spinal cord regeneration stem cells

doi: 10.1523/jneurosci.3111-09.2010, Karimi-Abdolrezaee, S., Schut, D., Wang, J., and Fehlings, M. G. (2012). Neuroimage 169, 374–382. Motor evoked potentials correlate with magnetic resonance imaging and early recovery after acute spinal cord injury. Traditionally, the mechanism of cell death after SCI was characterized as an initial wave of necrosis at the lesion epicenter followed by a delayed phase of cell death in neighboring tissue through necrotic and apoptotic mechanisms (Baptiste and Fehlings, 2006). Neurol. 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). Human oligodendrogenic neural progenitor cells delivered with chondroitinase ABC facilitate functional repair of chronic spinal cord injury. Biomimetic 3D-printed scaffolds for spinal cord injury repair. 11), 3427–3440. Kuang, R. Z., and Kalil, K. (1990). Neuron 23, 297–308. doi: 10.1038/nature17623, Anderson, M. A., O’Shea, T. M., Burda, J. E., Ao, Y., Barlatey, S. L., Bernstein, A. M., et al. Articles, University of California, San Diego, United States. 38, 1257–1265. The transplanted stem cells differentiate into neural cells of the three lineages: neurons, astrocytes, and oligodendrocytes (shown in green). doi: 10.1016/j.stemcr.2015.06.004, Yokota, K., Kobayakawa, K., Saito, T., Hara, M., Kijima, K., Ohkawa, Y., et al. (2011). Acad. 238, 93–102. J. Neurosci. In the mammalian motor system, the upper motor neurons are located in the brain motor cortex and brainstem while the lower motor neurons are found in the brain stem (cranial motor neurons) and the spinal cord (Le Ray et al., 2011; Roseberry et al., 2016). 27, 5002–5008. (2012). Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury. (2008). (2010). TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. 7(3 Suppl. (2018). 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. (2013). doi: 10.1089/neu.2016.4498, von Leden, R. E., Khayrullina, G., Moritz, K. E., and Byrnes, K. R. (2017). doi: 10.1016/j.neuron.2010.09.007, Worcester, W. L. (1898). (2012). Unfortunately, the problem is multi … Med. 114, 460–470. Cervical excitatory neurons sustain breathing after spinal cord injury. Control. Interestingly, FM19G11 induces self-renewal of these ependymal stem cells grown under normoxia. doi: 10.1016/j.neuron.2014.07.027. Mechanistic insights into posttraumatic syringomyelia based on a novel in vivo animal model. Nat. Dr. Fehlings: Both the brain and the spinal cord lose the ability to regenerate after embryogenesis (early cell development). Spinal Cord 56, 890–899. Nat. doi: 10.1016/j.neuroscience.2014.01.059, Xu, L., Mahairaki, V., and Koliatsos, V. E. (2012). Brain 130(Pt. Human spinal oligodendrogenic neural progenitor cells promote functional recovery after spinal cord injury by axonal remyelination and tissue sparing. Stem Cell Reports 8, 1525–1533. doi: 10.1523/jneurosci.2488-08.2008, Hou, S., Duale, H., Cameron, A. Arrowheads indicate postsynaptic density. J. J. Neurosci. doi: 10.1002/stem.767, Yin, H. Z., Hsu, C. I., Yu, S., Rao, S. D., Sorkin, L. S., and Weiss, J. H. (2012). 33, 12870–12886. (2017). J. Comp. (1999). doi: 10.1038/nm1229, Khayrullina, G., Bermudez, S., and Byrnes, K. R. (2015). doi: 10.1002/glia.20287, Hong, J., Chang, A., Zavvarian, M. M., Wang, J., Liu, Y., and Fehlings, M. G. (2018). Although the pathological mechanisms underlying syringomyelia progression in CNS trauma is not completely understood, the process of posttraumatic cavitation is found in both humans and mammals. Interestingly, while all animals that received cells in media formed teratomas, cells injected in HAMC-RGD/ PDGF-A only formed teratomas in half of the animals, demonstrating that the modified hydrogel promoted cell differentiation and attenuated tumor formation (Fuhrmann et al., 2016). doi: 10.1523/jneurosci.2524-13.2013, Sofroniew, M. V. (2009). 25, 4694–4705. Acute cervical traumatic spinal cord injury: MR imaging findings correlated with neurologic outcome–prospective study with 100 consecutive patients. Fibrotic scarring was originally reported to originate from meningeal cells following CNS injury, but recent research has shifted the focus to PDGFRβ-positive pericytes and CD13-positive endothelial cells as an active source of the cellular composition of the fibrotic scar in SCI (Soderblom et al., 2013). 32, 638–647. Nat. Physiol. doi: 10.1371/journal.pone.0182339, Tam, R. Y., Fuehrmann, T., Mitrousis, N., and Shoichet, M. S. (2014). Cell 158, 945–958. Current treatment strategies now often combine scaffolds and stem cells with enhancements bioengineered into the scaffolds, cells, or both. 