Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury.

Neuronal regeneration does generally not occur in the central nervous system (CNS) after injury, which has been attributed to the generation of glial scar tissue. In this report we show that the composition of the glial scar after traumatic CNS injury in rat and mouse is more complex than previously assumed: expression of the intermediate filament nestin is induced in reactive astrocytes. Nestin induction occurs within 48 hours in the spinal cord both at the site of lesion and in degenerating tracts and lasts for at least 13 months. Nestin expression is induced with similar kinetics in the crushed optic nerve. In addition to the expression in reactive astrocytes, we also observed nestin induction within 48 hours after injury in cells close to the central canal in the spinal cord, while nestin expressing cells at later timepoints were found progressively further out from the central canal. This dynamic pattern of nestin induction after injury was mimicked by lacZ expressing cells in nestin promoter/lacZ transgenic mice, suggesting that defined nestin regulatory regions mediate the injury response. We discuss the possibility that the spatiotemporal pattern of nestin expression reflects a population of nestin positive cells, which proliferates and migrates from a region close to the central canal to the site of lesion in response to injury.

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Biomaterial Approaches to Modulate Reactive Astroglial Response

Cells Tissues Organs ◽

10.1159/000494667 ◽

2018 ◽

Vol 205 (5-6) ◽

pp. 372-395 ◽

Cited By ~ 10

Author(s):

Jonathan M. Zuidema ◽

Ryan J. Gilbert ◽

Manoj K. Gottipati

Keyword(s):

Spinal Cord ◽

Glial Scar ◽

Secondary Injury ◽

Injury Site ◽

Beneficial Effects ◽

Cord Injury ◽

The Central Nervous System ◽

Preclinical Animal Models

Over several decades, biomaterial scientists have developed materials to spur axonal regeneration and limit secondary injury and tested these materials within preclinical animal models. Rarely, though, are astrocytes examined comprehensively when biomaterials are placed into the injury site. Astrocytes support neuronal function in the central nervous system. Following an injury, astrocytes undergo reactive gliosis and create a glial scar. The astrocytic glial scar forms a dense barrier which restricts the extension of regenerating axons through the injury site. However, there are several beneficial effects of the glial scar, including helping to reform the blood-brain barrier, limiting the extent of secondary injury, and supporting the health of regenerating axons near the injury site. This review provides a brief introduction to the role of astrocytes in the spinal cord, discusses astrocyte phenotypic changes that occur following injury, and highlights studies that explored astrocyte changes in response to biomaterials tested within in vitro or in vivo environments. Overall, we suggest that in order to improve biomaterial designs for spinal cord injury applications, investigators should more thoroughly consider the astrocyte response to such designs.

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Reactive Astrocytes in Glial Scar Attract Olfactory Ensheathing Cells Migration by Secreted TNF-α in Spinal Cord Lesion of Rat

PLoS ONE ◽

10.1371/journal.pone.0008141 ◽

2009 ◽

Vol 4 (12) ◽

pp. e8141 ◽

Cited By ~ 31

Author(s):

Zhida Su ◽

Yimin Yuan ◽

Jingjing Chen ◽

Li Cao ◽

Yanling Zhu ◽

...

Keyword(s):

Spinal Cord ◽

Glial Scar ◽

Spinal Cord Lesion ◽

Reactive Astrocytes ◽

Olfactory Ensheathing Cells ◽

Tnf Α ◽

Ensheathing Cells ◽

Cord Lesion

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The Origins of Syringomyelia: Numerical Models of Fluid/Structure Interactions in the Spinal Cord

Journal of Biomechanical Engineering ◽

10.1115/1.2073607 ◽

2005 ◽

Vol 127 (7) ◽

pp. 1099-1109 ◽

Cited By ~ 45

Author(s):

C. D. Bertram ◽

A. R. Brodbelt ◽

M. A. Stoodley

Keyword(s):

