Spinal cord injury (SCI) is a devastating condition with a complex pathology that affects a significant portion of the population and causes long-term consequences. After primary injury, an inflammatory cascade of secondary injury occurs, followed by neuronal cell death and glial scar formation. Together with the limited regenerative capacity of the central nervous system, these are the main reasons for the poor prognosis after SCI. Despite recent advances, there is still no effective treatment. Promising therapeutic approaches include stem cells transplantation, which has demonstrated neuroprotective and immunomodulatory effects in SCI. This positive effect is thought to be mediated by small extracellular vesicles (sEVs); membrane-bound nanovesicles involved in intercellular communication through transport of functional proteins and RNA molecules. In this review, we summarize the current knowledge about sEVs and microRNA as their cargo as one of the most promising therapeutic approaches for the treatment of SCI. We provide a comprehensive overview of their role in SCI pathophysiology, neuroprotective potential and therapeutic effect.

Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czechia

Department of Neuroscience 2nd Faculty of Medicine Charles University Prague Czechia

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Abels E. R., Breakefield X. O. (2016). Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell. Mol. Neurobiol. 36, 301–312. doi: 10.1007/s10571-016-0366-z, PMID: PubMed DOI PMC

Adlakha Y. K., Saini N. (2014). Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Mol. Cancer 13:33. doi: 10.1186/1476-4598-13-33, PMID: PubMed DOI PMC

Ahmad A., Ashraf S., Komai S. (2015). Optogenetics applications for treating spinal cord injury. Asian Spine J. 9, 299–305. doi: 10.4184/asj.2015.9.2.299, PMID: PubMed DOI PMC

Ahuja C. S., Nori S., Tetreault L., Wilson J., Kwon B., Harrop J., et al. . (2017a). Traumatic spinal cord injury – repair and regeneration. Clin. Neurosurg. 80, S9–S22. doi: 10.1093/neuros/nyw080 PubMed DOI

Ahuja C. S., Wilson J. R., Nori S., Kotter M. R. N., Druschel C., Curt A., et al. . (2017b). Traumatic spinal cord injury. Nat. Rev. Dis. Primers 3:17018. doi: 10.1038/nrdp.2017.18 PubMed DOI

Alizadeh A., Dyck S. M., Karimi-Abdolrezaee S. (2019). Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms. Front. Neurol. 10:282. doi: 10.3389/fneur.2019.00282, PMID: PubMed DOI PMC

Amemori T., Ruzicka J., Romanyuk N., Jhanwar-Uniyal M., Sykova E., Jendelova P. (2015). Comparison of intraspinal and intrathecal implantation of induced pluripotent stem cell-derived neural precursors for the treatment of spinal cord injury in rats. Stem Cell Res. Ther. 6:257. doi: 10.1186/s13287-015-0255-2, PMID: PubMed DOI PMC

Amo-Aparicio J., Martínez-Muriana A., Sánchez-Fernández A., López-Vales R. (2018). Neuroinflammation quantification for spinal cord injury. Curr. Protoc. Immunol. 123:e57. doi: 10.1002/cpim.57, PMID: PubMed DOI

Anderson M. A., Burda J. E., Ren Y., Ao Y., O’Shea T. M., Kawaguchi R., et al. . (2016). Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200. doi: 10.1038/nature17623, PMID: PubMed DOI PMC

Andreotti J. P., Silva W. N., Costa A. C., Picoli C. C., Bitencourt F. C. O., Coimbra-Campos L. M. C., et al. . (2019). Neural stem cell niche heterogeneity. Seminars Cell Dev. Biol. 95, 42–53. doi: 10.1016/j.semcdb.2019.01.005, PMID: PubMed DOI PMC

Azbill R. D., Mu X., Springer J. E. (2000). Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res. 871, 175–180. doi: 10.1016/S0006-8993(00)02430-6, PMID: PubMed DOI

Baglio S. R., Pegtel D. M., Baldini N. (2012). Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front. Physiol. 3:359. doi: 10.3389/fphys.2012.00359, PMID: PubMed DOI PMC

Balsam L. B., Wagers A. J., Christensen J. L., Kofidis T., Weissmann I. L., Robbins R. C. (2004). Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 668–673. doi: 10.1038/nature02460, PMID: PubMed DOI

Bartel D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. Cell. 116, 281–297. doi: 10.1016/S0092-8674(04)00045-5 PubMed DOI

Bazzan E., Tinè M., Casara A., Biondini D., Semenzato U., Cocconcelli E., et al. . (2021). Critical review of the evolution of extracellular vesicles’ knowledge: from 1946 to today. Int. J. Mol. Sci. 22:417. doi: 10.3390/ijms22126417, PMID: PubMed DOI PMC

Beattie R., Hippenmeyer S. (2017). Mechanisms of radial glia progenitor cell lineage progression. FEBS Lett. 591, 3993–4008. doi: 10.1002/1873-3468.12906, PMID: PubMed DOI PMC

Bhalala O. G., Pan L., Sahni V., McGuire T. L., Gruner K., Tourtellotte W. G., et al. . (2012). microRNA-21 regulates astrocytic response following spinal cord injury. J. Neurosci. 32, 17935–17947. doi: 10.1523/JNEUROSCI.3860-12.2012, PMID: PubMed DOI PMC

Bhalala O. G., Srikanth M., Kessler J. A. (2013). The emerging roles of microRNAs in CNS injuries. Nat Rev Neurol 9, 328–339. doi: 10.1038/nrneurol.2013.67, PMID: PubMed DOI PMC

Bonnamain V., Neveu I., Naveilhan P. (2012). Neural stem/progenitor cells as promising candidates for regenerative therapy of the central nervous system. Front. Cell. Neurosci. 6:17. doi: 10.3389/fncel.2012.00017, PMID: PubMed DOI PMC

Bosch S., De Beaurepaire L., Allard M., Mosser M., Heichette C., Chrétien D., et al. . (2016). Trehalose prevents aggregation of exosomes and cryodamage. Sci. Rep. 6:6162. doi: 10.1038/SREP36162, PMID: PubMed DOI PMC

Branscome H., Paul S., Yin D., El-Hage N., Agbottah E. T., Zadeh M. A., et al. . (2020). Use of stem cell extracellular vesicles as a “holistic” approach to CNS repair. Front. Cell Dev. Biol. 8:455. doi: 10.3389/fcell.2020.00455, PMID: PubMed DOI PMC

Campos-Melo D., Droppelmann C. A., He Z., Volkening K., Strong M. J. (2013). Altered microRNA expression profile in amyotrophic lateral sclerosis: a role in the regulation of NFL mRNA levels. Mol. Brain 6:26. doi: 10.1186/1756-6606-6-26, PMID: PubMed DOI PMC

