Manganese-enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice. The axons of most neurons are covered with a lipid layer knows as the myelin sheath, which insulates axons and speeds up transmission of action potentials through the axon. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. However, since conventional MRI depicts the white matter as uniform tissue and does not have the sensitivity or resolution to depict the complex array of directionally oriented nerve fibers in the spinal cord (Stroman et al., 2012), it becomes necessary to enhance the signals from neural tracts. The relationship between trans-lesional conduction, motor neuron pool excitability, and motor function in dogs with incomplete recovery from severe spinal cord injury. doi: 10.1038/nature13974, Lavdas, A. 31, 9910–9922. Nature 497, 332–337. doi: 10.1016/s0896-6273(00)80781-3, Cao, Q., He, Q., Wang, Y., Cheng, X., Howard, R. M., Zhang, Y., et al. doi: 10.1523/jneurosci.3111-09.2010, Karimi-Abdolrezaee, S., Schut, D., Wang, J., and Fehlings, M. G. (2012). 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. (2011). J. Neurotrauma 34, 2883–2891. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. (2017). B., Kulkarni, R. P., Deverman, B. E., Chen, C. K., Lubeck, E., et al. Motor evoked potentials correlate with magnetic resonance imaging and early recovery after acute spinal cord injury. (1999). Neuron 83, 1098–1116. doi: 10.1016/j.conb.2014.03.010, Lu, P., Wang, Y., Graham, L., McHale, K., Gao, M., Wu, D., et al. 98, 881–917. doi: 10.7554/eLife.39016, Wang, Y., Xie, H., and Zhao, X. The answer is “maybe,” “sometimes,” and “we don't know.” The reason for this ambiguity is that stem cell therapy for spinal cord injuries is in its infancy as a treatment. doi: 10.1089/ars.2015.6306, Liu, M., Wu, W., Li, H., Li, S., Huang, L. T., Yang, Y. Q., et al. Med. doi: 10.1523/jneurosci.2409-16.2017, Austin, J. W., Afshar, M., and Fehlings, M. G. (2012a). (2018b). 177, 306–313. J. Neurosci. doi: 10.1172/jci39780, Assinck, P., Duncan, G. J., Plemel, J. R., Lee, M. J., Stratton, J. F waves are often used to measure nerve conduction velocity, and any changes recorded in conduction velocity can reflect the remyelination of neural tracts (Moonen et al., 2016). J. Neurosci. (2002). doi: 10.1016/j.biomaterials.2017.05.024, Chen, B. K., Knight, A. M., de Ruiter, G. C., Spinner, R. J., Yaszemski, M. J., Currier, B. L., et al. 29, 114–131. Cell Stem Cell 7, 470–482. doi: 10.1111/ejn.12647, Kuzhandaivel, A., Nistri, A., and Mladinic, M. (2010). U.S.A. 114, E820–E829. B., Gabitto, M. I., Rivard, A. F., Drobac, E., Machado, T. A., Miri, A., et al. EMBO J. Because whilst there have been multiple attempts to develop stem cell transplantation approaches with the aim to regenerate damaged spinal cords before, this multicentre team is planning the first that might actually work, and be ethical to boot. Science 351:aac4750. doi: 10.1089/neu.2017.5012, Li, X., Xiao, Z., Han, J., Chen, L., Xiao, H., Ma, F., et al. A re-assessment of long distance growth and connectivity of neural stem cells after severe spinal cord injury. Brain 130(Pt. (2010). Brain 12:4. doi: 10.1186/s13041-018-0422-3, Yokota, K., Saito, T., Kobayakawa, K., Kubota, K., Hara, M., Murata, M., et al. The cystic cavities that form following SCI contain extracellular fluid, bands of connective tissue, and infiltrated monocytes/macrophages (Austin et al., 2012a), and the increasing cerebral spinal fluid (CSF) pressure within the cavity is detrimental for regeneration and acts to enlarge its size. doi: 10.1523/jneurosci.19-21-09289.1999, Koffler, J., Zhu, W., Qu, X., Platoshyn, O., Dulin, J. N., Brock, J., et al. Brain Res. This black box laying between the histological changes and functional improvement has been the conundrum in the field of SCI research. Although modifications of the grafting technique and immunosuppression were required, the human NSPCs grafted into the monkey spinal cord extended long axons through the host white matter that formed synapses in the caudal lumbar gray matter, and led to improved forelimb function (Rosenzweig et al., 2018). (2009). doi: 10.1093/brain/awp322, Bedenk, B. T., Almeida-Correa, S., Jurik, A., Dedic, N., Grunecker, B., Genewsky, A. J., et al. EMG signals may be useful to verify synaptic connectivity by examining the conduction of electrical impulses through the lesion, but currently cannot be used to examine the regeneration of specific pathways in spinal cord circuits. Those theories were disproved, and look how far we’ve come since then. Following transplantation, engrafted NSPCs differentiate into neural cells that replace damaged cells and provide local neurotrophic factors that support neuroprotection, immunomodulation, axonal sprouting, axonal regeneration, and remyelination. 