Gotowa bibliografia na temat „Glial scar formation”

Spinal cord injury (SCI) is a condition that affects between 8.8 and 246 people in a million and, unlike many other neurological disorders, it affects mostly young people, causing deficits in sensory, motor, and autonomic functions. Promoting the regrowth of axons is one of the most important goals for the neurological recovery of patients after SCI, but it is also one of the most challenging goals. A key event after SCI is the formation of a glial scar around the lesion core, mainly comprised of astrocytes, NG2+-glia, and microglia. Traditionally, the glial scar has been regarded as detrimental to recovery because it may act as a physical barrier to axon regrowth and release various inhibitory factors. However, more and more evidence now suggests that the glial scar is beneficial for the surrounding spared tissue after SCI. Here, we review experimental studies that used genetic and pharmacological approaches to ablate specific populations of glial cells in rodent models of SCI in order to understand their functional role. The studies showed that ablation of either astrocytes, NG2+-glia, or microglia might result in disorganization of the glial scar, increased inflammation, extended tissue degeneration, and impaired recovery after SCI. Hence, glial cells and glial scars appear as important beneficial players after SCI.

AbstractGlial scars are a common pathological occurrence in a variety of central nervous system (CNS) diseases and injuries. They are caused after severe damage and consist of reactive glia that form a barrier around the damaged tissue that leads to a non-permissive microenvironment which prevents proper endogenous regeneration. While there are a number of therapies that are able to address some components of disease, there are none that provide regenerative properties. Within the past decade, neural stem cells (NSCs) have been heavily studied due to their potent anti-inflammatory and reparative capabilities in disease and injury. Exogenously applied NSCs have been found to aid in glial scar healing by reducing inflammation and providing cell replacement. However, endogenous NSCs have also been found to contribute to the reactive environment by different means. Further understanding how NSCs can be leveraged to aid in the resolution of the glial scar is imperative in the use of these cells as regenerative therapies. To do so, humanised 3D model systems have been developed to study the development and maintenance of the glial scar. Herein, we explore the current work on endogenous and exogenous NSCs in the glial scar as well as the novel 3D stem cell–based technologies being used to model this pathology in a dish.

Inflammation is an essential component for glial scar formation. However, the upstream mediator(s) that triggers the process has not been identified. Previously, we showed that the expression of CD36, an inflammatory mediator, occurs in a subset of astcotyes in the peri-infarct area where the glial scar forms. This study investigates a role for CD36 in astrocyte activation and glial scar formation in stroke. We observed that the expression of CD36 and glial fibrillary acidic protein (GFAP) coincided in control and injured astrocytes and in the brain. Furthermore, GFAP expression was attenuated in CD36 small interfering RNA transfected astrocytes or in the brain of CD36 knockout (KO) mice, suggesting its involvement in GFAP expression. Using an in-vitro model of wound healing, we found that CD36 deficiency attenuated the proliferation of astrocytes and delayed closure of the wound gap. Furthermore, stroke-induced GFAP expression and scar formation were significantly attenuated in the CD36 KO mice compared with wild type. These findings identify CD36 as a novel mediator for injury-induced astrogliosis and scar formation. Targeting CD36 may serve as a potential strategy to reduce glial scar formation in stroke.

Understanding how the transcription factor signal transducer and activator of transcription–3 (STAT3) controls glial scar formation may have important clinical implications. We show that astrocytic STAT3 is associated with greater amounts of secreted MMP2, a crucial protease in scar formation. Moreover, we report that STAT3 inhibits the small GTPase RhoA and thereby controls actomyosin tonus, adhesion turnover, and migration of reactive astrocytes, as well as corralling of leukocytes in vitro. The inhibition of RhoA by STAT3 involves ezrin, the phosphorylation of which is reduced in STAT3-CKO astrocytes. Reduction of phosphatase and tensin homologue (PTEN) levels in STAT3-CKO rescues reactive astrocytes dynamics in vitro. By specific targeting of lesion-proximal, reactive astrocytes in Nestin-Cre mice, we show that reduction of PTEN rescues glial scar formation in Nestin-Stat3+/− mice. These findings reveal novel intracellular signaling mechanisms underlying the contribution of reactive astrocyte dynamics to glial scar formation.