Chang Y. H., Wu K. C., Harn H. J., Lin S. Z., Ding D. C. (2018). Exosomes and stem cells in degenerative disease diagnosis and therapy. Cell Transplant. 27, 349–363. doi: 10.1177/0963689717723636, PMID: PubMed DOI PMC

Chang F., Zhang L. H., Xu W. U. P., Jing P., Zhan P. Y. (2014). microRNA-9 attenuates amyloidβ-induced synaptotoxicity by targeting calcium/calmodulin-dependent protein kinase kinase 2. Mol. Med. Rep. 9, 1917–1922. doi: 10.3892/mmr.2014.2013, PMID: PubMed DOI

Chen Y., Tian Z., He L., Liu C., Wang N., Rong L., et al. . (2021). Exosomes derived from miR-26a-modified MSCs promote axonal regeneration via the PTEN/AKT/mTOR pathway following spinal cord injury. Stem Cell Res. Ther. 12:224. doi: 10.1186/s13287-021-02282-0, PMID: PubMed DOI PMC

Cheng L., Wang S., Zhu R., Zhu X., Zhu Y., Wang Z., et al. . (2021). Immunomodulatory layered double hydroxide nanoparticles enable neurogenesis by targeting transforming growth factor-β receptor 2. ACS Nano 15, 2812–2830. doi: 10.1021/acsnano.0c08727, PMID: PubMed DOI

Cheng Z., Zhu W., Cao K., Wu F., Li J., Wang G., et al. . (2016). Anti-inflammatory mechanism of neural stem cell transplantation in spinal cord injury. Int. J. Mol. Sci. 17:1380. doi: 10.3390/ijms17091380, PMID: PubMed DOI PMC

Clifford T., Finkel Z., Rodriguez B., Joseph A., Cai L. (2023). Current advancements in spinal cord injury research-glial scar formation and neural regeneration. Cells 12:853. doi: 10.3390/CELLS12060853, PMID: PubMed DOI PMC

Cofano F., Boido M., Monticelli M., Zenga F., Ducati A., Vercelli A., et al. . (2019). Mesenchymal stem cells for spinal cord injury: current options limitations, and future of cell therapy. Int. J. Mol. Sci. 20:2698. doi: 10.3390/ijms20112698, PMID: PubMed DOI PMC

Colombo M., Raposo G., Théry C. (2014). Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annual review of cell and developmental biology. Annu. Rev. Cell Dev. Biol. 30, 255–289. doi: 10.1146/annurev-cellbio-101512-122326, PMID: PubMed DOI

Cregg J. M., DePaul M. A., Filous A. R., Lang B. T., Tran A., Silver J. (2014). Functional regeneration beyond the glial scar. Exp. Neurol. 253, 197–207. doi: 10.1016/j.expneurol.2013.12.024, PMID: PubMed DOI PMC

Cunha N. S. C., Malvea A., Sadat S., Ibrahim G. M., Fehlings M. G. (2023). Pediatric spinal cord injury: a review. Children 10:1456. doi: 10.3390/CHILDREN10091456, PMID: PubMed DOI PMC

De Vrij J., Niek Maas S. L., Kwappenberg K. M. C., Schnoor R., Kleijn A., Dekker L., et al. . (2015). Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. Int. J. Cancer 137, 1630–1642. doi: 10.1002/ijc.29521, PMID: PubMed DOI

Ding S. Q., Chen J., Wang S. N., Duan F. X., Chen Y. Q., Shi Y. J., et al. . (2019). Highlight article: identification of serum exosomal microRNAs in acute spinal cord injured rats. Exp. Biol. Med. 244, 1149–1161. doi: 10.1177/1535370219872759, PMID: PubMed DOI PMC

Ding W., Hu S., Wang P., Kang H., Peng R., Dong Y., et al. . (2022). Spinal cord injury: the global incidence, prevalence, and disability from the global burden of disease study 2019. Spine 47, 1532–1540. doi: 10.1097/BRS.0000000000004417, PMID: PubMed DOI PMC

Donnelly D. J., Popovich P. G. (2008). Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp. Neurol. 209, 378–388. doi: 10.1016/j.expneurol.2007.06.009, PMID: PubMed DOI PMC

Dumont C. M., Margul D. J., Shea L. D. (2016). Tissue engineering approaches to modulate the inflammatory milieu following spinal cord injury. Cells Tissues Organs 202, 52–66. doi: 10.1159/000446646, PMID: PubMed DOI PMC

Dumont R. J., Okonkwo D. O., Verma S., Hurlbert R. J., Boulos P. T., Ellegala D. B., et al. . (2001). Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin. Neuropharmacol. 24, 254–264. doi: 10.1097/00002826-200109000-00002, PMID: PubMed DOI

Dutta D., Khan N., Wu J., Jay S. M. (2021). Extracellular vesicles as an emerging frontier in spinal cord injury pathobiology and therapy. Trends Neurosci. 44, 492–506. doi: 10.1016/j.tins.2021.01.003, PMID: PubMed DOI PMC

Elahi F. M., Farwell D. G., Nolta J. A., Anderson J. D. (2020). Preclinical translation of exosomes derived from mesenchymal stem/stromal cells. Stem Cells 38, 15–21. doi: 10.1002/stem.3061, PMID: PubMed DOI PMC

Erlich S., Alexandrovich A., Shohami E., Pinkas-Kramarski R. (2007). Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol. Dis. 26, 86–93. doi: 10.1016/j.nbd.2006.12.003 PubMed DOI

Eulalio A., Huntzinger E., Nishihara T., Rehwinkel J., Fauser M., Izaurralde E. (2009). Deadenylation is a widespread effect of miRNA regulation. RNA 15, 21–32. doi: 10.1261/rna.1399509, PMID: PubMed DOI PMC

Fehlings M. G., Vaccaro A., Wilson J. R., Singh A., Cadotte D. W., Harrop J. S., et al. . (2012). Early versus delayed decompression for traumatic cervical spinal cord injury: results of the surgical timing in acute spinal cord injury study (STASCIS). PLoS One 7:e32037. doi: 10.1371/journal.pone.0032037, PMID: PubMed DOI PMC

Fehlings M. G., Wilson J. R., Harrop J. S., Kwon B. K., Tetreault L. A., Arnold P. M., et al. . (2017). Efficacy and safety of methylprednisolone sodium succinate in acute spinal cord injury: a systematic review. Global Spine J 7, 116S–137S. doi: 10.1177/2192568217706366, PMID: PubMed DOI PMC

Festoff B. W., Ameenuddin S., Arnold P. M., Wong A., Santacruz K. S., Citron B. A. (2006). Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J. Neurochem. 97, 1314–1326. doi: 10.1111/j.1471-4159.2006.03799.x, PMID: PubMed DOI

