Axon regeneration in peripheral nerves is enhanced by proteoglycan degradation

Groves, Mari L.; McKeon, Robert J.; Werner, Erica; Nagarsheth, Mehul; Meador, William D.; English, Arthur W.

doi:10.1016/j.expneurol.2005.04.007

Cited by 90 publications

(72 citation statements)

References 64 publications

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“…This is simply a ratio of the number of fluorescent axon profiles measured in each mouse to the number of fluorescent axon profiles one mm proximal to the original surgical repair site. The index is a global measure of the average number of branches made by each cut axon (Groves, et al, 2005). These data are shown in Figure 3B.…”

Section: Resultsmentioning

confidence: 98%

“…The ratio of those counts, the number of distal profiles per proximal profile, was calculated as a sprouting index. This index is used as a global measure of the amount of regenerative sprouting that had occurred in the 2-week survival period (Groves, et al, 2005). The significance of differences in sprouting index in the different treatment groups was evaluated using analysis of variance (ANOVA) and the Fisher LSD post hoc test.…”

Section: Discussionmentioning

confidence: 99%

“…Statistical groups consisted of four (2-rep group), three (4-rep group), and four (4-rep group) nerve grafts in which axons were measured. The distribution of axon profile lengths measured in nerve allografts is not statistically normal , Groves, et al, 2005, a requirement for the use of parametric tests such as t-tests or analysis of variance (ANOVA). Thus, statistical significance of differences between treatment groups in these experiments was evaluated using two different approaches.…”

Section: Discussionmentioning

confidence: 99%

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Treadmill training promotes axon regeneration in injured peripheral nerves

Sabatier

Redmon

Schwartz

et al. 2008

Experimental Neurology

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Physical activity after spinal cord injury promotes improvements in motor function, but its effects following peripheral nerve injury are less clear. Although axons in peripheral nerves are known to regenerate better than those in the CNS, methods of accelerating regeneration are needed due to the slow overall rate of growth. Therefore we studied the effect of two weeks of treadmill locomotion on the growth of regenerating axons in peripheral nerves following injury. The common fibular nerves of thy-1-YFP-H mice, in which a subset of axons in peripheral nerves express yellow fluorescent protein (YFP), were cut and repaired with allografts from non-fluorescent littermates, and then harvested two weeks later. Mice were divided into groups of low-intensity continuous training (CT, 60 minutes), low-intensity interval training (IT; one group, 10 reps, 20 minutes total), and high-intensity IT (three groups, 2, 4, and 10 reps). One repetition consisted of two minutes of running and five minutes of rest. Sixty minutes of CT resulted in the highest exercise volume, whereas two reps of IT resulted in the lowest volume of exercise. The lengths of regenerating YFP + axons were measured in images of longitudinal optical sections of nerves. Axon profiles were significantly longer than control in all exercise groups except the low-intensity IT group. In the CT group and the high-intensity IT groups that trained with four or 10 repetitions axons were more than twice as long as unexercised controls. The number of intervals did not impact axon elongation. Axon sprouting was enhanced in IT groups but not the CT group. Thus exercise, even in very small quantities, increases axon elongation in injured peripheral nerves whereas continuous exercise resulting in higher volume (total steps) may have no net impact on axon sprouting.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Treadmill training promotes axon regeneration in injured peripheral nerves

Sabatier

Redmon

Schwartz

et al. 2008

Experimental Neurology

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150

153

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“…A fivefold reduction in DNA content and eradiation of sGAG content (which has been implicated in stunting axon regeneration (Groves et al, 2005;Hattori et al, 2008;Neubauer et al, 2007)) was observed. We have conclusively shown through biochemical and histological assays that the combination of enzyme and chemical treatments perform better than either stand-alone treatment.…”

Section: Discussionmentioning

confidence: 99%

Decellularized grafts with axially aligned channels for peripheral nerve regeneration

