The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms

Geoffroy, Cédric G.; Meves, Jessica M.; Zheng, Binhai

doi:10.1016/j.neulet.2016.11.003

Cited by 43 publications

(25 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As axon injury in humans can result from a variety of insults at any age, it is important to note that regeneration tends to be increasingly limited with age 210,211 . Indeed, epigenetic profiling revealed that promoter accessibility decreases with cortical maturation 110 , and methylation of histone H3K27, a mark that correlates with closed chromatin, increases with age in the brain in medium spiny neurons 212 .…”

Section: Discussionmentioning

confidence: 99%

Intrinsic mechanisms of neuronal axon regeneration

2018

View full text Add to dashboard Cite

Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Intrinsic mechanisms of neuronal axon regeneration

2018

View full text Add to dashboard Cite

show abstract

“…Studies have suggested that older age decreases the potential for, and delays, functional recovery of the nervous tissue following SCI. 18 Age has been shown to exacerbate microglial activation, increase oxidative stress, and activate inflammatory genes. 46 In addition, in the setting of SCI, older age has been associated with decreased expression and production of antiinflammatory cytokines such as IL-10 in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Value of aggressive surgical and intensive care unit in elderly patients with traumatic spinal cord injury

Lau

Ore

Tarapore

et al. 2019

Neurosurgical Focus

View full text Add to dashboard Cite

OBJECTIVEThe elderly are a growing subpopulation within traumatic spinal cord injury (SCI) patients. Studies have reported high morbidity and mortality rates in elderly patients who undergo surgery for SCI. In this study, the authors compare the perioperative outcomes of surgically managed elderly SCI patients with those of a younger cohort and those reported in the literature.METHODSData on a consecutive series of adult traumatic SCI patients surgically managed at a single institution in the period from 2007 to 2017 were retrospectively reviewed. The cohort was divided into two groups based on age: younger than 70 years and 70 years or older. Assessed outcomes included complications, in-hospital mortality, intensive care unit (ICU) stay, hospital length of stay (LOS), disposition, and neurological status.RESULTSA total of 106 patients were included in the study: 83 young and 23 elderly. The two groups were similar in terms of imaging features (cord hemorrhage and fracture), operative technique, and American Spinal Injury Association Impairment Scale (AIS) grade. The elderly had a significantly higher proportion of cervical SCIs (95.7% vs 71.1%, p = 0.047). There were no significant differences between the young and the elderly in terms of the ICU stay (13.1 vs 13.3 days, respectively, p = 0.948) and hospital LOS (23.3 vs 21.7 days, p = 0.793). Elderly patients experienced significantly higher complication (73.9% vs 43.4%, p = 0.010) and mortality (13.0% vs 1.2%, p = 0.008) rates; in other words, the elderly patients had 1.7 times and 10.8 times the rate of complications and mortality, respectively, than the younger patients. No elderly patients were discharged home (0.0% vs 18.1%, p = 0.029). Discharge AIS grade and AIS grade change were similar between the groups.CONCLUSIONSElderly patients had higher complication and mortality rates than those in younger patients and were less likely to be discharged home. However, it does seem that mortality rates have improved compared to those in prior historical reports.

show abstract

“…The promotion of CST growth after spinal injury has been a long-standing goal in regeneration research. In work spanning several decades, a great diversity of cell types have been transplanted into animal models of spinal injury in an effort to provide CST axons with a more growth-permissive tissue environment (30)(31)(32)(33)(34)(35)(36)(37)(38). Grafted cells have succeeded in eliciting growth from other supraspinal populations (e.g.…”

Section: Discussionmentioning

confidence: 99%

Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

Jayaprakash

Nowak

Eastwood

et al. 2019

Preprint

View full text Add to dashboard Cite

Injury to the spinal cord often disrupts long-distance axon tracts that link the brain and spinal cord, causing permanent disability. Axon regeneration is then prevented by a combination of inhibitory signals that emerge at the injury site and by a low capacity for regeneration within injured neurons. The corticospinal tract (CST) is essential for fine motor control but has proven refractory to many attempted pro-regenerative treatments. Although strategies are emerging to create relay or detour circuits that reroute cortical motor commands through spared circuits, these have only partially met the challenge of restoring motor control. Here, using a murine model of spinal injury, we elevated the intrinsic regenerative ability of CST neurons by supplying a pro-regenerative transcription factor, KLF6, while simultaneously supplying injured CST axons with a growth-permissive graft of neural progenitor cells (NPCs) transplanted into a site of spinal injury. The combined treatment produced robust CST regeneration directly through the grafts and into distal spinal cord. Moreover, selective optogenetic stimulation of regenerated CST axons and single-unit electrophysiology revealed extensive synaptic integration by CST axons with spinal neurons beyond the injury site. Finally, when KLF6 was delivered to injured neurons with a highly effective retrograde vector, combined KLF6/NPC treatment yielded significant improvements in forelimb function. These findings highlight the utility of retrograde gene therapy as a strategy to treat CNS injury and establish conditions that restore functional CST communication across a site of spinal injury. Significance StatementDamage to the spinal cord results in incurable paralysis because axons that carry descending motor commands are unable to regenerate. Here we deployed a two-pronged strategy in a rodent model of spinal injury to promote regeneration by the corticospinal tract, a critical mediator of fine motor control. Delivering pro-regenerative KLF6 to injured neurons while simultaneously transplanting neural progenitor cells to injury sites resulted in robust regeneration directly through sites of spinal injury, accompanied by extensive synapse formation with spinal neurons. In addition, when KLF6 was delivered with improved retrograde gene therapy vectors, the combined treatment significantly improved forelimb function in injured animals. This work represents important progress toward restoring regeneration and motor function after spinal injury.

show abstract

The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms

Cited by 43 publications

References 111 publications

Intrinsic mechanisms of neuronal axon regeneration

Intrinsic mechanisms of neuronal axon regeneration

Value of aggressive surgical and intensive care unit in elderly patients with traumatic spinal cord injury

Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

Contact Info

Product

Resources

About