Forostyak S., Forostyak O., Kwok J. C. F., Romanyuk N., Rehorova M., Kriska J., et al. . (2020). Transplantation of neural precursors derived from induced pluripotent cells preserve perineuronal nets and stimulate neural plasticity in ALS rats. Int. J. Mol. Sci. 21, 1–25. doi: 10.3390/ijms21249593, PMID: PubMed DOI PMC

Ge X., Tang P., Rong Y., Jiang D., Lu X., Ji C., et al. . (2021). Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury. Redox Biol. 41:101932. doi: 10.1016/j.redox.2021.101932, PMID: PubMed DOI PMC

Görgens A., Corso G., Hagey D. W., Jawad Wiklander R., Gustafsson M. O., Felldin U., et al. . (2022). Identification of storage conditions stabilizing extracellular vesicles preparations. J. Extracell. Ves. 11:e12238. doi: 10.1002/JEV2.12238, PMID: PubMed DOI PMC

Guo S., Perets N., Betzer O., Ben-Shaul S., Sheinin A., Michaelevski I., et al. . (2019). Intranasal delivery of mesenchymal stem cell derived exosomes loaded with phosphatase and Tensin homolog siRNA repairs complete spinal cord injury. ACS Nano 13, 10015–10028. doi: 10.1021/acsnano.9b01892, PMID: PubMed DOI

Gurunathan S., Kang M. H., Jeyaraj M., Qasim M., Kim J. H. (2019). Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes. Cells 8. doi: 10.3390/cells8040307, PMID: PubMed DOI PMC

György B., Fitzpatrick Z., Crommentuijn M. H. W., Mu D., Maguire C. A. (2014). Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo. Biomaterials 35, 7598–7609. doi: 10.1016/j.biomaterials.2014.05.032, PMID: PubMed DOI PMC

Hachem L. D., Ahuja C. S., Fehlings M. G. (2017). Assessment and management of acute spinal cord injury: from point of injury to rehabilitation. J. Spinal Cord Med. 40, 665–675. doi: 10.1080/10790268.2017.1329076, PMID: PubMed DOI PMC

Hausmann O. N. (2003). Post-traumatic inflammation following spinal cord injury. Spinal Cord 41, 369–378. doi: 10.1038/sj.sc.3101483 PubMed DOI

Hayta E., Elden H. (2018). Acute spinal cord injury: a review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention. J. Chem. Neuroanat. 87, 25–31. doi: 10.1016/j.jchemneu.2017.08.001, PMID: PubMed DOI

Holm M. M., Kaiser J., Schwab M. E. (2018). Extracellular Vesicles: Multimodal Envoys in Neural Maintenance and Repair. Trends Neurosci. doi: 10.1016/j.tins.2018.03.006 PubMed DOI

Hu J. Z., Huang J. H., Zeng L., Wang G., Cao M., Lu H. B. (2013). Anti-apoptotic effect of MicroRNA-21 after contusion spinal cord injury in rats. J. Neurotrauma 30, 1349–1360. doi: 10.1089/neu.2012.2748, PMID: PubMed DOI PMC

Hu J. R., Lv G. H., Yin B. L. (2013). Altered microRNA expression in the ischemic-reperfusion spinal cord with atorvastatin therapy. J. Pharmacol. Sci. 121, 343–346. doi: 10.1254/jphs.12235SC PubMed DOI

Hu J., Zeng L., Huang J., Wang G., Lu H. (2015). miR-126 promotes angiogenesis and attenuates inflammation after contusion spinal cord injury in rats. Brain Res. 1608, 191–202. doi: 10.1016/j.brainres.2015.02.036, PMID: PubMed DOI

Huang J. H., Xu Y., Yin X. M., Lin F. Y. (2020). Exosomes derived from miR-126-modified MSCs promote angiogenesis and neurogenesis and attenuate apoptosis after spinal cord injury in rats. Neuroscience 424, 133–145. doi: 10.1016/j.neuroscience.2019.10.043, PMID: PubMed DOI

Huang J. H., Yin X. M., Xu Y., Xu C. C., Lin X., Ye F. B., et al. . (2017). Systemic Administration of Exosomes Released from mesenchymal stromal cells attenuates apoptosis, inflammation, and promotes angiogenesis after spinal cord injury in rats. J. Neurotrauma 34, 3388–3396. doi: 10.1089/neu.2017.5063, PMID: PubMed DOI

Ihrie R. A., Alvarez-Buylla A. (2008). Cells in the astroglial lineage are neural stem cells. Cell Tissue Res. 331, 179–191. doi: 10.1007/s00441-007-0461-z PubMed DOI

Jee M. K., Jung J. S., Choi J. I., Jang J. A., Kang K. S., Im Y. B., et al. . (2012a). MicroRNA 486 is a potentially novel target for the treatment of spinal cord injury. Brain 135, 1237–1252. doi: 10.1093/brain/aws047, PMID: PubMed DOI

Jee M. K., Jung J. S., Im Y. B., Jung S. J., Kang S. K. (2012b). Silencing of miR20a is crucial for ngn1-mediated neuroprotection in injured spinal cord. Hum. Gene Ther. 23, 508–520. doi: 10.1089/hum.2011.121, PMID: PubMed DOI

Jeong J. O., Han J. W., Kim J. M., Cho H. J., Park C., Lee N., et al. . (2011). Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ. Res. 108, 1340–1347. doi: 10.1161/CIRCRESAHA.110.239848, PMID: PubMed DOI PMC

Jeppesen D. K., Fenix A. M., Franklin J. L., Higginbotham J. N., Zhang Q., Zimmerman L. J., et al. . (2019). Reassessment of exosome composition. Cell 177, 428–445.e18. doi: 10.1016/j.cell.2019.02.029, PMID: PubMed DOI PMC

Jiang D., Gong F., Ge X., Lv C., Huang C., Feng S., et al. . (2020). Neuron-derived exosomes-transmitted miR-124-3p protect traumatically injured spinal cord by suppressing the activation of neurotoxic microglia and astrocytes. J. Nanobiotechnol. 18, 105–120. doi: 10.1186/s12951-020-00665-8, PMID: PubMed DOI PMC

Johnstone R. M., Mathew A., Mason A. B., Teng K. (1991). Exosome formation during maturation of mammalian and avian reticulocytes: evidence that exosome release is a major route for externalization of obsolete membrane proteins. J. Cell. Physiol. 147, 27–36. doi: 10.1002/jcp.1041470105 PubMed DOI

Kalani A., Tyagi N. (2015). Exosomes in neurological disease, neuroprotection, repair and therapeutics: problems and perspectives. Neural Regen. Res. 10, 1565–1567. doi: 10.4103/1673-5374.165305, PMID: PubMed DOI PMC

