Axonal growth therapeutics: regeneration or sprouting or plasticity?

Cafferty, William B. J.; McGee, Aaron W.; Strittmatter, Stephen M.

doi:10.1016/j.tins.2008.02.004

Cited by 142 publications

(110 citation statements)

References 74 publications

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“…Recent mounting evidence suggests that there exists more intrinsic regenerative potential in the adult spinal cord than originally postulated. Specifically, axonal growth responses were observed in adult spinal cords after various interventions in animal models [56]. In clinical practice, modest neurological recovery was seen with rehabilitation or pharmacologic agents in chronic SCI patients [2,57].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

et al. 2013

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The transplantation of neural stem/precursor cells (NSPCs) is a promising therapeutic strategy for many neurodegenerative disorders including spinal cord injury (SCI) because it provides for neural replacement or trophic support. This strategy is now being extended to the treatment of chronic SCI patients. However, understanding of biological properties of chronically transplanted NSPCs and their surrounding environments is limited. Here, we performed temporal analysis of injured spinal cords and demonstrated their multiphasic cellular and molecular responses. In particular, chronically injured spinal cords were growth factorenriched environments, whereas acutely injured spinal cords were enriched by neurotrophic and inflammatory factors. To determine how these environmental differences affect engrafted cells, NSPCs transplanted into acutely, subacutely, and chronically injured spinal cords were selectively isolated by flow cytometry, and their whole transcriptomes were compared by RNA sequencing. This analysis revealed that NSPCs produced many regenerative/ neurotrophic molecules irrespective of transplantation timing, and these activities were prominent in chronically transplanted NSPCs. Furthermore, chronically injured spinal cords permitted engrafted NSPCs to differentiate into neurons/oligodendrocytes and provided more neurogenic environment for NSPCs than other environments. Despite these results demonstrate that transplanted NSPCs have adequate capacity in generating neurons/oligodendrocytes and producing therapeutic molecules in chronic SCI microenvironments, they did not improve locomotor function. Our results indicate that failure in chronic transplantation is not due to the lack of therapeutic activities of engrafted NSPCs but the refractory state of chronically injured spinal cords. Environmental modulation, rather modification of transplanting cells, will be significant for successful translation of stem cell-based therapies into chronic SCI patients.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

et al. 2013

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“…over the past decade, increasing evidence has attributed the failure of axonal regrowth after SCi to limited intrinsic neuronal plasticity and the local non-permissive microenvironment including myelin-associated growth inhibitors as well as the glial scar [86,87] . inhibition of glial scar formation by deleting key signals that mediate the process has shown an overt facilitation of the affected axon regrowth.…”

Section: Influence On Axonal Growthmentioning

confidence: 99%

The glial scar in spinal cord injury and repair

2013

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Glial scarring following severe tissue damage and inflammation after spinal cord injury (SCi) is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarring process includes the misalignment of activated astrocytes and the deposition of inhibitory chondroitin sulfate proteoglycans. Here, we first discuss recent developments in the molecular and cellular features of glial scar formation, with special focus on the potential cellular origin of scar-forming cells and the molecular mechanisms underlying glial scar formation after SCi. Second, we discuss the role of glial scar formation in the regulation of axonal regeneration and the cascades of neuro-inflammation. Last, we summarize the physical and pharmacological approaches targeting the modulation of glial scarring to better understand the role of glial scar formation in the repair of SCi.Keywords: glial scar; spinal cord injury; axonal regeneration; astrocyte activation; reactive astrogliosis; neuroinflammation IntroductionSpinal cord injury (SCi) is a common and devastating central nervous system (CNS) insult that results in disruption of cord microstructure and is followed by limited neuronal regeneration and insufficient functional recovery in adult mammals. After severe SCi, and in response to changes in the local microenvironment, astrocytes, the most abundant glial cells in the CNS, transform into reactive astrocytes and undergo dramatic morphological changes [1] as well as massive variations in gene expression [2] . Reactive astrocytes, the major component of glial scars, along with other cells in the spinal cord and blood-borne cells leaking from the damaged blood-spinal cord barrier, participate in the process of scar formation [3] .From the historical perspective, a glial scar is recognized as an impediment to the regeneration of axons in the cord because of the irregular rearrangement of hypertrophic astrocytic processes, as well as major components of the axonal inhibitory extracellular matrix (ECM), including chondroitin sulfate proteoglycans (CSPGs) that are secreted by the reactive astrocytes [4] . Currently, increasing evidence is advancing our knowledge of the mechanism of the formation of glial scars after a lesion and the roles of glial scars in the regulation of neuro-inflammation and repair processes [5,6] .This article reviews the following: (1) the molecular and cellular properties of glial scar formation following SCi;(2) the roles of glial scar formation in axonal regeneration and neuro-inflammation; and (3) the current status of scarmodulating therapeutic strategies for spinal cord repair after injury. Molecular and Cellular Properties of Glial Scars Characterization of Glial ScarsTraumatic damage of the spinal cord can result in seallike scar tissue in the lesion zone, which is filled with dense cellular components and a connective matrix. Generally, the scar tissue is classified into two parts, fibrotic and glial. 422The fibrotic scar, primarily composed of invading fibrobl...

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“…The degree of functional recovery following SCI depends on the reorganization of neuronal circuits by synaptic plasticity and collateral sprouting of injured and healthy descending tracts. 29,30 To examine the effect of Gal-1 treatment in the regeneration of injured axons, we performed immunohistochemical analysis using the specific neuronal marker bIII-tubulin and the axonal markers Neurofilament-M (NF-M) and axonal microtubule-stabilizing protein Tau-1. 31 The grey matter of vehicle-treated Lgals1 À / À mice exhibited no neurite regeneration at the epicenter of the lesion site ( Figure 3a) and evidenced no significant differences with vehicle-treated WT mice, suggesting that endogenous Gal-1 did not induce neurite regeneration.…”

Section: Gal-1 Promotes Locomotor Function Recovery After Scimentioning

confidence: 99%

Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury

et al. 2014

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Following spinal cord injury (SCI), semaphorin 3A (Sema3A) prevents axonal regeneration through binding to the neuropilin-1 (NRP-1)/PlexinA4 receptor complex. Here, we show that galectin-1 (Gal-1), an endogenous glycan-binding protein, selectively bound to the NRP-1/PlexinA4 receptor complex in injured neurons through a glycan-dependent mechanism, interrupts the Sema3A pathway and contributes to axonal regeneration and locomotor recovery after SCI. Although both Gal-1 and its monomeric variant contribute to de-activation of microglia, only high concentrations of wild-type Gal-1 (which co-exists in a monomer-dimer equilibrium) bind to the NRP-1/PlexinA4 receptor complex and promote axonal regeneration. Our results show that Gal-1, mainly in its dimeric form, promotes functional recovery of spinal lesions by interfering with inhibitory signals triggered by Sema3A binding to NRP-1/PlexinA4 complex, supporting the use of this lectin for the treatment of SCI patients.

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Axonal growth therapeutics: regeneration or sprouting or plasticity?

Cited by 142 publications

References 74 publications

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

The glial scar in spinal cord injury and repair

Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury

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