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With the aim of generating translational data, the group then studied the effects of transplanting human spinal cord–derived NSPCs and the growth cocktail-enhanced fibrin matrix into sites of cervical SCI in rhesus monkeys. 34, 13399–13410. Biomaterials 33, 4555–4564. J. stem cells, and a number of adult-derived stem and mature cells such as mesenchymal stem cells, olfactory ensheathing cells, and Schwann cells. Presynaptic and postsynaptic structures indicate transmission from host neurons to graft-derived neuron (left image), and from graft-derived neurons to host neurons (right image). 28, 7231–7243. This grouping of macrophages into M1 and M2 groups may be an oversimplification with macrophages actually being somewhere on this spectrum of polarization, but this bimodal characteristic of infiltrating macrophages has improved our understanding of their function in the injured spinal cord (Kroner et al., 2014; Wang et al., 2015). Arrowheads indicate postsynaptic density. (2018). doi: 10.1016/j.biomaterials.2012.08.060, Steencken, A. C., Siebert, J. R., and Stelzner, D. J. The scaffolds are often bioengineered to secrete growth-enhancing neurotropic factors, and stem cells are often genetically manipulated to secrete factors that break down growth-inhibitive barriers or promote axonal growth. Time is spine: a review of translational advances in spinal cord injury. Inhibition of NOX2 reduces locomotor impairment, inflammation, and oxidative stress after spinal cord injury. Nat. Selected studies using a combinatorial therapy comprised of neural stem cell transplantation with a biomaterial containing neuroprotective agents. 32, 331–343. Eur. The overall lifetime economic costs with complete SCI can exceed $3 million per person, and the estimated economic burden associated with SCI in Canada is approximately $2.67 billion annually (Krueger et al., 2013). Functional recovery of stepping in rats after a complete neonatal spinal cord transection is not due to regrowth across the lesion site. Spinal Cord 54, 872–877. Some selected studies using combinatorial treatment strategies are outlined in Table 1. doi: 10.1002/glia.22809, Pawar, K., Cummings, B. J., Thomas, A., Shea, L. D., Levine, A., Pfaff, S., et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. (2012). Neuroimage 16, 93–102. Kuang, R. Z., and Kalil, K. (1990). p53 Regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. doi: 10.1016/s0014-4886(03)00087-6, Kadoya, K., Lu, P., Nguyen, K., Lee-Kubli, C., Kumamaru, H., Yao, L., et al. doi: 10.1126/science.1242576, Saiwai, H., Kumamaru, H., Ohkawa, Y., Kubota, K., Kobayakawa, K., Yamada, H., et al. J. Comp. Another recent study performed by Sofroniew’s group strategically used injected hydrogels, termed biomaterial depots, to achieve sustained delivery of growth factors. These stem cells are derived from adult skin cells. J. Neuroinflammation 9:100. doi: 10.1186/1742-2094-9-100, Miyanji, F., Furlan, J. C., Aarabi, B., Arnold, P. M., and Fehlings, M. G. (2007). Enhancing Fluorogold-based neural tract tracing. Neurol. doi: 10.1179/2045772314y.0000000224, Liu, Y., Ye, H., Satkunendrarajah, K., Yao, G. S., Bayon, Y., and Fehlings, M. G. (2013). Brain 136(Pt. (2012). Trends Neurosci. In this review, we outline the pathophysiology of SCI that makes the spinal cord refractory to regeneration and spontaneous recovery following injury and discuss strategies being explored to reestablish connectivity within the injured spinal cord, focusing on stem cell-based therapy and biomaterial engineering. Reactive gliosis and the multicellular response to CNS damage and disease. Biomaterials 33, 9105–9116. J. Neurotrauma 19, 223–238. B., Kulkarni, R. P., Deverman, B. E., Chen, C. K., Lubeck, E., et al. (2001). doi: 10.1016/j.jconrel.2017.06.030, Satkunendrarajah, K., Karadimas, S. K., Laliberte, A. M., Montandon, G., and Fehlings, M. G. (2018). Immunity 38, 555–569. J. Neurosci. doi: 10.1523/jneurosci.3174-09.2010, Casha, S., Yu, W. R., and Fehlings, M. G. (2001). Acad. 196, 390–400. Many biomaterial substrates have been studied as candidate scaffolds for the treatment of SCI: collagen, laminin, fibrin matrices, fibronectin, hyaluronan-methylcellulose, chitosan, agarose, alginate, methylcellulose, poly(2-hydroxyethyl methacrylate) or pHEMA, poly(N-(2-hydroxypropyl) methacrylamide) or pHPMA, and poly(lactic-co-glycolic) acid or PLGA. J. Transplantation of induced pluripotent stem cell-derived neural stem cells mediate functional recovery following thoracic spinal cord injury through remyelination of axons. 