Kang J., Li Z., Zhi Z., Wang S., Xu G. (2019). MiR-21 derived from the exosomes of MSCs regulates the death and differentiation of neurons in patients with spinal cord injury. Gene Ther. 26, 491–503. doi: 10.1038/s41434-019-0101-8, PMID: PubMed DOI

Kanno H., Ozawa H., Sekiguchi A., Yamaya S., Tateda S., Yahata K., et al. . (2012). The role of mTOR signaling pathway in spinal cord injury. Cell Cycle 11, 3175–3179. doi: 10.4161/cc.21262, PMID: PubMed DOI PMC

Karova K., Wainwright J. V., MacHova-Urdzikova L., Pisal R. V., Schmidt M., Jendelova P., et al. . (2019). Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-κB pathway inhibition. J. Neuroinflammation 16:12. doi: 10.1186/s12974-019-1394-7, PMID: PubMed DOI PMC

Khan N. Z., Cao T., He J., Ritzel R. M., Li Y., Henry R. J., et al. . (2021). Spinal cord injury alters microRNA and CD81+ exosome levels in plasma extracellular nanoparticles with neuroinflammatory potential. Brain Behav. Immun. 92, 165–183. doi: 10.1016/j.bbi.2020.12.007, PMID: PubMed DOI PMC

Khan M., Nickoloff E., Abramova T., Johnson J., Verma S. K., Krishnamurthy P., et al. . (2015). Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ. Res. 117, 52–64. doi: 10.1161/CIRCRESAHA.117.305990, PMID: PubMed DOI PMC

Krämer-Albers E. M., Hill A. F. (2016). Extracellular vesicles: interneural shuttles of complex messages. Curr. Opin. Neurobiol. 39, 101–107. doi: 10.1016/j.conb.2016.04.016, PMID: PubMed DOI

Kwon B. K., Mann C., Sohn H. M., Hilibrand A. S., Phillips F. M., Wang J. C., et al. . (2008). Hypothermia for spinal cord injury. Spine J. 8, 859–874. doi: 10.1016/j.spinee.2007.12.006 PubMed DOI

Lai C. P. K., Breakefield X. O. (2012). Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front. Physiol. 3:228. doi: 10.3389/fphys.2012.00228, PMID: PubMed DOI PMC

Lankford K. L., Arroyo E. J., Nazimek K., Bryniarski K., Askenase P. W., Kocsis J. D. (2018). Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS One 13:e0190358. doi: 10.1371/journal.pone.0190358, PMID: PubMed DOI PMC

Lewis B. P., Shih I. H., Jones-Rhoades M. W., Bartel D. P., Burge C. B. (2003). Prediction of mammalian MicroRNA targets. Cell 115, 787–798. doi: 10.1016/S0092-8674(03)01018-3 PubMed DOI

Li X. G., Du J. H., Lu Y., Lin X. J. (2019). Neuroprotective effects of rapamycin on spinal cord injury in rats by increasing autophagy and Akt signaling. Neural Regen. Res. 14, 721–727. doi: 10.4103/1673-5374.247476, PMID: PubMed DOI PMC

Li H., Wang C., He T., Zhao T., Chen Y., Shen Y.-l., et al. . (2019). Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction. Theranostics 9, 2017–2035. doi: 10.7150/thno.29400, PMID: PubMed DOI PMC

Li W., Yao S., Li H., Meng Z., Sun X. (2021). Curcumin promotes functional recovery and inhibits neuronal apoptosis after spinal cord injury through the modulation of autophagy. J. Spinal Cord Med. 44, 37–45. doi: 10.1080/10790268.2019.1616147, PMID: PubMed DOI PMC

Lim Y. J., Jung G. N., Park W. T., Seo M. S., Lee G. W. (2023). Therapeutic potential of small extracellular vesicles derived from mesenchymal stem cells for spinal cord and nerve injury. Front. Cell Dev. Biol. 11:1357. doi: 10.3389/fcell.2023.1151357, PMID: PubMed DOI PMC

Lin J., Huo X., Liu X. (2017). “mTOR signaling pathway”: a potential target of curcumin in the treatment of spinal cord injury. Biomed. Res. Int. 2017, 1–7. doi: 10.1155/2017/1634801 PubMed DOI PMC

Liu W., Rong Y., Wang J., Zhou Z., Ge X., Ji C., et al. . (2020). Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization. J. Neuroinflammation 17:1726. doi: 10.1186/s12974-020-1726-7 PubMed DOI PMC

Liu S., Sarkar C., Dinizo M., Faden A. I., Koh E. Y., Lipinski M. M., et al. . (2015). Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death. Cell Death Dis. 6:e1582. doi: 10.1038/cddis.2014.527, PMID: PubMed DOI PMC

Liu D. Z., Tian Y., Ander B. P., Xu H., Stamova B. S., Zhan X., et al. . (2010). Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J. Cereb. Blood Flow Metab. 30, 92–101. doi: 10.1038/jcbfm.2009.186, PMID: PubMed DOI PMC

Liu W., Wang Y., Gong F., Rong Y., Luo Y., Tang P., et al. . (2019). Exosomes derived from bone mesenchymal stem cells repair traumatic spinal cord injury by suppressing the activation of a1 neurotoxic reactive astrocytes. J. Neurotrauma 36, 469–484. doi: 10.1089/neu.2018.5835, PMID: PubMed DOI

Liu N. K., Wang X. F., Lu Q. B., Xu X. M. (2009). Altered microRNA expression following traumatic spinal cord injury. Exp. Neurol. 219, 424–429. doi: 10.1016/j.expneurol.2009.06.015, PMID: PubMed DOI PMC

Ludwig P. E., Thankam F. G., Patil A. A., Chamczuk A. J., Agrawal D. K. (2018). Brain injury and neural stem cells. Neural Regen. Res. 13, 7–18. doi: 10.4103/1673-5374.224361, PMID: PubMed DOI PMC

Ma K., Xu H., Zhang J., Zhao F., Liang H., Sun H., et al. . (2019). Insulin-like growth factor-1 enhances neuroprotective effects of neural stem cell exosomes after spinal cord injury via an miR-219a-2-3p/YY1 mechanism. Aging 11, 12278–12294. doi: 10.18632/aging.102568, PMID: PubMed DOI PMC

Maas S. L. N., Breakefield X. O., Weaver A. M. (2017). Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 27, 172–188. doi: 10.1016/j.tcb.2016.11.003, PMID: PubMed DOI PMC

Machova Urdzikova L., Ruzicka J., Karova K., Kloudova A., Svobodova B., Amin A., et al. . (2017). A green tea polyphenol epigallocatechin-3-gallate enhances neuroregeneration after spinal cord injury by altering levels of inflammatory cytokines. Neuropharmacology 126, 213–223. doi: 10.1016/j.neuropharm.2017.09.006, PMID: PubMed DOI

