You are standing in the middle of King’s Cross with a postcode in your hands, your feet trodden on by the busy crowd. So much has changed since you were last here 20 years ago, and every way you go seems to meet frowning faces set in their own path. By a lucky coincidence, somebody recognizes you and shakes your hand—they are going the same way. What are the odds! “Thank you”, you mutter, “you are a star”.
Through thistles and thorns
Spinal cord injury (SCI) leaves patients isolated from their own bodies with devastating life-long consequences. The limited nature of adult human spinal cord repair is frustrating but understandable from a developmental point of view. If fasciculis gracilis, a tract of the spinal cord responsible for lower limb sensations that relays touch from the foot, gets traumatically disrupted, the dorsal root ganglion (DRG) cell axon would not only have to cross over the site of injury, but also find the correct path all the way up—up to 50 cm in a tall individual. Even if that tremendous task is accomplished, there still remains the challenge of finding the correct second order neuron of the nucleus gracilis that, in turn, connects to the third order thalamic neuron transmitting signals to the part of the somatosensory cortex representing that foot. Not something that can be easily done without help.
On the way to connectivity restoration
It has been noted that:
The three main aims of [axon regeneration] research are: to initiate and maintain axonal growth and elongation; to direct regenerating axons to reconnect with their target neurons; and to reconstitute original circuitry (or the equivalent), which will ultimately lead to functional restoration. Although many interventions have now been reported to promote functional recovery after experimental SCI, none has fulfilled all three of these aims. In fact, only the first aim has been extensively studied and convincingly demonstrated.1
Indeed, even though the possibility of axon regrowth in the adult mammalian nervous system has been shown, the evidence supporting neuronal connectivity restoration is rarely convincing. Without careful guidance, aberrant axonal regrowth is a serious obstacle to functional regeneration.2,3
Interestingly, long-distance regeneration of axons is not the only mechanism through which normal spinal cord function can be restored. Injury is known to induce plasticity by several mechanisms including unmasking inactive spared pathways, compensatory collateral sprouting from the intact pathways, or an increase in receptor number due to denervation hypersensitivity.1,4. For example, Hofstetter et al. commented that:
Excessive local sprouting in our present study might have facilitated the formation of [novel corticospinal tract] pathways, although we could not detect a correlation between the amount of local sprouting and motor recovery.5
Whilst researchers are trying to find a way to artificially guide axons to their correct targets and induce plasticity, there is a cell type that routinely orchestrates these processes. Astrocytes express a range of axon-attractive and repulsive molecules that are crucial for proper development and adult nervous system plastic reorganisation.6,7 They provide a physical adherent substrate for growing neurons,8 secrete extracellular neuro-attractants like vimentin9 and repellents like chondroitin sulphate proteoglycans (CSPGs)10 and semaphorins.11
A scar or a star?
The neurocentric paradigm considered astrocytes to be a barrier to healing after the SCI for almost a century12 despite the lack of evidence that purely neuron-based therapies are sufficient for full regeneration. However, if the derogatory-dubbed astrocytic scar is removed or prevented from forming in the SCI context, not only do axons fail to spontaneously regrow through the lesion, they also become unable to regrow upon delivery of stimulating growth factors that promote growth in the presence of astrocytes.
Anderson et al. show that astrocytes are not responsible for the bulk of the inhibitory CSPG production after the SCI lesion, as hypothesized previously, but instead provide crucial axon-supporting molecules.13 The injury environment primes reactive astrocytes to re-express developmental synaptogenic molecules such as thrombospondin-1 that result in protective neuroplasticity.14
Not all are created equal
Despite these recent discoveries, skepticism towards astrocyte-based therapies prevails. To exacerbate this view, several studies that used neural stem cell (NSC) transplantation in an attempt to repair spinal cord damage observed neuropathic pain development that correlates with the astrocytic differentiation of NSCs.5,15
Nevertheless, it is becoming clear that the astrocytic population is far from homogeneous. Subsets of astrocytes with different permissive and restrictive qualities towards the growth of specific types of axons are found within different regions of the spinal cord that guide region-specific development of sensory and motor axonal tracts.11 Not surprisingly, certain astrocytic types are more selective towards regeneration and plasticity of specific types of neurons.
Davies at al. have discovered that astrocytes pre-differentiated from embryonic glial-restricted precursors (GRPs) (GRP-derived astrocytes or GDAs) are capable of promoting axonal regrowth alongside functional recovery and prevention of axotomized neuron atrophy upon transplantation in rodents with SCI, where this method supersedes transplantation of undifferentiated neural precursors.16
Importantly, the method of astrocytic differentiation of precursor cells plays a crucial role in determining their regenerative capacity. If bone morphogenic protein-4 (BMP4) is used in GDA astrogenesis, the resulting population creates a strongly supportive environment upon transplantation. In contrast, the same GRPs treated with ciliary neurotrophic factor (CNTF) have poor locomotor regenerative properties, but induce active calcitonin-gene-related peptide (CGRP)-positive nociceptive c-fiber sprouting that is associated with allodynia.17
This raises the possibility that the inflammatory environment of the injured spinal cord promotes differentiation of endogenous and transplanted astrocytes into the subtype that is not optimal for rubrospinal or dorsal column tract axon restoration, but, in turn, may be selectively supportive to pain-conducting c-fibers.