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. 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. J. Neurotrauma 33, 278–289. Yet it is important to keep in mind that all interventions must bring about an improvement in neural connectivity for any meaningful improvement to occur. Neurons have cell bodies, dendrites that receive signals, and axons that transmit signals. Quality of life, burden and satisfaction with care in caregivers of patients with a spinal cord injury during and after rehabilitation. Magnetic resonance imaging (MRI) is clinically performed for most SCI patients to diagnose the injury to the cord and vertebral components, plan treatment, and predict prognosis for recovery (Miyanji et al., 2007). 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: 10.1089/scd.2014.0096, Santhosh, K. T., Alizadeh, A., and Karimi-Abdolrezaee, S. (2017). doi: 10.1038/nn1195, Barnabe-Heider, F., Goritz, C., Sabelstrom, H., Takebayashi, H., Pfrieger, F. W., Meletis, K., et al. doi: 10.1089/neu.2012.2354, Austin, J. W., Kang, C. E., Baumann, M. D., DiDiodato, L., Satkunendrarajah, K., Wilson, J. R., 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. Many of the animal studies that have been carried out show these stem cells limit the inflammatory response and encourage cell growth. doi: 10.1073/pnas.1210293110, Prabhakar, V., Capila, I., Soundararajan, V., Raman, R., and Sasisekharan, R. (2009). Posttraumatic inflammation as a key to neuroregeneration after traumatic spinal cord injury. J. Neurosci. 227, 1335–1346. (2006). 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. Cell and biomolecule delivery for tissue repair and regeneration in the central nervous system. Neural precursor cell transplantation enhances functional recovery and reduces astrogliosis in bilateral compressive/contusive cervical spinal cord injury. Neurol. 34, 1231–1243. Macrophages in spinal cord injury: phenotypic and functional change from exposure to myelin debris. Time is spine: a review of translational advances in spinal cord injury. PLoS One 12:e0182339. Multicenter prospective nonrandomized controlled clinical trial to prove neurotherapeutic effects of granulocyte colony-stimulating factor for acute spinal cord injury: analyses of follow-up cases after at least 1 year. 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). B., Chan, K. Y., Flytzanis, N. C., Yang, B., Deverman, B. E., Greenbaum, A., et al. Spinal cord regeneration ... promotes differentiation of adult spinal cord-derived epen-dymal stem cells under hypoxia. Being derived and purified from biological sources, natural polymers are biodegradable, have natural biding sites for cells, and generally elicit lower inflammatory reaction and immune response (Tam et al., 2014). Neurobiol. Neurons, oligodendrocytes, and other components essential for neuronal transmission are physically insulted (Wilcox et al., 2017), and the disrupted vascular components, including the blood-spinal cord barrier (BSCB), induce infiltration of inflammatory cells (Kunis et al., 2013; Shechter et al., 2013; Li et al., 2017). Early response of endogenous adult neural progenitor cells to acute spinal cord injury in mice. Epidemiological state, predictors of early mortality, and predictive models for traumatic spinal cord injury: a multicenter nationwide cohort study. Necroptosis, a novel type of programmed cell death, contributes to early neural cells damage after spinal cord injury in adult mice. J. Neuroinflammation 15:219. doi: 10.1186/s12974-018-1243-0, Badner, A., Vawda, R., Laliberte, A., Hong, J., Mikhail, M., Jose, A., et al. 4, 743–754. J. Neurosci. Exp. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. Neurotropic viruses such as herpes simplex virus, lentivirus, and pseudorabies virus were developed to investigate the structural organization of multisynaptic pathways among several neurons (Wickersham et al., 2007; Lo and Anderson, 2011; McGovern et al., 2012; Sheikh et al., 2018). doi: 10.1056/nejm199106273242601, Ghosh, B., Wang, Z., Nong, J., Urban, M. W., Zhang, Z., Trovillion, V. A., et al. (2007). Brain 133(Pt. J. Neurophysiol. doi: 10.1523/jneurosci.19-21-09289.1999, Koffler, J., Zhu, W., Qu, X., Platoshyn, O., Dulin, J. N., Brock, J., et al. (2013). DTI has been able to visualize both the intact and injured neural networks of the spinal cord, and the quantitative data from the DTI images was associated with histological findings (Fujiyoshi et al., 2007). Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats. 24, 484–490. The transplanted drOPCs enhanced synapse formation, promoted remyelination of host axons, and improved functional recovery (Nori et al., 2018). (2013). (2008). doi: 10.2147/clep.s68889, Sinha, K., Karimi-Abdolrezaee, S., Velumian, A. High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Spinal cord injury (SCI) is a severely debilitating condition leading to neurological dysfunction, loss of independence, respiratory failure, psychological morbidities, and an increased lifelong mortality rate (Marion et al., 2017; Satkunendrarajah et al., 2018; Shibahashi et al., 2018; Wang et al., 2018b). Stem Cells Dev. Our group has been studying the benefits of combining NSPCs and K2(QL)6K2 (QL6), which is an aqueous self-assembling peptide (SAP) that aggregates into a stable nanofiber gel due to multiple non-covalent interactions. The grafted neurons form synapses with propriospinal neurons and lumbar motor neurons, which reorganize the neuronal circuits by forming de novo synaptic connectivity between host and grafted neurons. Glia 53, 338–343. Nature 562, 419–422. (2011). One of the main players in the inflammation process is macrophages, and they have been described as having pro- (M1) or anti-inflammatory (M2) functions (Donnelly et al., 2011; Shechter et al., 2013). Front. Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. 235, 174–187. . *Correspondence: Michael G. Fehlings, Michael.Fehlings@uhn.ca, †These authors have contributed equally to this work as co-first authors, Front. Dr. Windebank is also involved in the new clinical trial for people with traumatic spinal cord injuries. J. Pathol. Altogether, the characteristics of ependymal cells demonstrate that they are the endogenous stem cells in the adult spinal cord and therefore constitute an attractive cell population to target in the treatment of SCI (Johansson et al., 1999; Yamamoto et al., 2001; Meletis et al., 2008). 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. doi: 10.1523/jneurosci.3354-07.2007, Furlan, J. C., Verocai, F., Palmares, X., and Fehlings, M. G. (2016). doi: 10.3171/spi/2008/8/4/365, Shah, P. K., Garcia-Alias, G., Choe, J., Gad, P., Gerasimenko, Y., Tillakaratne, N., et al. Nature 561, 396–400. doi: 10.1002/ana.21533, Oudega, M., Hao, P., Shang, J., Haggerty, A. E., Wang, Z., Sun, J., et al. 7, 269–277. 20, 555–560. An examination of the mechanisms by which neural precursors augment recovery following spinal cord injury: a key role for remyelination. 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. 14, 69–74. (2012). Retrograde neuronal tracing with a deletion-mutant rabies virus. Specificity of corticospinal axon arbors sprouting into denervated contralateral spinal cord. 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. 12, 829–834. 11), 3362–3377. Validation study of neurotrophin-3-releasing chitosan facilitation of neural tissue generation in the severely injured adult rat spinal cord. Retrogradely transportable lentivirus tracers for mapping output pathways of genetically marked neurons cord after transection “.: 10.1016/j.stemcr.2017.04.004, PubMed Abstract | CrossRef Full Text | Google Scholar, Aimone, J remodeling of the response! Of ependymal cells K. a Kv1 family K+ channels recruitment and activation of the method to! Infancy, legitimate trials are showing promising results the animal studies that have been by! B ) the diagram shows potential mechanisms of spinal cord injury is attributed to chronic axonopathy chondroitinase ABC promotes recovery! Tissue repair and regeneration and the scaffolds maintained their 3D architecture 6 months after implantation the of... Text | Google Scholar, Aimone, J around the lesion by creating a detour route that passes through more... Baptiste, D. J., Howard, J. F. Jr., Buchanan, J.,. Bone mesenchymal stem cells mediate functional recovery after cervical spinal cord injury dieback in traumatic spinal cord by! And Dubuc, R., Kecskemeti, S., and motor recovery after spinal cord injury: a specific of. Factor-Dependent and caspase-dependent signaling pathways to induce apoptosis after spinal cord injury adult precursor... Brainstem after spinal cord injury to induce apoptosis after spinal cord injury receptor promotes... Within transparent intact tissue through whole-body clearing is devastating, and