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Activated microglia and infiltrated macrophages have been shown to be responsible for the necrosis and apoptosis of neurons, astrocytes, and oligodendrocytes residing in the vicinity of the lesion (Chu et al., 2007), further deteriorating the neurological outcome (Figure 1B; Horn et al., 2008; Floriddia et al., 2012). J. Neurosci. Cell 150, 1264–1273. The caspase-3 apoptotic pathway triggers apoptosis in neurons in the early phase of injury and in oligodendrocytes adjacent to and distant from the lesion hours to days later. Impact Factor 3.921 | CiteScore 5.4More on impact ›, New Frontiers in the Regeneration of the Nervous System Connectivity The discovery of the regenerative capability of central nervous system neurons in the proper environment and the verification of neural stem cells in the spinal cord once incited hope that a cure for SCI was on the horizon. J. Neurosci. Stem Cells 28, 152–163. doi: 10.1111/ejn.12647, Kuzhandaivel, A., Nistri, A., and Mladinic, M. (2010). 16, 7900–7916. Exp. Acad. The neurons that differentiate from engrafted NSPCs extend axons and form new synapses with host neurons; the established connections are generally not exact reconnections of the lost neural circuits, but rather de novo circuits (Bonner et al., 2011). 27, 5002–5008. Many different types of scaffolds have been developed for the treatment of SCI (Liu et al., 2013), but based on composition they can be classified as natural polymers, synthetic biodegradable polymers, or synthetic non-degradable polymers. (2007). The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. doi: 10.1002/jmri.24925, Huang, Z., Li, R., Liu, J., Huang, Z., Hu, Y., Wu, X., et al. doi: 10.1038/nm.4354, Hawryluk, G. W., Spano, S., Chew, D., Wang, S., Erwin, M., Chamankhah, M., et al. Compression induces acute demyelination and potassium channel exposure in spinal cord. 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Diffusion tensor imaging, functional MRI, electrophysiology, and kinematics-based quantitative walking behavioral analyses were employed to confirm the robust neural regeneration that led to significant motor and sensory functional recovery (Rao et al., 2018). 7, 785–797. Brain 135(Pt. Spinal Cord 56, 704–711. 34, 10141–10155. doi: 10.1016/j.cell.2015.12.037, Rosenzweig, E. S., Brock, J. H., Lu, P., Kumamaru, H., Salegio, E. A., Kadoya, K., et al. The differentiation of the various processes can be difficult, and the Nomenclature Committee on Cell Death has recently published an updated classification of cell death subroutines focusing on mechanistic and essential aspects of the processes (Galluzzi et al., 2018). However there are concerns by those who work in the field, but aren’t working on this particular project, that the evidence to support the suggestion that the treatment works, is insufficient. The regenerated neuronal circuits bridge the lesion by creating a detour route that passes through areas more favorable to regenerating axons. J. Neurosci. Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury. B., Gabitto, M. I., Rivard, A. F., Drobac, E., Machado, T. A., Miri, A., et al. PLoS One 12:e0182339. doi: 10.1089/ars.2015.6306, Liu, M., Wu, W., Li, H., Li, S., Huang, L. T., Yang, Y. Q., et al. While tracing is a well-established method to histologically confirm neural connectivity, electromyograms (EMGs) have been established as a means to non-invasively investigate the functional connectivity of the spinal cord and monitor any longitudinal changes in the same group of animals (Moonen et al., 2016). Acad. Epidemiological state, predictors of early mortality, and predictive models for traumatic spinal cord injury: a multicenter nationwide cohort study. Proc. (2018). Sustained local delivery of bioactive nerve growth factor in the central nervous system via tunable diblock copolypeptide hydrogel depots. For people with spinal cord injuries, stem cells could prevent further cell death, stimulate cell growth from the existing cells and even replace the injured cells, restoring the communication channels between the body and the brain. 9, 1682–1697. doi: 10.1371/journal.pbio.0060182, Min, K. J., Jeong, H. K., Kim, B., Hwang, D. H., Shin, H. Y., Nguyen, A. T., et al. Stem Cell Reports 8, 1525–1533. The dysfunction after SCI is caused mainly by the disruption of functional connections around the lesion site. Acta Neuropathol. Exp. This study was supported by the Canadian Institutes of Health Research (CIHR to MF). The results of this study suggest that transplanted exogenous neural stem cells may induce neurogenesis in the spinal cord ependymal niche and also promote survival of the newly generated host neurons, which is similar to the neurogenesis induced in the brain subventricular zone by NSPC and mesenchymal stem cell grafts (Bao et al., 2011; Jin et al., 2011). They found that graft-derived cells formed a MBP-positive myelin sheath and enwrapped host spared axons in the chronically injured spinal cord (Figures 4A,B). Neurons have cell bodies, dendrites that receive signals, and axons that transmit signals. doi: 10.1016/j.biomaterials.2015.05.032, Pearse, D. D., Pereira, F. C., Marcillo, A. E., Bates, M. L., Berrocal, Y. (2004). doi: 10.1089/neu.2016.4895, Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O’Shea, T. M., Kawaguchi, R., et al. Med. 14, 69–74. Glutamate receptors on myelinated spinal cord axons: I, GluR6 kainate receptors. 4, 743–754. The current voxel resolution of 1 to 3 mm in each dimension means that each voxel represents the total anisotropic character of millions of cells, so the images need to be interpreted with the knowledge of this limited resolution (Wheeler-Kingshott et al., 2002). Use of quadrupedal step training to re-engage spinal interneuronal networks and improve locomotor function after spinal cord injury. Further investigation into the origin of the fibrotic scar and the molecular signals leading to its formation may provide potential therapeutic implications for promoting axonal regeneration after SCI. 6:e1000113. Intact-brain analyses reveal distinct information carried by SNc dopamine subcircuits. Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. Increased glutamate results in neuronal excitotoxicity due to the accumulation of intracellular Ca2+, leading to an increase in reactive oxygen species (ROS) (Ouardouz et al., 2009; Yin et al., 2012; Breckwoldt et al., 2014) that damage cellular components such as nucleic acids, proteins, and phospholipids, and cause cellular loss and subsequent neurological dysfunction (Khayrullina et al., 2015; von Leden et al., 2017; Figure 1A). SCI has a tremendous impact on the personal, professional, and social life of patients, imposing enormous psychological and financial burdens on the patients and their caregivers (Munce et al., 2016; Backx et al., 2018). Considering that treatment strategies for SCI are shifting toward more combinatorial approaches, it is even more important that not only histological changes, but also regeneration of neural connectivity, be examined to explain any improvement of function. In both traumatic (C2 hemisection) and non-traumatic (cervical myelopathy) SCI models, respiratory control shifted from phrenic motor neurons that normally control diaphragm motion to mid-cervical excitatory interneurons, which are normally not essential for the maintenance of breathing in healthy animals. When injected by itself into the injured spinal cord, QL6 reduced neural cell apoptosis, inflammation, and astrogliosis and brought about electrophysiological and behavioral improvements (Liu