Spinal Cord ◽

Cerebrospinal Fluid ◽

Wave Propagation ◽

Numerical Models ◽

Scar Tissue ◽

Central Canal ◽

Radial Wave ◽

Wave Speeds ◽

Arterial Pulsation ◽

Elastic Cord

A two-dimensional axi-symmetric numerical model is constructed of the spinal cord, consisting of elastic cord tissue surrounded by aqueous cerebrospinal fluid, in turn surrounded by elastic dura. The geometric and elastic parameters are simplified but of realistic order, compared with existing measurements. A distal reflecting site models scar tissue formed by earlier trauma to the cord, which is commonly associated with syrinx formation. Transients equivalent to both arterial pulsation and percussive coughing are used to excite wave propagation. Propagation is investigated in this model and one with a central canal down the middle of the cord tissue, and in further idealized versions of it, including a model with no cord, one with a rigid cord, one with a rigid dura, and a double-length untapered variant of the rigid-dura model. Analytical predictions for axial and radial wave-speeds in these different situations are compared with, and used to explain, the numerical outcomes. We find that the anatomic circumstances of the spinal cerebrospinal fluid cavity probably do not allow for significant wave steepening phenomena. The results indicate that wave propagation in the real cord is set by the elastic properties of both the cord tissue and the confining dura mater, fat, and bone. The central canal does not influence the wave propagation significantly.

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Abnormal Reaction to Central Nervous System Injury in Mice Lacking Glial Fibrillary Acidic Protein and Vimentin

The Journal of Cell Biology ◽

10.1083/jcb.145.3.503 ◽

1999 ◽

Vol 145 (3) ◽

pp. 503-514 ◽

Cited By ~ 239

Author(s):

Milos Pekny ◽

Clas B. Johansson ◽

Camilla Eliasson ◽

Josefina Stakeberg ◽

Åsa Wallén ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Glial Fibrillary Acidic Protein ◽

Intermediate Filament ◽

Glial Scar ◽

Scar Formation ◽

Brain Lesions ◽

Acidic Protein ◽

The Central Nervous System

In response to injury of the central nervous system, astrocytes become reactive and express high levels of the intermediate filament (IF) proteins glial fibrillary acidic protein (GFAP), vimentin, and nestin. We have shown that astrocytes in mice deficient for both GFAP and vimentin (GFAP−/−vim−/−) cannot form IFs even when nestin is expressed and are thus devoid of IFs in their reactive state. Here, we have studied the reaction to injury in the central nervous system in GFAP−/−, vimentin−/−, or GFAP−/−vim−/− mice. Glial scar formation appeared normal after spinal cord or brain lesions in GFAP−/− or vimentin−/− mice, but was impaired in GFAP−/−vim−/− mice that developed less dense scars frequently accompanied by bleeding. These results show that GFAP and vimentin are required for proper glial scar formation in the injured central nervous system and that some degree of functional overlap exists between these IF proteins.

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The Development of Pneumostrongylus tenuis in the Central Nervous System of White-tailed Deer

Pathologia veterinaria ◽

10.1177/030098586500200404 ◽

1965 ◽

Vol 2 (4) ◽

pp. 360-379 ◽

Cited By ~ 4

Author(s):

Roy C. Anderson

Keyword(s):

Spinal Cord ◽

White Matter ◽

Medulla Oblongata ◽

Grey Matter ◽

Plasma Cells ◽

Central Canal ◽

Surrounding Tissue ◽

Parasite Relationship ◽

Central Nervous Systems ◽

The Central Nervous System

The central nervous systems of five fawns (Odocoileus virginianus borealis), infected experimentally with Pneumostrongylus tenuis, were studied histologically 10, 20, 25, 30, and 40 days after infection. In the 10–30 day fawns young developing worms were found in dorsal horns of the grey matter of all regions of the spinal cord. A few worms were found in white matter and in the medulla oblongata. In the fawn autopsied 40 days after infection all but one of about 25 worms found were in the subdural space. Worms in the grey matter usually lay in cell-free tunnels surrounded by compressed neural tissue. There was little reaction of, or cellular infiltration in, surrounding tissue. Malacia was absent in all parts of grey matter. The central canal was normal and the brain, other than the medulla oblongata, was not involved. In the white matter, scattered single myelin sheath degeneration as well as degeneration and disappearance of axis cylinders were common. Occasionally there were tiny malacic areas in white matter, especially near worms. Infiltrations of eosinophils, lymphocytes, and plasma cells were commonly observed in and on the dura mater, the epineurium, ganglion capsules, and other tissues of the epidural space. The relative dearth of histopathologic findings helps to explain the rarity and slightness of neurologic signs in infected fawns and is indicative perhaps of a long and well established host-parasite relationship. This is in contrast to the situation in moose (Alces a. americana) where severe traumatic damage to the spinal cord by P. tenuis is associated with ataxia and paralysis.

