One strategy for spinal cord injury repair is to make cellular bridges that support axon regeneration. However, the bridging cells often fail to integrate with host tissue and may lead to increased pain sensitivity. Recent work has tested bridging with two forms of progenitor-derived astrocyte. One type integrates, suppresses scar formation and promotes axon regeneration, whereas another very similar type, reported in Journal of Biology, does not support regeneration and increases pain sensitivity.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Fawcett, James W

Apollo (Cambridge)

MinireviewBridging spinal cord injuriesJames W FawcettAddress: Cambridge University Centre for Brain Repair, Robinson Way, Cambridge CB2 0PY, UK. Email: jf108@cam.ac.ukRepair of the injured spinal cord has been one of the greatquests of experimental neuroscience since Tello and Cajalfirst showed in 1903 that axons in the central nervoussystem (CNS) can be made to regenerate. Sadly, we have yetto achieve a treatment that is licensed for this purpose inhuman patients, although advances such as that describedby Davies et al. in this issue of the Journal of Biology [1] willhelp to bring this goal closer.One of the earliest concepts in spinal cord repair was tobuild a bridge across the injury that would provide a roadalong which regenerating axons could cross the injury siteto find suitable targets, form connections and restorefunction. This was first attempted by Peter Richardson, SamDavid and Albert Aguayo in 1981 [2,3], when theyimplanted grafts of peripheral nerve tissue (which ispermissive to axon regeneration) across a spinal injury.These experiments demonstrated both the possibilities andthe problems of the bridging concept. Axons regeneratedinto the grafts, but only from nearby neurons, and hardlyany of the axons could then leave the attractive environ-ment of the graft to re-enter CNS tissue. In terms of bridgedesign, axons could traverse the on-ramp to get into thegraft and they could grow across the bridge, but they gotstuck on the off-ramp. What was the problem? The first wasthat the Schwann cells - the supporting glial cells of theperipheral nervous system (PNS) - exert a honey-pot effect;growing axons are very good at selecting pathways and theywill seldom grow from a permissive PNS environment to aless permissive CNS one. The second was that Schwann cellswill not mix with astrocytes (the CNS glial cells), so a sharpcellular boundary of astrocytes reacting to the Schwann cellsblocks the off-ramp.Clearly, if the bridge concept is to work, we need to find abetter type of cell with which to construct the bridge. Thiscell type must integrate seamlessly into spinal cord tissue, itmust not stimulate a glial scar reaction and it mustpromote axon growth but not be so attractive that axonscannot pass on into the cord. Various cell types have beengrafted into the spinal cord in the hope that they wouldhave these properties, one of the most successful beingolfactory ensheathing glia [4]. In this issue of Journal ofBiology, Stephen Davies and co-workers [1] describe aparticular type of immature astrocyte that seems to providea very successful bridging material.The idea of using embryonic CNS tissue and embryonicastrocytes for repairing the spinal cord has a long history.Axons grow in the embryonic CNS, so why not transplantAbstractOne strategy for spinal cord injury repair is to make cellular bridges that support axonregeneration. However, the bridging cells often fail to integrate with host tissue and may leadto increased pain sensitivity. Recent work has tested bridging with two forms of progenitor-derived astrocyte. One type integrates, suppresses scar formation and promotes axonregeneration, whereas another very similar type, reported in Journal of Biology, does notsupport regeneration and increases pain sensitivity.Journal of Biology 2008, 7:25Published: 15 October 2008Journal of Biology 2008, 7:25 (doi:10.1186/jbiol89)The electronic version of this article is the complete one and can befound online at http://jbiol.com/content/7/7/25© 2008 BioMed Central Ltd embryonic spinal cord into injuries? Host axons regenerateinto these transplants, but seldom through them. In thegrafts they can connect to graft neurons, which in turn cansend their axons back into the host cord, the grafts acting asrelays [5]. If embryonic CNS tissue promotes growth, thentransplantation of embryonic glia is a logical