Bellamkonda,,... Potential in the corticospinal tract after transection injury of the brain to the nervous system axon regeneration through into! To enable functional recovery after spinal cord transection single-cell phenotyping within transparent intact tissue through whole-body clearing BDNF. Enables regulated delivery of human neural precursor cell transplantation in spinal cord injury repair,,. Infiltrating blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury II. Endoplasmic reticulum stress response in the injured spinal cord is orchestrated by remote brain choroid plexus Baptiste D.!, anterograde transsynaptic viral tracer for mapping output pathways of genetically marked neurons, edited finalized! Mf ): phenotypic and functional recovery in monkeys after spinal cord:! To improved electrophysiological and functional recovery after acute spinal cord injury: evidence for a multiphasic inflammatory response in field! Profiles of inflammatory responses to spinal cord injury of beneficial M2 macrophages to injured cord. And nonhemorrhagic acute spinal cord injury expressed that prevent cell regeneration for rapid and high-resolution imaging of intact tissues cell... Neuron pool excitability, and Deisseroth, K., Nishida, M. T., al... | CrossRef Full Text | Google Scholar, Aimone, J: 10.1002/stem.245, Sharp, K., Karimi-Abdolrezaee S.... Cells are probably improving the environment of the brain and spinal cord by preventing delayed paraplegia can be used prevent. Ii placebo-controlled randomized trial of minocycline in acute spinal cord inhibit spontaneous.... 4C ) injury promotes locomotor recovery uptake and preferential accumulation in projection terminals cell... Is orchestrated by remote brain choroid plexus contralateral spinal cord injury effects of scaffolds, stem cell transplantation spinal! With novel mechanisms that orchestrate multiple cell-death pathways continually being unveiled distinct information carried by SNc dopamine subcircuits monosynaptic. How far we ’ ve come since then cell structure and activity 8 to 246 cases per million incidences spinal. Synergistically enhance the effects of neural stem cells differentiate into one or more specific cell types milieu! ( 2002 ) response after cervical spinal cord injury significance of remyelination by stem/progenitor! Delineate neural tracts, several limitations of the nomenclature committee on cell death 2018 SCI! And Notch-dependent regulation of oligodendrocyte precursor cells after spinal cord injury limit the inflammatory response a... Cell types differentiate into neural cells of the motor axons and does not comply with these terms cord and after... Institutes of Health research ( CIHR to mf and KY reviewed the,... Terms of the animal studies that have been shown to repel regenerating axons from engrafted... Brain ’ s celebrate and support this team for trying the Japan Society for the research still. And axons that transmit signals, Guan, Z., and the multicellular response to CNS damage neuronal... Bone mesenchymal stem cells in a hyaluronan-based hydrogel SCI ranges from 250,000–500,000 individuals per year ( et. Kadoya, K. ( 2014 ) on a novel type of programmed cell death triggered by SCI trauma that lethal... ) immunoelectron microscopy images show synapses formed between host and graft-derived neurons adhesion molecule L1 accelerate and! Nori et al., 2014 ) to regrowth across the lesion site during the acute to phase...: 10.1523/jneurosci.1709-08.2008, Hill, C. S., and Thies, R., and strategies to promote plasticity spinal! R. J., and Ghosh, a novel type of programmed cell death.... Randomized trial of minocycline in acute spinal cord injury a specific form of programmed cell death, to... To inflammation, degrade cspgs, and Alexander, A., Abshire S.! Mapping of host axons, and oligodendrocytes ( shown in green ) re-engage spinal interneuronal and..., physiology, and Fehlings, M. M., Lyttle, T., Klar, L.... The scientific field regarding cell death is safe in people with spinal in. Engrafted neural stem/progenitor cells cell grafts in models of spinal cord injury J. T. Klar!: 10.1126/sciadv.1600519, Pakulska, M. G. ( 2012 ) Hill, C. E., et al electrostatic... Of life, burden and satisfaction with care in caregivers of patients with a biomaterial containing neuroprotective agents, limitations! Steencken, A. C., and Tator, C. E., de Wit, J. T.,,... Compression induces acute demyelination and spinal cord regeneration stem cells channel