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Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

Neural Plasticity ◽

10.1155/2016/1279051 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Ping Li ◽

Zhao-Qian Teng ◽

Chang-Mei Liu

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Axon Regeneration ◽

Therapeutic Potential ◽

Glial Scar ◽

Scar Formation ◽

Extrinsic Factors ◽

Cord Injury ◽

The Central Nervous System

Spinal cord injury is a devastating disease which disrupts the connections between the brain and spinal cord, often resulting in the loss of sensory and motor function below the lesion site. Most injured neurons fail to regenerate in the central nervous system after injury. Multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration after injury. MicroRNAs can modulate multiple genes’ expression and are tightly controlled during nerve development or the injury process. Evidence has demonstrated that microRNAs and their signaling pathways play important roles in mediating axon regeneration and glial scar formation after spinal cord injury. This article reviews the role and mechanism of differentially expressed microRNAs in regulating axon regeneration and glial scar formation after spinal cord injury, as well as their therapeutic potential for promoting axonal regeneration and repair of the injured spinal cord.

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The structural integrity of glial scar tissue associated with a chronic spinal cord lesion can be altered by transplanted fetal spinal cord tissue

Journal of Neuroscience Research ◽

10.1002/jnr.490310117 ◽

1992 ◽

Vol 31 (1) ◽

pp. 120-130 ◽

Cited By ~ 35

Author(s):

J. Houle

Keyword(s):

Spinal Cord ◽

Structural Integrity ◽

Scar Tissue ◽

Glial Scar ◽

Spinal Cord Lesion ◽

Spinal Cord Tissue ◽

Cord Lesion

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Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review

F1000Research ◽

10.12688/f1000research.74087.1 ◽

2022 ◽

Vol 11 ◽

pp. 16

Author(s):

Kurosh Mojtabavi ◽

Morteza Gholami ◽

Zahra Ghodsi ◽

Narges Mahmoodi ◽

Sina Shool ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Data Extraction ◽

Included Study ◽

Cns Injury ◽

Neuronal Regeneration ◽

Self Assembling ◽

Cord Injury ◽

Injury Treatment

Background: In many cases, central nervous system (CNS) injury is unchanging due to the absence of neuronal regeneration and repair capabilities. In recent years, regenerative medicine, and especially hydrogels, has reached a significant amount of attention for their promising results for the treatment of spinal cord injury (SCI) currently considered permanent. Hydrogels are categorized based on their foundation: synthetic, natural, and combination. The objective of this study was to compare the properties and efficacy of commonly used hydrogels, like collagen, and other natural peptides with synthetic self-assembling peptide hydrogels in the treatment of SCI. Methods: Articles were searched in PubMed, Scopus, Web of Science, and Embase. All studies from 1985 until January 2020 were included in the primary search. Eligible articles were included based on the following criteria: administering hydrogels (both natural and synthetic) for SCI treatment, solely focusing on spinal cord injury treatment, and published in a peer-reviewed journal. Data on axonal regeneration, revascularization, elasticity, drug delivery efficacy, and porosity were extracted. Results: A total of 24 articles were included for full-text review and data extraction. There was only one experimental study comparing collagen I (natural hydrogel) and polyethylene glycol (PEG) in an in vitro setting. The included study suggested the behavior of cells with PEG is more expectable in the injury site, which makes it a more reliable scaffold for neurites. Conclusions: There is limited research comparing and evaluating both types of natural and self-assembling peptides (SAPs) in the same animal or in vitro study, despite its importance. Although we assume that the remodeling of natural scaffolds may lead to a stable hydrogel, there was not a definitive conclusion that synthetic hydrogels are more beneficial than natural hydrogels in neuronal regeneration.

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