next step, andthere are reports going back to 1990 using this strategy topromote axon regeneration [6].However, astrocytes are hugely diverse, some types beingpermissive to regeneration, others inhibitory. We now knowmuch more about the various subtypes of glia and theirdevelopmental profiles, so it is possible to be more specificabout which type of glial cell to transplant, and it is thisknowledge that has formed the basis for the work fromDavies and colleagues [1], who used immature glialprecursor cells whose differentiation they manipulated invitro. Various types of glial stem cell have been tried inearlier experiments, with mixed effects in the injured spinalcord. The transplants may protect the cord from secondarydegeneration after injury and may produce myelinatingcells, but they have not been very effective at promotingregeneration [7,8]. Indeed, Lars Olson and colleagues [9]report that stem cell transplants can stimulate sprouting ofsensory axons leading to allodynia - a condition in whichnormal sensory stimuli cause pain.In an earlier paper [10], Stephen Davies and collaboratorsreported the identification of a type of immature precursor-derived astrocyte that provides an excellent buildingmaterial for spinal cord bridges, produced by treating glial-restricted precursors with bone morphogenetic protein(BMP)-4. The cells migrate into host tissue and mix withhost glia while suppressing scar formation, and they promoteregeneration of sensory axons and improved locomotorfunction. It will be interesting to compare these cells withthe radial glial cells transplanted by the Grumet lab, whichalso had beneficial effects [11], and to see whether theypromote the regeneration of motor pathways.Davies and colleagues now report [1] the identification of aform of astrocyte, derived from exactly the same precursorpopulation as used previously [10], that integrates poorly,does not stimulate regeneration or recovery and, worse still,induces allodynia by increasing sprouting of pain fibers inthe dorsal horn of the spinal cord. These astrocytes wereproduced by treating the precursors with ciliary neuro-trophic factor (CNTF) and have many of the properties ofthe ‘type 2’ astrocyte identified in glial cultures. This isimportant progress because grafts of embryonic orundifferentiated cells might be expected to produce boththe good and bad types of astrocyte, and it emphasizes thatsmall differences between closely related cells can beassociated with very different potentials for CNS repair. Inthis context it is interesting that infusing a CNTF-neutralizingantibody into a spinal cord containing transplanted neuralstem cells reduced scarring and improved the outcome [12].The finding by Davies and colleagues [1] and in a previouspublication from the Olson lab [9] that a graft of the wrongtype of glial cells can produce allodynia is particularlyworrying. A third or more of spinal injury patients haveintractable and continuous pain following their injury,which in some cases never responds satisfactorily to treat-ment. Spinal injury researchers worry that treatments thatpromote axon regeneration might also cause sprouting ofpain fibers, making pain worse. Treating the injured spinalcord with nerve growth factor (NGF) can do this becausepain fibers express the NGF receptor trkA [13], but thefinding that glial transplants can cause a pain syndrome is ashock. It is not clear from either paper [1,9] why this mighthave happened, but Davies and colleagues [1] suggest thatactivation of microglia might be involved.If progenitor-derived astrocytes produced by BMP-4treatment are the cells we need in spinal cord injuries, howare we to get them there? In this paper [1] the cells werederived from spinal cord taken from rats at embryonic day13.5. Can they be derived from embryonic stem cells, orfrom induced pluripotent state cells taken from the patient?Or are there glial precursors in the injured cord that couldbe induced to produce the right cell type? There will alsohave to be a decision on whether the progenitor-derivedastrocyte is a more or less effective bridging cell than theolfactory ensheathing cell. From a practical point of view,cells derived in some way from individual patients willavoid the need for immunosuppression. However, suchautologous cells will not be available until some time afterinjury, and it will be important to know for how long afterdamage the transplants remain effective. Current