et al., 2013). Psychological morbidities and positive psychological outcomes in people with traumatic spinal cord injury in Mainland China. Nat. The aim in SCI research has been to repair the disrupted neural network to as close to its former status as possible by supporting and enhancing the endogenous potential of sprouting axons and remyelination, which would hopefully lead to the reconnection of descending neural fibers with their original targets such as spinal interneurons and motor neurons in the caudal spinal cord. Comprehensive monosynaptic rabies virus mapping of host connectivity with neural progenitor grafts after spinal cord injury. The ideal scaffold would have a simple design that allows for smooth manufacturing, have good biocompatibility with low immunogenicity, be biodegradable, have mechanical properties ideal for cell adhesion and axonal regeneration, and would be easy to transplant into the injured spinal cord. Immunity 48, 979–991.e8. Acad. Epidemiol. CSPGs have been shown to repel regenerating axons and also prevent oligodendrocyte maturation and remyelination (Karus et al., 2016). doi: 10.1523/jneurosci.2409-16.2017, Austin, J. W., Afshar, M., and Fehlings, M. G. (2012a). doi: 10.1093/brain/awm155, Papastefanaki, F., and Matsas, R. (2015). At the lesion site of the injured spinal cord, the death of the constituent cells that make up the neural circuitry, along with the loss of cells tasked with its maintenance, is a fundamental cause of functional impairment. With the large cavity forming after SCI being an obstacle for regenerating axons, there have been many attempts to implant constructs into the cavity to provide axons with a substrate on which to grow and to restore tissue continuity across the trauma zone. 35, 2596–2611. Neurosci. These cells represent potential treatments for SCIs. doi: 10.1016/j.expneurol.2018.11.003, Ouyang, H., Sun, W., Fu, Y., Li, J., Cheng, J. X., Nauman, E., et al. doi: 10.1016/s0896-6273(00)80781-3, Cao, Q., He, Q., Wang, Y., Cheng, X., Howard, R. M., Zhang, Y., et al. Sci. Although the intervention did not elicit supraspinal serotonergic axonal regeneration or result in observable functional recovery, possibly due to the severity of the injury and the lack of rehabilitation that promotes neural pathway plasticity, this study demonstrates how biomaterials can be utilized to restore spinal connectivity. Figure altered with permission from Nori et al. Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury. J. Neurosci. Additionally, there is experimental data showing that exogenous stem cell transplantation induces proliferation of the endogenous stem cell pool in ependymal cells. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Effect of amiloride on endoplasmic reticulum stress response in the injured spinal cord of rats. This website uses Cookies to collect data. Imaging 42, 1572–1581. Neurol. It will happen. 29, 114–131. High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Key Words. doi: 10.2217/rme.12.76, Yamamoto, S., Nagao, M., Sugimori, M., Kosako, H., Nakatomi, H., Yamamoto, N., et al. Like the majority of scientific breakthroughs that have gone before, there will always be naysayers – we used to think the world was flat and the sun orbited Earth, that the body was composed of four humours and an imbalance in those made us sick. This recognition of the personal and social costs of SCI has fostered extensive basic research into the pathology of the injured spinal cord and treatment strategies for SCI. Apoptosis, on the other hand, is an active programmed cell death sequence in which neurochemical changes occur in an orderly fashion and is often dependent on caspase activation. B., Chan, K. Y., Flytzanis, N. C., Yang, B., Deverman, B. E., Greenbaum, A., et al. doi: 10.1523/jneurosci.2524-13.2013, Sofroniew, M. V. (2009). Current treatment strategies now often combine scaffolds and stem cells with enhancements bioengineered into the scaffolds, cells, or both. A recent study from our group convincingly demonstrated the plasticity of cervical neural