Mahdavipour M., Hassanzadeh G., Seifali E., Mortezaee K., Aligholi H., Shekari F., et al. . (2020). Effects of neural stem cell-derived extracellular vesicles on neuronal protection and functional recovery in the rat model of middle cerebral artery occlusion. Cell Biochem. Funct. 38, 373–383. doi: 10.1002/cbf.3484, PMID: PubMed DOI

Martino G., Pluchino S., Bonfanti L., Schwartz M. (2011). Brain regeneration in physiology and pathology: The immune signature driving therapeutic plasticity of neural stem cells. Physiol. Rev. 91, 1281–1304. doi: 10.1152/physrev.00032.2010, PMID: PubMed DOI PMC

Martirosyan N. L., Kalani M. Y. S., Bichard W. D., Baaj A. A., Fernando Gonzalez L., Preul M. C., et al. . (2015). Cerebrospinal fluid drainage and induced hypertension improve spinal cord perfusion after acute spinal cord injury in pigs. Neurosurgery 76, 461–469. doi: 10.1227/NEU.0000000000000638, PMID: PubMed DOI

Matsushita T., Lankford K. L., Arroyo E. J., Sasaki M., Neyazi M., Radtke C., et al. . (2015). Diffuse and persistent blood-spinal cord barrier disruption after contusive spinal cord injury rapidly recovers following intravenous infusion of bone marrow mesenchymal stem cells. Exp. Neurol. 267, 152–164. doi: 10.1016/j.expneurol.2015.03.001, PMID: PubMed DOI

Maumus M., Jorgensen C., Noël D. (2013). Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie 95, 2229–2234. doi: 10.1016/j.biochi.2013.04.017, PMID: PubMed DOI

McKeon R. J., Schreiber R. C., Rudge J. S., Silver J. (1991). Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J. Neurosci. 11, 3398–3411. doi: 10.1523/jneurosci.11-11-03398.1991, PMID: PubMed DOI PMC

McKinley W. O., Seel R. T., Hardman J. T. (1999). Nontraumatic spinal cord injury: incidence, epidemiology, and functional outcome. Arch. Phys. Med. Rehabil. 80, 619–623. doi: 10.1016/S0003-9993(99)90162-4 PubMed DOI

Mohammed I., Ijaz S., Mokhtari T., Gholaminejhad M., Mahdavipour M., Jameie B., et al. . (2020). Subventricular zone-derived extracellular vesicles promote functional recovery in rat model of spinal cord injury by inhibition of NLRP3 inflammasome complex formation. Metab. Brain Dis. 35, 809–818. doi: 10.1007/s11011-020-00563-w, PMID: PubMed DOI

Moreno-Manzano V., Rodriguez-Jimenez F. J., Garcia-Rosello M., Lainez S., Erceg S., Calvo M. T., et al. . (2009). Activated spinal cord ependymal stem cells rescue neurological function. Stem Cells 27, 733–743. doi: 10.1002/stem.24, PMID: PubMed DOI

Nakagomi T., Takagi T., Beppu M., Yoshimura S., Matsuyama T. (2019). Neural regeneration by regionally induced stem cells within poststroke brains: novel therapy perspectives for stroke patients. World J. Stem Cells 11, 452–463. doi: 10.4252/wjsc.v11.i8.452, PMID: PubMed DOI PMC

Nakajima H., Uchida K., Guerrero A. R., Watanabe S., Sugita D., Takeura N., et al. . (2012). Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. J. Neurotrauma 29, 1614–1625. doi: 10.1089/neu.2011.2109, PMID: PubMed DOI PMC

Nakanishi K., Nakasa T., Tanaka N., Ishikawa M., Yamada K., Yamasaki K., et al. . (2010). Responses of microRNAs 124a and 223 following spinal cord injury in mice. Spinal Cord 48, 192–196. doi: 10.1038/sc.2009.89, PMID: PubMed DOI

Ni H., Jin W., Zhu T., Wang J., Yuan B., Jiang J., et al. . (2015). Curcumin modulates TLR4/NF-κB inflammatory signaling pathway following traumatic spinal cord injury in rats. J. Spinal Cord Med. 38, 199–206. doi: 10.1179/2045772313Y.0000000179, PMID: PubMed DOI PMC

Nieto-Diaz M., Esteban F. J., Reigada D., Muñoz-Galdeano T., Yunta M., Caballero-López M., et al. . (2014). MicroRNA dysregulation in spinal cord injury: causes, consequences, and therapeutics. Front. Cell. Neurosci. 8:53. doi: 10.3389/fncel.2014.00053, PMID: PubMed DOI PMC

Ning B., Gao L., Liu R. H., Liu Y., Zhang N. S., Chen Z. Y. (2014). microRNAs in spinal cord injury: Potential roles and therapeutic implications. Int. J. Biol. Sci. 10, 997–1006. doi: 10.7150/ijbs.9058, PMID: PubMed DOI PMC

Noltet Hoen E. N. M., Buermans H. P. J., Waasdorp M., Stoorvogel W., Wauben M. H. M., Hoen P. A. C. T. (2012). Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. Nucleic Acids Res. 40, 9272–9285. doi: 10.1093/nar/gks658, PMID: PubMed DOI PMC

O’Brien J., Hayder H., Zayed Y., Peng C. (2018). Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. 9:402. doi: 10.3389/fendo.2018.00402, PMID: PubMed DOI PMC

Ostrowski M., Carmo N. B., Krumeich S., Fanget I., Raposo G., Savina A., et al. . (2010). Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19–30. doi: 10.1038/ncb2000, PMID: PubMed DOI

Oyinbo C. A. (2011). Secondary injury mechanisms in traumatic spinal cord injury: a nugget of this multiply cascade. Acta Neurobiol. Exp. 71, 281–299. doi: 10.55782/ane-2011-1848, PMID: PubMed DOI

Pan D., Li Y., Yang F., Lv Z., Zhu S., Shao Y., et al. . (2021). Increasing toll-like receptor 2 on astrocytes induced by Schwann cell-derived exosomes promotes recovery by inhibiting CSPGs deposition after spinal cord injury. J. Neuroinflammation 18, 172–114. doi: 10.1186/s12974-021-02215-x, PMID: PubMed DOI PMC

Parr A. M., Kulbatski I., Tator C. H. (2007). Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury. J. Neurotrauma 24, 835–845. doi: 10.1089/neu.2006.3771 PubMed DOI

Pekny M., Nilsson M. (2005). Astrocyte activation and reactive gliosis. GLIA Glia 50, 427–434. doi: 10.1002/glia.20207 PubMed DOI