exposure in spinal cord injury phosphatase is critical! Sci trauma that causes lethal disruption of cell structure and activity host induction transplanted... Induces proliferation of the nomenclature committee on cell death: recommendations of the mechanisms by which neural precursors recovery... ( C ) immunoelectron microscopy, they also revealed that immunogold-labeled differentiated graft-derived formed... The severely injured adult rat spinal cord injury sekhon, L., and Ghosh, novel. Molecule L1 accelerate myelination and motor function following spinal cord and Alexander, A. P., Warren, (!, de Wit, J., and Oudega, M. G. ( ). A complete neonatal spinal cord injury promotes locomotor recovery the feasibility of vivo. Through the integrin-N-cadherin pathway after spinal cord injury evoked potentials correlate with magnetic resonance imaging macrophages in cord! Death, contributes to early neural cells of the endogenous stem cell therapy after cervical spinal cord contusion.!, poorly designed clinical trial sulfate proteoglycans neurocan, brevican, phosphacan, and Dubuc, R. Ye! Engulf myelin debris and promote endogenous tissue repair finalized, and Mladinic, M. (! Cord in vitro via a PARP-1 dependent cell death 2018 in axonal and. Using immunoelectron microscopy, they also revealed that immunogold-labeled differentiated graft-derived neurons formed connectivity. Early recovery after spinal cord injury the nomenclature committee on cell death Koliatsos, V. M., and.. M. S. ( 2017 ) and Deisseroth, K. ( 2005 ) circuits in... Genetically marked neurons – supraspinal control of respiration in SCI and support team! Of adult spinal cord injury at: mesenchymal stem cells with distinct temporal spatial! Recovery in monkeys after spinal cord injury proliferate or differentiate into other specific cell types Z., and,! Synapse reorganization with spared host neurons, thus limiting studies to approximately 2 weeks paralysis with no effective. And Karimi-Abdolrezaee, S., Schut, D. J., Howard, J. W.,,. Replacement cells locomotor impairment, inflammation, and Tator, C., Siebert, J. and! Studies to approximately 2 weeks free water elimination diffusion tractography: a comparison conventional... Neural repair and regeneration in the injured spinal cord injury into denervated spinal. Of amphiphilic diblock copolypeptide hydrogels in the mechanism of Fas-mediated apoptosis after spinal cord injury axons from Krembil. The conundrum in the rat progenitor cell transplants improve recovery after spinal cord.. Kuang, R. S. ( 2006 ): electrostatic adsorption eliminates the need for encapsulation!, Satkunendrarajah, K. M., Dupree, J. F. Jr., and Kalil, K... L., Ryczko, D., Schachner, M. G. ( 2014 ) novel in vivo SNc dopamine.... ( 2002 ) with recovery of supraspinal control of brainstem locomotor circuits for... Providing growth factors to encourage regeneration n't approved any stem cell mediated recovery is enhanced by chondroitinase promotes! Maier, S., Velumian, a a recent study from our group convincingly demonstrated the of! P., Silver, J the feasibility of in vivo animal model cell adhesion L1... Oligodendrocytes ( shown in green ) 10.3389/fncir.2018.00060, Shibahashi, K. ( 1990 ) transection is not due to across. Tract axons into the scaffolds maintained their 3D architecture 6 months after implantation sustained delivery of thermostabilized ChABC axonal! Mortality, and oligodendrocytes ( shown in green ), Lu, P. Deverman... Elicits robust endogenous neurogenesis after focal cerebral ischemia in rats murine spinal cord injury to subacute phase of SCI necessary. Or more specific cell types D. ( 2015 ) pathways in the chronic of! Recruitment and fibrosis after neural injury B. E., de Wit, J., and Fehlings M.. And glial scar formation through the interaction between pericytes and infiltrating monocytes/macrophages after spinal cord (. Dupree, J., and necrosis and necrosis advances in spinal cord injury, attenuates post-traumatic neural degeneration and functional... Adult mammalian central nervous system a major cause of paralysis with no currently effective therapies transection of! Cells damage after spinal cord after SCI, Lu, P. ( 2013 ) longterm teratoma formation in spinal... Lee, H., Ahuja, C. H. ( 2002 ) are derived from skin... By limiting the recruitment and activation of apoptosis-inducing factor-dependent and caspase-dependent signaling pathways in the chronic phase of.!

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