11): 2138-2149.

O’Brien, K., Breyne, K., Ughetto, S., Laurent, L.C. and Breakefield, X.O. (2020). RNA delivery by extracellular vesicles in mammalian cells and its applications. Nature reviews Molecular cell biology, 21(10): 585-606.

Parr, A.M., Kulbatski, I., Zahir, T., Wang, X., Yue, C., Keating, A. and Tator, C.H. (2008). Transplanted adult spinal cord–derived neural stem/progenitor cells promote early functional recovery after rat spinal cord injury. Neuroscience, 155(3): 760-770.

Pointillart, V., Petitjean, M.E., Wiart, L., Vital, J.M., Lassié, P., Thicoipé, M. and Dabadie, P. (2000). Pharmacological therapy of spinal cord injury during the acute phase. Spinal cord, 38(2): 71-76.

Pool, M., Leuvenink, H. and Moers, C. (2019). Reparative and Regenerative Effects of Mesenchymal Stromal Cells—Promising Potential for Kidney Transplantation?. International Journal of Molecular Sciences, 20(18): 4614.

Rabchevsky, A.G., Patel, S.P. and Springer, J.E. (2011). Pharmacological interventions for spinal cord injury: where do we stand? How might we step forward?. Pharmacology & therapeutics, 132(1): 15-29.

Saville, L.R., Pospisil, C.H., Mawhinney, L.A., Bao, F., Simedrea, F.C., Peters, A.A., O'Connell, P.J., Weaver, L.C. and Dekaban, G.A. (2004). A monoclonal antibody to CD11d reduces the inflammatory infiltrate into the injured spinal cord: a potential neuroprotective treatment. Journal of neuroimmunology, 156(1-2): 42-57.

Shepard, M.J. and Bracken, M.B. (1994). The effect of methylprednisolone, naloxone, and spinal cord trauma on four liver enzymes: observations from NASCIS 2. Spinal Cord, 32(4): 236-245.

Shultz, R.B. and Zhong, Y. ( 2017). Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury. Neural regeneration research, 12(5): 702-713.

Sterner, R.C. and Sterner, R.M. (2022). Immune response following traumatic spinal cord injury: Pathophysiology and therapies. Frontiers in Immunology, 13.

Sung, S.E., Seo, M.S., Kim, Y.I., Kang, K.K., Choi, J.H., Lee, S., Sung, M., Yim, S.G., Lim, J.H., Seok, H.G. and Yang, S.Y. (2022). Human Epidural AD–MSC Exosomes Improve Function Recovery after Spinal Cord Injury in Rats. Biomedicines, 10(3): 678.

Tator, C.H. and Fehlings, M.G. (1991). Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. Journal of neurosurgery, 75(1):15-26.

Teng, Y.D., Mocchetti, I., Taveira-DaSilva, A.M., Gillis, R.A. and Wrathall, J.R. (1999). Basic fibroblast growth factor increases long-term survival of spinal motor neurons and improves respiratory function after experimental spinal cord injury. Journal of Neuroscience, 19(16): 7037-7047.

Tzekou, A. and Fehlings, M.G. (2014). Treatment of spinal cord injury with intravenous immunoglobulin G: preliminary evidence and future perspectives. Journal of clinical immunology, 34: 132-138.

Villarroya-Beltri, C., Baixauli, F., Gutiérrez-Vázquez, C., Sánchez-Madrid, F. and Mittelbrunn, M. (2014). Sorting it out: regulation of exosome loading. In Seminars in cancer biology. 28: 3-13. Academic Press.

Viswanathan, S. and Read, E.J. (2013). Bench-to-bedside development of MSC therapies: A multidisciplinary approach. Mesenchymal Stromal Cells: Biology and Clinical Applications. 279-315.

Wang, J., Wang, J., Lu, P., Cai, Y., Wang, Y., Hong, L., Ren, H., Heng, B.C., Liu, H., Zhou, J. and Ouyang, H. (2015). Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis. Biomaterials, 62:76-87.

Wu, R., Gao, W., Yao, K. and Ge, J. (2019). Roles of exosomes derived from immune cells in cardiovascular diseases. Frontiers in Immunology, 10: 648.

Yılmaz, T. and Kaptanoğlu, E. (2015). Current and future medical therapeutic strategies for the functional repair of spinal cord injury. World journal of orthopedics, 6(1): 42.

Yin, K., Wang, S. and Zhao, R.C. (2019). Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomarker research, 7(1): 1-8.

Zhang, X., Jiang, W., Lu, Y., Mao, T., Gu, Y., Ju, D. and Dong, C. (2023). Exosomes combined with biomaterials in the treatment of spinal cord injury. Frontiers in Bioengineering and Biotechnology, 11.

Zhang, Y., Al Mamun, A., Yuan, Y., Lu, Q., Xiong, J., Yang, S., Wu, C., Wu, Y. and Wang, J. (2021). Acute spinal cord injury: Pathophysiology and pharmacological intervention. Molecular medicine reports, 23(6): 1-18.

Zhou, X., Liu, X., Liu, L., Han, C., Xie, Z., Liu, X., Xu, Y., Li, F., Bi, J. and Zheng, C. (2020). Transplantation of IFN-γ primed hUCMSCs significantly improved outcomes of experimental autoimmune encephalomyelitis in a mouse model. Neurochemical Research, 45: 1510-1517.

Zhou, Y., Wen, L.L., Li, Y.F., Wu, K.M., Duan, R.R., Yao, Y.B., Jing, L.J., Gong, Z., Teng, J.F. and Jia, Y.J. (2022). Exosomes derived from bone marrow mesenchymal stem cells protect the injured spinal cord by inhibiting pericyte pyroptosis. Neural Regeneration Research, 17(1): 194.