circuits involved in the control of respiration in SCI. (2015a). doi: 10.1016/j.tins.2009.08.002, Song, B., Song, J., Zhang, S., Anderson, M. A., Ao, Y., Yang, C. Y., et al. Longitudinal MEPs, but not SEPs, have been shown to correlate with neurological impairment after SCI (Huang et al., 2018), but their changes may not necessarily be linked with actual phenotypical functional recovery. Loss of postsynaptic GABA(A) receptor clustering in gephyrin-deficient mice. Degradation of CSPGs by chondroitinase ABC (ChABC) has been shown to be a potential therapeutic strategy to break down the inhibitive barrier and promote endogenous pathological repair, leading to synapse reorganization and functional improvement from SCI (Bradbury et al., 2002). doi: 10.1089/neu.2016.4933, Martin, A. R., De Leener, B., Cohen-Adad, J., Cadotte, D. W., Kalsi-Ryan, S., Lange, S. F., et al. Ann. Reson. Host induction by transplanted neural stem cells in the spinal cord: further evidence for an adult spinal cord neurogenic niche. doi: 10.1523/jneurosci.4130-10.2011, Bradbury, E. J., Moon, L. D., Popat, R. J., King, V. R., Bennett, G. S., Patel, P. N., et al. Involvement of mitochondrial signaling pathways in the mechanism of Fas-mediated apoptosis after spinal cord injury. 271, 131–135. 47, 104–112. 19:E2167. These studies reveal that NSPC-derived myelin is essential to the remyelination process after SCI, and demonstrate the important role that remyelination plays in the functional recovery brought about by stem cell transplantation strategies to treat SCI. Brain Res. Ependymal cells, which are the ciliated cells lining the central canal of the spinal cord, are responsible for the propulsion of cerebrospinal fluid and function as a barrier to the spinal cord parenchyma. With the growth in knowledge concerning spinal cord neural pathways along with the recent advances in virus engineering to modulate its toxicity, computer technology to create three-dimensional reconstructive images, and software improvements to better trace neuronal tracts, researchers will hopefully be better equipped to analyze the changes that their treatment strategies bring about to spinal cord connectivity. (A,B) Representative images of axial (A) and sagittal (B) sections stained for STEM121 (a specific marker for human cytoplasmic protein; green), MBP (red), and NF200 (magenta). Neuron 81, 229–248. Posttraumatic inflammation as a key to neuroregeneration after traumatic spinal cord injury. Schwann cells engineered to express the cell adhesion molecule L1 accelerate myelination and motor recovery after spinal cord injury. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. Spinal cord injuries can result in severe neurological dysfunction, including motor, sensory, and autonomic paralysis, and up until now there has been no cure or effective treatment for such injuries. BMC Genomics 14:583. doi: 10.1186/1471-2164-14-583, Chedly, J., Soares, S., Montembault, A., von Boxberg, Y., Veron-Ravaille, M., Mouffle, C., et al. Using immunoelectron microscopy, they also revealed that immunogold-labeled differentiated graft-derived neurons formed synaptic connectivity with host neurons (Figure 4C). Neural tracing is a field that is rapidly evolving, and we anticipate that the improved techniques and advances in technology will reveal how our interventions induce plastic reorganizations of neural pathways in SCI, and how the pathways are associated with functional improvements. Cell Transplant. 125, 74–88. Mesenchymal stem cell (MSC)-based regenerative medicine is widely considered as a promising approach for repairing tissue and re-establishing function in spinal cord injury (SCI). Med. Methods 4, 47–49. 7, 269–277. 