Pereira I. M., Marote A., Salgado A. J., Silva N. A. (2019). Filling the gap: neural stem cells as a promising therapy for spinal cord injury. Pharmaceuticals 12:65. doi: 10.3390/ph12020065, PMID: PubMed DOI PMC

Quertainmont R., Cantinieaux D., Botman O., Sid S., Schoenen J., Franzen R. (2012). Mesenchymal stem cell graft improves recovery after spinal cord injury in adult rats through neurotrophic and pro-angiogenic actions. PLoS One 7:e39500. doi: 10.1371/journal.pone.0039500, PMID: PubMed DOI PMC

Rajgor D. (2018). Macro roles for microRNAs in neurodegenerative diseases. Non-Coding RNA Res. 3, 154–159. doi: 10.1016/j.ncrna.2018.07.001, PMID: PubMed DOI PMC

Raposo G., Stoorvogel W. (2013). Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200, 373–383. doi: 10.1083/jcb.201211138, PMID: PubMed DOI PMC

Redell J. B., Moore A. N., Ward N. H., Hergenroeder G. W., Dash P. K. (2010). Human traumatic brain injury alters plasma microrna levels. J. Neurotrauma 27, 2147–2156. doi: 10.1089/neu.2010.1481, PMID: PubMed DOI PMC

Ren H., Chen X., Tian M., Zhou J., Ouyang H., Zhang Z. (2018). Regulation of inflammatory cytokines for spinal cord injury repair through local delivery of therapeutic agents. Adv. Sci. 5. doi: 10.1002/advs.201800529, PMID: PubMed DOI PMC

Ren Z. W., Zhou J. G., Xiong Z. K., Zhu F. Z., Guo X. D. (2019). Effect of exosomes derived from MiR-133bmodified ADSCs on the recovery of neurological function after SCI. Eur. Rev. Med. Pharmacol. Sci. 23, 52–60. doi: 10.26355/eurrev_201901_16747, PMID: PubMed DOI

Reynolds B. A., Weiss S. (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710. doi: 10.1126/science.1553558 PubMed DOI

Romanyuk N., Amemori T., Turnovcova K., Prochazka P., Onteniente B., Sykova E., et al. . (2015). Beneficial effect of human induced pluripotent stem cell-derived neural precursors in spinal cord injury repair. Cell Transplant. 24, 1781–1797. doi: 10.3727/096368914X684042, PMID: PubMed DOI

Rong Y., Liu W., Lv C., Wang J., Luo Y., Jiang D., et al. . (2019a). Neural stem cell small extracellular vesicle-based delivery of 14-3-3t reduces apoptosis and neuroinflammation following traumatic spinal cord injury by enhancing autophagy by targeting Beclin-1. Aging 11, 7723–7745. doi: 10.18632/aging.102283, PMID: PubMed DOI PMC

Rong Y., Liu W., Wang J., Fan J., Luo Y., Li L., et al. . (2019b). Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death Dis. 10, 340–318. doi: 10.1038/s41419-019-1571-8, PMID: PubMed DOI PMC

Russell A. E., Sneider A., Witwer K. W., Bergese P., Bhattacharyya S. N., Cocks A., et al. . (2019). Biological membranes in EV biogenesis, stability, uptake, and cargo transfer: an ISEV position paper arising from the ISEV membranes and EVs workshop. J. Extracel. Vesicles 8:4862. doi: 10.1080/20013078.2019.1684862, PMID: PubMed DOI PMC

Ruzicka J., Machova-Urdzikova L., Gillick J., Amemori T., Romanyuk N., Karova K., et al. . (2017). A comparative study of three different types of stem cells for treatment of rat spinal cord injury. Cell Transplant. 26, 585–603. doi: 10.3727/096368916X693671, PMID: PubMed DOI PMC

Salewski R. P., Mitchell R. A., Li L., Shen C., Milekovskaia M., Nagy A., et al. . (2015). Transplantation of induced pluripotent stem cell-derived neural stem cells mediate functional recovery following thoracic spinal cord injury through Remyelination of axons. Stem Cells Transl. Med. 4, 743–754. doi: 10.5966/sctm.2014-0236, PMID: PubMed DOI PMC

Sardar Sinha M., Ansell-Schultz A., Civitelli L., Hildesjö C., Larsson M., Lannfelt L., et al. . (2018). Alzheimer’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathol. 136, 41–56. doi: 10.1007/s00401-018-1868-1, PMID: PubMed DOI PMC

Saxton R. A., Sabatini D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976. doi: 10.1016/j.cell.2017.02.004, PMID: PubMed DOI PMC

Schepici G., Silvestro S., Mazzon E. (2023). Regenerative effects of exosomes-derived MSCs: An overview on spinal cord injury experimental studies. Biomedicines 11. doi: 10.3390/biomedicines11010201, PMID: PubMed DOI PMC

Selbach M., Schwanhäusser B., Thierfelder N., Fang Z., Khanin R., Rajewsky N. (2008). Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63. doi: 10.1038/nature07228, PMID: PubMed DOI

Shi Z., Zhou H., Lu L., Li X., Fu Z., Liu J., et al. . (2017). The roles of microRNAs in spinal cord injury. Int. J. Neurosci. 127, 1104–1115. doi: 10.1080/00207454.2017.1323208 PubMed DOI

Simard J. M., Tsymbalyuk O., Keledjian K., Ivanov A., Ivanova S., Gerzanich V. (2012). Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury. Exp. Neurol. 233, 566–574. doi: 10.1016/j.expneurol.2011.11.044, PMID: PubMed DOI PMC

Stevanato L., Thanabalasundaram L., Vysokov N., Sinden J. D. (2016). Investigation of content, stoichiometry and transfer of miRNA from human neural stem cell line derived exosomes. PLoS One 11:e0146353. doi: 10.1371/journal.pone.0146353, PMID: PubMed DOI PMC

Strickland E. R., Hook M. A., Balaraman S., Huie J. R., Grau J. W., Miranda R. C. (2011). microRNA dysregulation following spinal cord contusion: implications for neural plasticity and repair. Neuroscience 186, 146–160. doi: 10.1016/j.neuroscience.2011.03.063, PMID: PubMed DOI PMC

Sun G., Li G., Li D., Huang W., Zhang R., Zhang H., et al. . (2018). hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater. Sci. Eng. C 89, 194–204. doi: 10.1016/j.msec.2018.04.006, PMID: PubMed DOI

Sun M. K., Passaro A. P., Latchoumane C. F., Spellicy S. E., Bowler M., Goeden M., et al. . (2020). Extracellular vesicles mediate neuroprotection and functional recovery after traumatic brain injury. J. Neurotrauma 37, 1358–1369. doi: 10.1089/neu.2019.6443, PMID: PubMed DOI PMC