Sridharan

Reilly

Buckley

2015

Journal of the Mechanical Behavior of Biomedical Materials

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At least 2 million people worldwide suffer annually from peripheral nerve injuries (PNI), with estimated costs of $7 billion incurred due to paralysis alone. The current "gold" standard for treatment of PNI is the autograft, which poses disadvantages such as high fiscal cost, possible loss of sensation at donor site and the requirement of two surgeries. Allografts are viable alternatives; however, intensive immunosuppressive treatments are often necessary to prevent host rejection. For this reason, significant efforts have been made to remove cellular material from allografts. These decellularized nerve grafts perform better than other clinically available grafts but not as well as autografts; therefore, current research on these grafts includes the incorporation of additional components such as growth factors and cells to provide chemical guidance to regenerating axons. However, effective cellular and axonal penetration is not achieved due to the small pore size (5-10μm) of the decellularized grafts.The overall objective of this study was to induce axially aligned channels in decellularized nerve grafts to facilitate enhanced cell penetration. The specific aims of this study were to optimize a decellularization method to enhance cellular removal, to induce axially aligned pore formation in decellularized grafts through a novel unidirectional freeze drying method, to study the bulk mechanical properties of these modified decellularized grafts and to assess cell penetration into these grafts. To this end we modified an existing decellularization protocol to improve cellular removal while preserving matrix structure in rat sciatic nerve sections. Standard freeze drying and unidirectional freeze drying were employed to impart the necessary pore architecture, and our results suggest that unidirectional freezing is a pertinent modification to the freeze drying process to obtain axially aligned channels. These highly porous scaffolds obtained using unidirectional freeze-drying possessed similar tensile properties to native nerve tissue and exhibited enhanced cellular penetration after 14 days of culture when compared to non-freeze dried and standard freeze-dried scaffolds. The results of this study not only highlight the importance of aligned pores of diameters ~20-60μm on cellular infiltration, but also presents unidirectional freeze drying as a viable technique for producing this required architecture in decellularized nerves. To the best of our knowledge, this study represents the first attempt to manipulate the physical structure of decellularized nerves to enhance cell penetration which may serve as a basis for future peripheral nerve regenerative strategies using decellularized allografts.

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“…A major factor contributing to these poor functional outcomes is the need for regenerating axons to elongate in a pathway in the distal segment of a cut nerve to reach their targets (3). The regenerating axons enter this pathway over a protracted period (4), and once in the pathway, their elongation is dependent upon a favorable balance of growth-promoting and growth-inhibiting molecules (5). The availability of growth-promoting molecules can be limiting.…”

mentioning

confidence: 99%

Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves

English¹,

Liu²,

Nicolini³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Treatments with two-small molecule tropomyosin receptor kinase B (trkB) ligands, 7,8 dihydroxyflavone (7,8 DHF) and deoxygedunin, were evaluated for their ability to promote the regeneration of cut axons in injured peripheral nerves in mice in which sensory and motor axons are marked by YFP. Peripheral nerves were cut and repaired with grafts from strain-matched, nonfluorescent donors and secured in place with fibrin glue. Lengths of profiles of regenerating YFP + axons were measured 2 wk later from confocal images. Axon regeneration was enhanced when the fibrin glue contained dilutions of 500-nM solution of either small-molecule trkB agonist. In mice in which the neurotrophin receptor trkB is knocked out selectively in neurons, axon regeneration is very weak, and topical treatment with 7,8 DHF had no effect on axon regeneration. Similar treatments with deoxygedunin had only a modest effect. In conditional BDNF knockout mice, topical treatments with either 7,8 DHF or deoxygedunin resulted in a reversal of the poor regeneration found in controls and produced significant enhancement of regeneration. In WT mice treated with 2 wk of daily i.p. injections of either 7,8 DHF or deoxygedunin (5 mg/kg), regenerating axon profiles were nearly twice as long as in controls. Restoration of direct muscle responses evoked by sciatic nerve stimulation to pretransection levels over an 8-wk survival period was found only in the treated mice. Treatments with either small-molecule trkB agonist enhanced axon regeneration and muscle reinnervation after peripheral nerve injuries.

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Axon regeneration in peripheral nerves is enhanced by proteoglycan degradation

Cited by 90 publications

References 64 publications

Treadmill training promotes axon regeneration in injured peripheral nerves

Treadmill training promotes axon regeneration in injured peripheral nerves

Decellularized grafts with axially aligned channels for peripheral nerve regeneration

Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves

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