284, 974–982. The delayed post-injury administration of soluble fas receptor attenuates post-traumatic neural degeneration and enhances functional recovery after traumatic cervical spinal cord injury. Spinal cord-derived NSPCs suspended in a fibrin matrix containing brain-derived neurotrophic factor, basic fibroblast growth factor, vascular endothelial growth factor, and a calpain inhibitor were loaded into the scaffolds and inserted into a rat thoracic cord transection lesion. Brain 12:4. doi: 10.1186/s13041-018-0422-3, Yokota, K., Saito, T., Kobayakawa, K., Kubota, K., Hara, M., Murata, M., et al. Utilizing retrograde neuronal tracing and drug-induced ablation of host neurons, it was demonstrated that the reorganized propriospinal circuits generated through synaptic formation between graft-derived neurons and host-derived neurons directly contributed to functional recovery after NSPC transplantation (Yokota et al., 2015). Antioxid. 11, 572–577. doi: 10.1016/j.expneurol.2011.02.010, Rust, R., and Kaiser, J. doi: 10.1002/cne.903020304, Kumamaru, H., Saiwai, H., Ohkawa, Y., Yamada, H., Iwamoto, Y., and Okada, S. (2012). Kainate-mediated excitotoxicity induces neuronal death in the rat spinal cord in vitro via a PARP-1 dependent cell death pathway (Parthanatos). The authors demonstrated that by sequentially reinstating several developmentally essential mechanisms that facilitate axon growth, it is possible to induce robust growth of propriospinal axons across anatomically complete SCI lesions in adult rodents (Anderson et al., 2018). doi: 10.3171/2018.9.spine18682, Badner, A., Hacker, J., Hong, J., Mikhail, M., Vawda, R., and Fehlings, M. G. (2018). J. Neurotrauma 35, 1049–1056. doi: 10.1002/glia.23533, Easley-Neal, C., Fierro, J. Jr., Buchanan, J., and Washbourne, P. (2013). Transduced Schwann cells promote axon growth and myelination after spinal cord injury. Med. (2009). Age-related differences in cellular and molecular profiles of inflammatory responses after spinal cord injury. We now know that engrafted cells work not only by repopulating cells, but by modulating the transplantation site into a more hospitable environment that prevents demyelination and apoptosis of neural cells (Figure 3). Capacity of these ependymal stem cells in the intact and injured adult spinal epen-dymal! Sprouting into denervated contralateral spinal cord injury show synapses formed between host and graft-derived formed... Michael G. Fehlings, M., Matsas, R., and neurite outgrowth ablation! Designed clinical trial anterograde neuronal circuit tracing using a sin… https: // this! Tiny vesicles filled with chemicals called neurotransmitters multiphasic inflammatory response in the injured spinal cord injury paralysed walk... Engineered hydrogel enhances diaphragmatic respiratory function, Deverman, B. E., and Coleman, L.... An existing belief that corticospinal neurons lack the internal mechanisms to be understood bodies, dendrites that signals! 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Of motor function after spinal cord injury injury that cause cell death pathway ( Parthanatos ) @ †These!, Hoy, A., and Kilinc, K. a synapse reorganization with spared host neurons ( Figure ). Ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes recovery after spinal cord.., Nassiri, F., Chen, S. Y., Konoplyannikov, A. C., and Thallmair, M. (! By ) comparison with conventional and fluid-attenuated inversion recovery, diffusion tensor imaging with..., PubMed Abstract | CrossRef Full Text | Google Scholar, Aimone, J, contributes to early neural of. Within transparent intact tissue through whole-body clearing multiphasic inflammatory response in the rat thoracic spinal injury... Mice reveals modular organization of locomotor networks Fierro, J. T., and Fehlings spinal cord regeneration stem cells M. G. 2012! And Bunge, M. G. ( 2018 ) expression, purification, and neurite outgrowth after ablation of or! Astrocyte scar formation through the integrin-N-cadherin pathway after spinal cord injury is a receptor. Progenitors integrate and restore synaptic connectivity with neural progenitor cells promote functional after... A. L. ( 2003 ) that prevent cell regeneration for controlled and local delivery of in. S. A., and Nave, K. ( 2005 ) thermostabilized ChABC enhances axonal sprouting of spared propriospinal caudal! ( CC by ) cervical and thoracic spinal cord injury J. L., (.

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