Sung S. E., Seo M. S., Kim Y. I., Kang K. K., Choi J. H., Lee S., et al. . (2022). Human epidural AD–MSC exosomes improve function recovery after spinal cord injury in rats. Biomedicines 10:678. doi: 10.3390/biomedicines10030678, PMID: PubMed DOI PMC

Tator C. H., Fehlings M. G. (1991). Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J. Neurosurg. 75, 15–26. doi: 10.3171/jns.1991.75.1.0015, PMID: PubMed DOI

Théry C., Witwer K. W., Aikawa E., Alcaraz M. J., Anderson J. D., Andriantsitohaina R., et al. . (2018). Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracellular Vesicles 7:5750. doi: 10.1080/20013078.2018.1535750, PMID: PubMed DOI PMC

Tian Y., Li S., Song J., Ji T., Zhu M., Anderson G. J., et al. . (2014). A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 35, 2383–2390. doi: 10.1016/j.biomaterials.2013.11.083, PMID: PubMed DOI

Tigchelaar S., Gupta R., Shannon C. P., Streijger F., Sinha S., Flibotte S., et al. . (2019). MicroRNA biomarkers in cerebrospinal fluid and serum reflect injury severity in human acute traumatic spinal cord injury. J. Neurotrauma 36, 2358–2371. doi: 10.1089/neu.2018.6256, PMID: PubMed DOI

Tigchelaar S., Streijger F., Sinha S., Flibotte S., Manouchehri N., So K., et al. . (2017). Serum MicroRNAs reflect injury severity in a large animal model of thoracic spinal cord injury. Sci. Rep. 7:1376. doi: 10.1038/s41598-017-01299-x, PMID: PubMed DOI PMC

Tran A. P., Warren P. M., Silver J. (2018). The biology of regeneration failure and success after spinal cord injury. Am. Physiol. Society 98, 881–917. doi: 10.1152/physrev.00017.2017, PMID: PubMed DOI PMC

Urabe F., Kosaka N., Ito K., Kimura T., Egawa S., Ochiya T. (2020). Extracellular vesicles as biomarkers and therapeutic targets for cancer. Am. J. Physiol. Cell Physiol. 318, C29–C39. doi: 10.1152/ajpcell.00280.2019 PubMed DOI

Van Niel G., D’Angelo G., Raposo G. (2018). Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. doi: 10.1038/nrm.2017.125 PubMed DOI

Vogel L. C., Anderson C. J. (2003). Spinal cord injuries in children and adolescents: a review. J. Spinal Cord Med. 26, 193–203. doi: 10.1080/10790268.2003.11753682 PubMed DOI

Vogel A., Upadhya R., Shetty A. K. (2018). Neural stem cell derived extracellular vesicles: Attributes and prospects for treating neurodegenerative disorders. EBioMedicine 38, 273–282. doi: 10.1016/j.ebiom.2018.11.026, PMID: PubMed DOI PMC

Vrijsen K. R., Maring J. A., Chamuleau S. A. J., Verhage V., Mol E. A., Deddens J. C., et al. . (2016). Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via EMMPRIN. Adv. Healthc. Mater. 5, 2555–2565. doi: 10.1002/adhm.201600308, PMID: PubMed DOI

Wang Y., Balaji V., Kaniyappan S., Krüger L., Irsen S., Tepper K., et al. . (2017). The release and trans-synaptic transmission of tau via exosomes. Mol. Neurodegener. 12:5. doi: 10.1186/s13024-016-0143-y, PMID: PubMed DOI PMC

Wang Y., Lai X., Wu D., Liu B., Wang N., Rong L. (2021). Umbilical mesenchymal stem cell-derived exosomes facilitate spinal cord functional recovery through the miR-199a-3p/145-5p-mediated NGF/TrkA signaling pathway in rats. Stem Cell Res. Ther. 12:117. doi: 10.1186/s13287-021-02148-5, PMID: PubMed DOI PMC

Wang Z. Y., Liu W. G., Muharram A., Wu Z. Y., Lin J. H. (2014). Neuroprotective effects of autophagy induced by rapamycin in rat acute spinal cord injury model. Neuroimmunomodulation 21, 257–267. doi: 10.1159/000357382, PMID: PubMed DOI

Wang L., Pei S., Han L., Guo B., Li Y., Duan R., et al. . (2018). Mesenchymal stem cell-derived exosomes reduce A1 astrocytes via downregulation of phosphorylated NFκB P65 subunit in spinal cord injury. Cell. Physiol. Biochem. 50, 1535–1559. doi: 10.1159/000494652, PMID: PubMed DOI

Wang W. X., Rajeev B. W., Stromberg A. J., Ren N., Tang G., Huang Q., et al. . (2008). The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of β-site amyloid precursor protein-cleaving enzyme 1. J. Neurosci. 28, 1213–1223. doi: 10.1523/JNEUROSCI.5065-07.2008, PMID: PubMed DOI PMC

Wang J., Rong Y., Ji C., Lv C., Jiang D., Ge X., et al. . (2020). MicroRNA-421-3p-abundant small extracellular vesicles derived from M2 bone marrow-derived macrophages attenuate apoptosis and promote motor function recovery via inhibition of mTOR in spinal cord injury. J. Nanobiotechnol. 18:72. doi: 10.1186/s12951-020-00630-5, PMID: PubMed DOI PMC

Wang Z., Song Y., Han X., Qu P., Wang W. (2020). Long noncoding RNA PTENP1 affects the recovery of spinal cord injury by regulating the expression of miR-19b and miR-21. J. Cell. Physiol. 235, 3634–3645. doi: 10.1002/jcp.29253, PMID: PubMed DOI

Wang Y., Zhang L., Li Y., Chen L., Wang X., Guo W., et al. . (2015). Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int. J. Cardiol. 192, 61–69. doi: 10.1016/j.ijcard.2015.05.020 PubMed DOI PMC

Webb R. L., Kaiser E. E., Scoville S. L., Thompson T. A., Fatima S., Pandya C., et al. . (2018). Human neural stem cell extracellular vesicles improve tissue and functional recovery in the murine thromboembolic stroke model. Transl. Stroke Res. 9, 530–539. doi: 10.1007/s12975-017-0599-2, PMID: PubMed DOI PMC

Wiklander O. P. B., Brennan M., Lötvall J., Breakefield X. O., Andaloussi S. E. L. (2019). Advances in therapeutic applications of extracellular vesicles. Sci. Transl. Med. 11:8521. doi: 10.1126/scitranslmed.aav8521, PMID: PubMed DOI PMC

Wiliams R. R., Bunge M. B. (2012). Schwann cell transplantation: a repair strategy for spinal cord injury? Progress Brain Res. 201, 295, 14–312. doi: 10.1016/B978-0-444-59544-7.00014-7 PubMed DOI

