A New Paradigm in Spinal Cord Injury Therapy: from Cell-free Treatment to Engineering Modifications

Overview

Journal CNS Neurol Disord Drug Targets

Publisher Bentham Science Publishers

Specialties Neurology
Pharmacology

Date 2023 Apr 19

PMID 37076458

Authors

Bo Qin

Xi-Min Hu

Yan-Xia Huang

Rong-Hua Yang

Kun Xiong

Affiliations

Soon will be listed here.

Abstract

Spinal cord injury (SCI) is an intractable and poorly prognostic neurological disease, and current treatments are still unable to cure it completely and avoid sequelae. Extracellular vesicles (EVs), as important carriers of intercellular communication and pharmacological effects, are considered to be the most promising candidates for SCI therapy because of their low toxicity and immunogenicity, their ability to encapsulate endogenous bioactive molecules (e.g., proteins, lipids, and nucleic acids), and their ability to cross the blood-brain/cerebrospinal barriers. However, poor targeting, low retention rate, and limited therapeutic efficacy of natural EVs have bottlenecked EVs-based SCI therapy. A new paradigm for SCI treatment will be provided by engineering modified EVs. Furthermore, our limited understanding of the role of EVs in SCI pathology hinders the rational design of novel EVbased therapeutic approaches. In this study, we review the pathophysiology after SCI, especially the multicellular EVs-mediated crosstalk; briefly describe the shift from cellular to cell-free therapies for SCI treatment; discuss and analyze the issues related to the route and dose of EVs administration; summarize and present the common strategies for EVs drug loading in the treatment of SCI and point out the shortcomings of these drug loading methods; finally, we analyze and highlight the feasibility and advantages of bio-scaffold-encapsulated EVs for SCI treatment, providing scalable insights into cell-free therapy for SCI.

References

Aziz I, Che Ramli M, Mohd Zain N, Sanusi J . Behavioral and Histopathological Study of Changes in Spinal Cord Injured Rats Supplemented with Spirulina platensis. Evid Based Complement Alternat Med. 2014; 2014:871657. PMC: 4135169. DOI: 10.1155/2014/871657. View

Sykova E, Cizkova D, Kubinova S . Mesenchymal Stem Cells in Treatment of Spinal Cord Injury and Amyotrophic Lateral Sclerosis. Front Cell Dev Biol. 2021; 9:695900. PMC: 8290345. DOI: 10.3389/fcell.2021.695900. View

Bhat I, T B S, Somal A, Pandey S, Bharti M, Panda B . An allogenic therapeutic strategy for canine spinal cord injury using mesenchymal stem cells. J Cell Physiol. 2018; 234(3):2705-2718. DOI: 10.1002/jcp.27086. View

Vismara I, Papa S, Rossi F, Forloni G, Veglianese P . Current Options for Cell Therapy in Spinal Cord Injury. Trends Mol Med. 2017; 23(9):831-849. DOI: 10.1016/j.molmed.2017.07.005. View

Streijger F, So K, Manouchehri N, Gheorghe A, Okon E, Chan R . A Direct Comparison between Norepinephrine and Phenylephrine for Augmenting Spinal Cord Perfusion in a Porcine Model of Spinal Cord Injury. J Neurotrauma. 2018; 35(12):1345-1357. DOI: 10.1089/neu.2017.5285. View

Hawryluk G, Whetstone W, Saigal R, Ferguson A, Talbott J, Bresnahan J . Mean Arterial Blood Pressure Correlates with Neurological Recovery after Human Spinal Cord Injury: Analysis of High Frequency Physiologic Data. J Neurotrauma. 2015; 32(24):1958-67. PMC: 4677564. DOI: 10.1089/neu.2014.3778. View

Wutte C, Klein B, Becker J, Mach O, Panzer S, Strowitzki M . Earlier Decompression (< 8 Hours) Results in Better Neurological and Functional Outcome after Traumatic Thoracolumbar Spinal Cord Injury. J Neurotrauma. 2018; 36(12):2020-2027. DOI: 10.1089/neu.2018.6146. View

Fehlings M, Vaccaro A, Wilson J, Singh A, Cadotte D, Harrop J . Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PLoS One. 2012; 7(2):e32037. PMC: 3285644. DOI: 10.1371/journal.pone.0032037. View

Yang M, Yin X, Liu S, Hui H, Yan L, He B . Letter: Ultra-Early (<12 Hours) Surgery Correlates With Higher Rate of American Spinal Injury Association Impairment Scale Conversion After Cervical Spinal Cord Injury. Neurosurgery. 2019; 85(2):E399-E400. DOI: 10.1093/neuros/nyz154. View

10.

Bracken M, Shepard M, COLLINS W, Holford T, Young W, Baskin D . 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. N Engl J Med. 1990; 322(20):1405-11. DOI: 10.1056/NEJM199005173222001. View

11.

Bracken M, Shepard M, Hellenbrand K, COLLINS W, LEO L, Freeman D . Methylprednisolone and neurological function 1 year after spinal cord injury. Results of the National Acute Spinal Cord Injury Study. J Neurosurg. 1985; 63(5):704-13. DOI: 10.3171/jns.1985.63.5.0704. View

12.

Jones C, Newell R, Lee J, Cripton P, Kwon B . The pressure distribution of cerebrospinal fluid responds to residual compression and decompression in an animal model of acute spinal cord injury. Spine (Phila Pa 1976). 2012; 37(23):E1422-31. DOI: 10.1097/BRS.0b013e31826ba7cd. View

13.

Squair J, Belanger L, Tsang A, Ritchie L, Mac-Thiong J, Parent S . Spinal cord perfusion pressure predicts neurologic recovery in acute spinal cord injury. Neurology. 2017; 89(16):1660-1667. DOI: 10.1212/WNL.0000000000004519. View

14.

OBrien K, Breyne K, Ughetto S, Laurent L, Breakefield X . RNA delivery by extracellular vesicles in mammalian cells and its applications. Nat Rev Mol Cell Biol. 2020; 21(10):585-606. PMC: 7249041. DOI: 10.1038/s41580-020-0251-y. View

15.

Thery C, Witwer K, Aikawa E, Alcaraz M, Anderson J, Andriantsitohaina R . 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 Extracell Vesicles. 2019; 7(1):1535750. PMC: 6322352. DOI: 10.1080/20013078.2018.1535750. View

16.

Kumar A, Kumar S . Inhibition of extracellular vesicle pathway using neutral sphingomyelinase inhibitors as a neuroprotective treatment for brain injury. Neural Regen Res. 2021; 16(12):2349-2352. PMC: 8374560. DOI: 10.4103/1673-5374.313014. View

17.

Couch Y, Buzas E, Di Vizio D, Gho Y, Harrison P, Hill A . A brief history of nearly EV-erything - The rise and rise of extracellular vesicles. J Extracell Vesicles. 2021; 10(14):e12144. PMC: 8681215. DOI: 10.1002/jev2.12144. View

18.

Hu Y, Sun Y, Wan C, Dai X, Wu S, Lo P . Microparticles: biogenesis, characteristics and intervention therapy for cancers in preclinical and clinical research. J Nanobiotechnology. 2022; 20(1):189. PMC: 9006557. DOI: 10.1186/s12951-022-01358-0. View

19.

van Niel G, DAngelo G, Raposo G . Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018; 19(4):213-228. DOI: 10.1038/nrm.2017.125. View

20.

Rufino-Ramos D, Albuquerque P, Carmona V, Perfeito R, Nobre R, de Almeida L . Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases. J Control Release. 2017; 262:247-258. DOI: 10.1016/j.jconrel.2017.07.001. View