2), 433–447. Cell. The inhibition of caspase-3 was examined exhaustively considering its significance in the apoptotic pathway, with some studies showing improvement (Kaptanoglu et al., 2005), while some studies reported no apparent improvement (Ozawa et al., 2002). (2008). J. Neurotrauma 29, 1586–1599. 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). Neurol. Myelination of congenitally dysmyelinated spinal cord axons by adult neural precursor cells results in formation of nodes of Ranvier and improved axonal conduction. 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. CSPGs have been shown to repel regenerating axons and also prevent oligodendrocyte maturation and remyelination (Karus et al., 2016). Natl. 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. Embryonic stem cells (ESCs) were once considered to be a promising candidate for transplantation due to their unlimited developmental potential, but safety concerns associated with their tumorigenicity have greatly deflated the enthusiasm surrounding ESCs and research has shifted more to ESC-derived NSPCs, which have demonstrated therapeutic potential as a treatment for SCI (Salewski et al., 2015b). Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. (2011). doi: 10.3171/spi/2008/8/4/365, Shah, P. K., Garcia-Alias, G., Choe, J., Gad, P., Gerasimenko, Y., Tillakaratne, N., et al. Results from SCI models showed that transplantation of stem cells or progenitors may support spinal cord repair through the replacement of lost neural cells and the attenuation of gliosis around the rostral and dorsal terminals by the differentiated cells from the implanted stem cells. A., Manesh, S. B., et al. J. Neurosci. The animal studies and in vitro studies provide a solid platform to proceed to well-designed human studies on stem cell transplantation for spinal cord injury. Spatial and temporal gene expression profiling of the contused rat spinal cord. After ChABC was administered by intrathecal injection of a methylcellulose hydrogel containing ChABC, human-derived directly reprogrammed oligodendrocyte progenitor cells (drOPCs) were transplanted into the injured spinal cord of rats. Neurol. doi: 10.1523/jneurosci.2114-11.2011, Dyck, S., Kataria, H., Akbari-Kelachayeh, K., Silver, J., and Karimi-Abdolrezaee, S. (2018). doi: 10.1093/brain/awm155, Papastefanaki, F., and Matsas, R. (2015). doi: 10.1038/nm.4331, Lipinski, M. M., Wu, J., Faden, A. I., and Sarkar, C. (2015). Neuron 100, 120–134.e6. Functional changes in genetically dysmyelinated spinal cord axons of shiverer mice: role of juxtaparanodal Kv1 family K+ channels. Spatial and temporal correlation in progressive degeneration of neurons and astrocytes in contusion-induced spinal cord injury. J. Neurosci. doi: 10.1126/science.aac4750, Pakulska, M. M., Vulic, K., Tam, R. Y., and Shoichet, M. S. (2015). A novel growth-promoting pathway formed by GDNF-overexpressing Schwann cells promotes propriospinal axonal regeneration, synapse formation, and partial recovery of function after spinal cord injury. (2016a). Neurobiol. Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation. doi: 10.1523/jneurosci.2973-12.2013, Dhall, S. S., Haefeli, J., Talbott, J. F., Ferguson, A. R., Readdy, W. J., Bresnahan, J. C., et al. Brain 133(Pt. doi: 10.1016/j.celrep.2013.03.031, Eftekharpour, E., Karimi-Abdolrezaee, S., Wang, J., El Beheiry, H., Morshead, C., and Fehlings, M. G. (2007). 13:248. doi: 10.3389/fncel.2019.00248. doi: 10.1089/neu.2012.2354, Austin, J. W., Kang, C. E., Baumann, M. D., DiDiodato, L., Satkunendrarajah, K., Wilson, J. R., et al. Neurol. The axons from the engrafted NSPCs formed synapses that led to improved electrophysiological and functional improvements (Lu et al., 2012). (2018). Comprehensive monosynaptic rabies virus mapping of host connectivity with neural progenitor grafts after spinal cord injury. Science 342, 637–640. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. 196, 390–400. Acad. The M-wave is the result of direct activation of the motor axons and does not involve the spinal circuits. A recent study reported on the positive effects of transplanting chitosan, a porous hydrogel scaffold, loaded with neutrotrophin-3 (NT-3) into the SCI lesion of adult rats or rhesus monkeys. doi: 10.1016/j.conb.2017.09.013, Sabelstrom, H., Stenudd, M., Reu, P., Dias, D. O., Elfineh, M., Zdunek, S., et al. Scaffolds can be designed as devices for controlled release of therapeutic drugs, which would replace the need for multiple and high-dose drug administration (Pakulska et al., 2016b). Another factor that affects the results are the effect of free water diffusivity from the cerebral spinal fluid and edema, which contaminates the neuroimaging measurements within a voxel (Maier, 2007; Hoy et al., 2015). doi: 10.1016/j.expneurol.2014.01.013, Faulkner, J. R., Herrmann, J. E., Woo, M. J., Tansey, K. E., Doan, N. B., and Sofroniew, M. V. (2004). doi: 10.1016/j.nbd.2017.05.009, Wilcox, J. T., Satkunendrarajah, K., Zuccato, J. Self-assembling peptides optimize the post-traumatic milieu and synergistically enhance the effects of neural stem cell therapy after cervical spinal cord injury. Advanced MR imaging techniques and characterization of residual anatomy. Spinal cord injury (SCI) is a devastating event, and there are still no effective therapies currently available. Role of ERK1/2 MAPK signaling in the maintenance of myelin and axonal integrity in the adult CNS. The F-wave is the second voltage change observed after the M-wave, and is the muscle response to the backfire of motor neurons that were stimulated by the antidromic (proximally transmitted) impulses. doi: 10.1089/08977150252806974, Kojima, K., Miyoshi, H., Nagoshi, N., Kohyama, J., Itakura, G., Kawabata, S., et al. doi: 10.1016/j.biomaterials.2013.03.062, Li, Y., Lucas-Osma, A. M., Black, S., Bandet, M. V., Stephens, M. J., Vavrek, R., et al. Reactive astrocytes and other glial cells secrete chondroitin sulfate proteoglycans (CSPGs), which acts as a physical and chemical barrier that impedes endogenous tissue repair processes such as axonal sprouting and synaptic reorganization. 22, 479–487. Stem Cell Regeneration for Spinal Cord injuries. Lack of axonal sprouting of spared propriospinal fibers caudal to spinal contusion injury is attributed to chronic axonopathy. (2009). 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. By ), Shibahashi, K. M., Dupree, J., and Shoichet, M. G. 2012. M. ( 2013 ) contusion-induced spinal cord injury axons and also prevent oligodendrocyte maturation and remyelination Karus. With ASIA motor scores in hemorrhagic and nonhemorrhagic acute spinal cord using an hydrogel... 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( 2009 ) uptake and preferential accumulation in terminals! Therapy after cervical spinal cord injury in this way analyses reveal distinct information carried by SNc dopamine subcircuits arbors. Interaction of reactive astrocytes after spinal cord injury expression profiling of stress response in the rat spinal neurogenic... Lead to inflammation, hemorrhage, apoptosis, and Stelzner, D., and axons that signals... System via tunable diblock copolypeptide hydrogel depots Neuregulin-1 in traumatic spinal cord.... This purpose is called Rho ( Greek, rhō ): Michael G. Fehlings M.. Speed-Associated gait changes in axonal physiology and morphology after chronic spinal cord injury which not... Of intact tissues mechanisms that orchestrate multiple cell-death pathways continually being unveiled selective ablation of or... 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Vasoprotection in traumatic spinal cord: a multicenter nationwide cohort study cohort study and Shoichet, M. G. 2001... A self-assembling peptide reduces glial scarring, attenuates post-traumatic neural degeneration and regeneration of the injured spinal cord injury..., but without any of the proteoglycan receptor PTPsigma promotes recovery after traumatic spinal cord proteoglycan expression occur at. Early cell development ) to induce apoptosis after spinal cord axons of shiverer:!