Wilson J. R., Forgione N., Fehlings M. G. (2013). Emerging therapies for acute traumatic spinal cord injury. CMAJ 185, 485–492. doi: 10.1503/cmaj.121206, PMID: PubMed DOI PMC

Withrow J., Murphy C., Liu Y., Hunter M., Fulzele S., Hamrick M. W. (2016). Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis. Arthritis Res. Ther. 18:286. doi: 10.1186/s13075-016-1178-8, PMID: PubMed DOI PMC

Witwer K. W., Buzás E. I., Bemis L. T., Bora A., Lässer C., Lötvall J., et al. . (2013). Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracel. Vesicles 2:360. doi: 10.3402/JEV.V2I0.20360, PMID: PubMed DOI PMC

Xu G., Ao R., Zhi Z., Jia J., Yu B. (2019). miR-21 and miR-19b delivered by hMSC-derived EVs regulate the apoptosis and differentiation of neurons in patients with spinal cord injury. J. Cell. Physiol. 234, 10205–10217. doi: 10.1002/jcp.27690, PMID: PubMed DOI

Yu Y. M., Gibbs K. M., Davila J., Campbell N., Sung S., Todorova T. I., et al. . (2011). MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish. Eur. J. Neurosci. 33, 1587–1597. doi: 10.1111/j.1460-9568.2011.07643.x, PMID: PubMed DOI PMC

Yu Y., Hou K., Ji T., Wang X., Liu Y., Zheng Y., et al. . (2021). The role of exosomal microRNAs in central nervous system diseases. Molecular and cellular biochemistry. Mol. Cell. Biochem. 476, 2111–2124. doi: 10.1007/s11010-021-04053-0 PubMed DOI

Yu T., Zhao C., Hou S., Zhou W., Wang B., Chen Y. (2019). Exosomes secreted from miRNA-29b-modified mesenchymal stem cells repaired spinal cord injury in rats. Braz. J. Med. Biol. Res. 52:e8735. doi: 10.1590/1414-431x20198735, PMID: PubMed DOI PMC

Yuan Y. M., He C. (2013). The glial scar in spinal cord injury and repair. Neurosci. Bull. 29, 421–435. doi: 10.1007/s12264-013-1358-3, PMID: PubMed DOI PMC

Yuan X., Wu Q., Wang P., Jing Y., Yao H., Tang Y., et al. . (2019). Exosomes derived from Pericytes improve microcirculation and protect blood-spinal cord barrier after spinal cord injury in mice. Front. Neurosci. 13:319. doi: 10.3389/fnins.2019.00319, PMID: PubMed DOI PMC

Yunta M., Nieto-Díaz M., Esteban F. J., Caballero-López M., Navarro-Ruíz R., Reigada D., et al. . (2012). MicroRNA dysregulation in the spinal cord following traumatic injury. PLoS One 7:34534. doi: 10.1371/journal.pone.0034534, PMID: PubMed DOI PMC

Zappulli V., Pagh Friis K., Fitzpatrick Z., Maguire C. A., Breakefield X. O. (2016). Extracellular vesicles and intercellular communication within the nervous system. J. Clin. Invest. 126, 1198–1207. doi: 10.1172/JCI81134, PMID: PubMed DOI PMC

Zhang Z., Cheng Y. (2014). miR-16-1 promotes the aberrant α-synuclein accumulation in parkinson disease via targeting heat shock protein 70. Sci. World J. 2014:8348. doi: 10.1155/2014/938348, PMID: PubMed DOI PMC

Zhang L., Tang P., Hou H., Zhang L., Lan X., Mao Z., et al. . (2014). Autophagy reduces neuronal damage and promotes locomotor recovery via inhibition of apoptosis after spinal cord injury in rats. Totowa, NJ: Humana Press Inc. PubMed

Zhang B., Yeo R. W. Y., Tan K. H., Lim S. K. (2016). Focus on extracellular vesicles: therapeutic potential of stem cell-derived extracellular vesicles. Int. J. Mol. Sci. 17:174. doi: 10.3390/ijms17020174, PMID: PubMed DOI PMC

Zhang C., Zhang C. L., Xu Y., Li C., Cao Y., Li P. (2020). Exosomes derived from human placenta-derived mesenchymal stem cells improve neurologic function by promoting angiogenesis after spinal cord injury. Neurosci. Lett. 739:135399. doi: 10.1016/j.neulet.2020.135399, PMID: PubMed DOI

Zhong D., Cao Y., Li C. J., Li M., Rong Z. J., Jiang L., et al. . (2020). Highlight article: neural stem cell-derived exosomes facilitate spinal cord functional recovery after injury by promoting angiogenesis. Exp. Biol. Med. 245, 54–65. doi: 10.1177/1535370219895491, PMID: PubMed DOI PMC

Zhou Z., Li C., Bao T., Zhao X., Xiong W., Luo C., et al. . (2022). Exosome-shuttled miR-672-5p from anti-inflammatory microglia repair traumatic spinal cord injury by inhibiting AIM2/ASC/Caspase-1 signaling pathway mediated neuronal Pyroptosis. J. Neurotrauma 39, 1057–1074. doi: 10.1089/neu.2021.0464, PMID: PubMed DOI

Zhou K., Sansur C. A., Xu H., Jia X. (2017). The temporal pattern, flux, and function of autophagy in spinal cord injury. Int. J. Mol. Sci. 18:466. doi: 10.3390/ijms18020466, PMID: PubMed DOI PMC

Zhou Y., Wang Z., Li J., Li X., Xiao J. (2018). Fibroblast growth factors in the management of spinal cord injury. J. Cellular Mol. Med. 22, 25–37. doi: 10.1111/jcmm.13353 PubMed DOI PMC

Zhou Y., Wen L. L., Li Y. F., Wu K. M., Duan R. R., Yao Y. B., et al. . (2022). Exosomes derived from bone marrow mesenchymal stem cells protect the injured spinal cord by inhibiting pericyte pyroptosis. Neural Regen. Res. 17, 194–202. doi: 10.4103/1673-5374.314323, PMID: PubMed DOI PMC

Zhu J., Huang F., Hu Y., Liu S., Liu Y., Qiao W., et al. . (2023). Non-coding RNAs regulate spinal cord injury-related neuropathic pain via Neuroinflammation. J. Inflamm. Res. 16, 2477–2489. doi: 10.2147/JIR.S413264, PMID: PubMed DOI PMC

Zou Y., Yin Y., Xiao Z., Zhao Y., Han J., Chen B., et al. . (2022). Transplantation of collagen sponge-based three-dimensional neural stem cells cultured in a RCCS facilitates locomotor functional recovery in spinal cord injury animals. Biomater. Sci. 10, 915–924. doi: 10.1039/d1bm01744f, PMID: PubMed DOI