In addition to transplantation strategies, modification of endogenous astrocyte function can be employed. For example, oral administration of denosomin results in functional recovery in mice after SCI through increases in astrocyte proliferation, survival, and vimentin secretion that promotes locomotor raphespinal axon outgrowth.18
Learning from the experts
Finally, it is noteworthy that astrocytic subtypes that promote recovery appear to physically realign local astrocytic processes in a linear fashion.16 Authors speculate that this linear organization provides more straightforward routes for regenerating axons to follow. Another exciting and unexplored possibility is that these astrocytes help to restore the endogenous astrocytic network function that gets disrupted by the injury, whilst beneficial neuroplasticity is its natural corollary.
Stepping back from the exclusively neurocentric view of SCI may allow for unexpected advances in functional restoration. Ultimately, the bulk of research on the intricacies of axonal guidance and plastic synapse rearrangement is an attempt at recapitulation of normal astrocytic functions. When offered a helping hand, take it, and see where it leads you.
References
Bradbury EJ, McMahon SB. Spinal cord repair strategies: why do they work? Nat Rev Neurosci. 2006;7(8):644–53. doi: 10.1038/nrn1964.
Pernet V, Schwab ME. Lost in the jungle: New hurdles for optic nerve axon regeneration. Vol. 37, Trends in Neurosciences. 2014. p. 381–7. doi: 10.1016/j.tins.2014.05.002.
Smith GM, Falone AE, Frank E. Sensory axon regeneration: Rebuilding functional connections in the spinal cord. Vol. 35, Trends in Neurosciences. 2012. p. 156–63. doi: 10.1016/j.tins.2011.10.006.
Weidner N, Tuszynski MH. Spontaneous plasticity in the injured spinal cord — Implications for repair strategies. Mol Psychiatry. 2002;(7):9–11. doi: 10.1038/sj.mp.4001983.
Hofstetter CP, Holmström N a V, Lilja J a, Schweinhardt P, Hao J, Spenger C, et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005;8(3):346–53. doi: 10.1038/nn1405.
Allen NJ, Barres BA. Signaling between glia and neurons: Focus on synaptic plasticity. Vol. 15, Current Opinion in Neurobiology. 2005. p. 542–8. doi: 10.1016/j.conb.2005.08.006.
Freeman MR. Sculpting the nervous system: Glial control of neuronal development. Curr Opin Neurobiol. 2006;16(1):119–25. doi: 10.1016/j.conb.2005.12.004.
Fallon JR. Preferential outgrowth of central nervous system neurites on astrocytes and Schwann cells as compared with nonglial cells in vitro. J Cell Biol. 1985;100(1):198–207. PMID: 3880751.
Shigyo M, Tohda C. Extracellular vimentin is a novel axonal growth facilitator for functional recovery in spinal cord-injured mice. Sci Rep. 2016;6(February):28293. doi: 10.1038/srep28293.
Wang H, Katagiri Y, McCann TE, Unsworth E, Goldsmith P, Yu Z-X, et al. Chondroitin-4-sulfation negatively regulates axonal guidance and growth. J Cell Sci. 2008;121(18):3083–91. doi: 10.1242/jcs.032649.
Molofsky A V, Kelley KW, Tsai H-H, Redmond SA, Chang SM, Madireddy L, et al. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature. 2014;509(7499):189–94. doi: 10.1038/nature13161.
Chu T, Zhou H, Li F, Wang T, Lu L, Feng S. Astrocyte transplantation for spinal cord injury: Current status and perspective. Vol. 107, Brain Research Bulletin. 2014. p. 18–30. doi: 10.1016/j.brainresbull.2014.05.003.
Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016;0(1):1–20. doi: 10.1038/nature17623.
Tyzack GE, Sitnikov S, Barson D, Adams-Carr KL, Lau NK, Kwok JC, et al. Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression. Nat Commun. 2014;5:4294. doi: 10.1038/ncomms5294.
Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR, Kurpad SN. Pain with no gain: Allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol. 2006;201(2):335–48. doi: 10.1016/j.expneurol.2006.04.035.
Davies JE, Huang C, Proschel C, Noble M, Mayer-Proschel M, Davies SJA. Astrocytes derived from glial-restricted precursors promote spinal cord repair. J Biol. 2006;5(3):7. doi: 10.1186/jbiol35.
Davies JE, Pröschel C, Zhang N, Noble M, Mayer-Pröschel M, Davies SJA. Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury. J Biol. 2008;7(7):24. doi: 10.1186/jbiol85.
Teshigawara K, Kuboyama T, Shigyo M, Nagata A, Sugimoto K, Matsuya Y, et al. A novel compound, denosomin, ameliorates spinal cord injury via axonal growth associated with astrocyte-secreted vimentin. Br J Pharmacol. 2013;168(4):903–19. doi: 10.1111/j.1476-5381.2012.02211.x.
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