work hasinvolved transplantation at the time of injury, which will bedifficult to achieve in human patients.There are several treatments under development for spinalcord injury, aimed at various mechanisms, including neutrali-zation of inhibitory molecules, promotion of plasticity,direct stimulation of axon regeneration, bridging andcontrol of inflammation. A combination of two or more ofthese approaches will be needed to achieve optimal spinalcord repair. So far there have been relatively few attempts atcombination treatments, mainly because most of theindividual treatments have not been fully optimized andbecause spinal repair experiments involving many experi-mental groups are very demanding. The work from Daviesand collaborators [1] and other groups in identifying anoptimized cell type for grafting into injuries is very25.2 Journal of Biology 2008, Volume 7, Article 25 Fawcett http://jbiol.com/content/7/7/25Journal of Biology 2008, 7:25welcome, and it should provide a transplant strategy thatcan be combined with other treatments.What do these findings mean for patients with spinal cordinjuries? Unfortunately they do not lead immediately to atreatment applicable to injured humans. However, graftingcells into injuries to suppress scarring and provide a bridgewill be an important component of a successful combinatorialtreatment, and the findings reported by Davies and colleagues[1] bring safe and efficacious grafts appreciably closer.References1. Davies JE, Pröschel C, Zhang N, Noble M, Mayer-Pröschel M,Davies SJ: Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recoveryand allodynia after spinal cord injury. J Biol 2008, 7:24.2. Richardson PM, McGuinness UM, Aguayo AJ: Axons from CNSneurons regenerate into PNS grafts. Nature 1980, 284:264-265.3. David S, Aguayo AJ: Axonal elongation into peripheral nervoussystem “bridges” after central nervous system injury in adult rats.Science 1981, 214:931-933.4. Raisman G: Olfactory ensheathing cells - another miracle cure forspinal cord injury? Nat Rev Neurosci 2001, 2:369-375.5. Bregman BS, Kunkel-Bagden E, Reier PJ, Dai HN, McAtee M, GaoD: Recovery of function after spinal cord injury: mechanismsunderlying transplant-mediated recovery of function differ afterspinal cord injury in newborn and adult rats. Exp Neurol 1993,123:3-16.6. Kliot M, Smith GM, Siegal JD, Silver J: Astrocyte polymer implantspromote regeneration of dorsal-root fibers into the adult mammalianspinal-cord. Exp Neurol 1990, 109:57-69.7. Hill CE, Pröschel C, Noble M, Mayer-Pröschel M, Gensel JC, BeattieMS, Bresnahan JC: Acute transplantation of glial-restricted precursorcells into spinal cord contusion injuries: survival, differentiation andeffects on lesion environment and axonal regeneration. Exp Neurol2004, 190:289-310.8. Nakamura M, Okano H, Toyama Y, Dai HN, Finn TP, Bregman BS:Transplantation of embryonic spinal cord-derived neurospheressupport growth of supraspinal projections and functional recoveryafter spinal cord injury in the neonatal rat. J Neurosci Res 2005,81:457-468.9. Hofstetter CP, Holmstrom NA, Lilja JA, Schwainhardt P, Hao J,Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisen J, Olson L:Allodynia limits the usefulness of intraspinal neural stem cell grafts;directed differentiation improves outcome. Nat Neurosci 2005,8:346-353.10. Davies JE, Huang C, Pröschel C, Noble M, Mayer-Pröschel M,Davies SJ: Astrocytes derived from glial-restricted precursorspromote spinal cord repair. J Biol 2006, 5:7.11. Hasegawa K, Chang YW, Li H, Berlin Y, Ikeda O, Kane-GoldsmithN, Grumet M: Embryonic radial glia bridge spinal cord lesions andpromote functional recovery following spinal cord injury. ExpNeurol 2005, 193:394-410.12. Ishii K, Nakamura M, Dai H, Finn TP, Okano H, Toyama Y, BregmanBS: Neutralization of ciliary neurotrophic factor reduces astrocyteproduction from transplanted neural stem cells and promotesregeneration of corticospinal tract fibers in spinal cord injury. JNeurosci Res 2006, 84:1669-1681.13. Romero MI, Rangrappa N, Li L, Lightfoot S, Garry MG, Smith GM:NGF gene transfer induces extensive sprouting of sensory spinalcord afferents and hyperalgesia which can be modulated by theconditional expression of L1. Soc Neurosci Abstr 1999, 25:2031.http://jbiol.com/content/7/7/25 Journal of Biology 2008, Volume 7, Article 25 Fawcett 25.3Journal of Biology 2008, 7:25

Bridging spinal cord injuries.

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