Object. Matrix metalloproteinases (MMPs), particularly MMP-9/gelatinase B, promote early inflammation and barrier disruption after spinal cord injury (SCI). Early blockade of MMPs after injury provides neuroprotection and improves motor outcome. There is recent evidence, however, that MMP-9 and MMP-2/gelatinase A participate in later wound healing in the injured cord. The authors therefore examined the activity of these gelatinases during revascularization and glial scar formation in the contused murine spinal cord. Methods. Gelatinase activity was evaluated using gelatin zymography 24 hours after a mild, moderate, or severe contusion injury. The active form of MMP-2 was not detected, whereas MMP-9 activity was evident in all SCI groups and rose with increasing injury severity. The temporal expression of gelatinases was then examined using gelatin zymography after a moderate SCI. The active form of MMP-9 was most prominent at 1 day, extended through the early period of revascularization, and returned to control by 14 days. The active form of MMP-2 appeared at 7 days postinjury and remained elevated compared with that documented in sham-treated mice for at least 21 days. Increased MMP-2 activity coincided with both revascularization and glial scar formation. Using in situ zymography, gelatinolytic activity was detected in the meninges, vascular elements, glia, and macrophage-like cells in the injured cord. Results of immunolabeling confirmed the presence of gelatinase in vessels during revascularization and in reactive astrocytes associated with glial scar formation. Conclusions. These findings suggest that although MMP-9 and -2 exhibit overlapping expression during revascularization, the former is associated with acute injury responses and the latter with formation of a glial scar.

Object A glial scar is thought to be responsible for halting neuroregeneration following spinal cord injury (SCI). However, little quantitative evidence has been provided to show the relationship of a glial scar and axonal regrowth after injury. Methods In this study performed in rats and dogs, a traumatic SCI model was made using a weight-drop injury device, and tissue sections were stained with H & E for immunohistochemical analysis. The function and behavior of model animals were tested using electrophysiological recording and the Basso-Beattie-Bresnahan Locomotor Rating Scale, respectively. The cavity in the spinal cord after SCI in dogs was observed using MR imaging. Results The morphological results showed that the formation of an astroglial scar was defined at 4 weeks after SCI. While regenerative axons reached the vicinity of the lesion site, the glial scar blocked the extension of regrown axons. In agreement with these findings, the electrophysiological, behavioral, and in vivo MR imaging tests showed that functional recovery reached a plateau at 4 weeks after SCI. The thickness of the glial scars in the injured rat spinal cords was also measured. The mean thickness of the glial scar rostral and caudal to the lesion cavity was 107.00 ± 20.12 μm; laterally it was 69.92 ± 15.12 μm. Conclusions These results provide comprehensive evidence indicating that the formation of a glial scar inhibits axonal regeneration at 4 weeks after SCI. This study reveals a critical time window of postinjury recovery and a detailed spatial orientation of glial scar, which would provide an important basis for the development of therapeutic strategy for glial scar ablation.

Object. The glial scar composed of astrogliosis and extracellular matrix deposition represents a major impediment to axonal regeneration. The authors investigated the role of a novel profibrotic and angiogenic peptide connective tissue growth factor (CTGF [Hcs24/IGFBP-r2P]) in glial scar formation following spinal cord injury (SCI) in rats. Methods. The effects of SCI on CTGF expression during glial scar maturation 1 day to 1 month post-SCI were investigated using fluorescein-activated cell sorter (FACS) immunohistochemical analysis; these findings were compared with those obtained in sham-operated (control) spinal cords. The CTGF-positive cells accumulated at the spinal cord lesion site (p < 0.0001) corresponding to areas of glial scar formation. In the perilesional rim, CTGF expression was confined to invading vimentin-positive, glial fibrillary acidic protein (GFAP)—negative fibroblastoid cells, endothelial and smooth-muscle cells of laminin-positive vessels, and GFAP-positive reactive astrocytes. The CTGF-positive astrocytes coexpressed the activation-associated intermediate filaments nestin, vimentin (> 80%), and mesenchymal scar component fibronectin (50%). Conclusions. The restricted accumulation of CTGF-reactive astrocytes and CTGF-positive fibroblastoid cells lining the laminin-positive basal neolamina suggests participation of these cells in scar formation. In addition, perilesional upregulation of endothelial and smooth-muscle CTGF expression points to a role in blood—brain barrier function modulating edema-induced secondary damage.

A major factor in the failure of central nervous system (CNS) axon regeneration is the formation of glial scar after the injury of CNS. Glial scar generates a dense barrier which the regenerative axons cannot easily pass through or by. In this paper, a mathematical model was established to explore how the regenerative axons grow along the surface of glial scar or bypass the glial scar. This mathematical model was constructed based on the spinal cord injury (SCI) repair experiments by transplanting Schwann cells as bridge over the glial scar. The Lattice Boltzmann Method (LBM) was used in this model for three-dimensional numerical simulation. The advantage of this model is that it provides a parallel and easily implemented algorithm and has the capability of handling complicated boundaries. Using the simulated data, two significant conclusions were made in this study:(1)the levels of inhibitory factors on the surface of the glial scar are the main factors affecting axon elongation and(2)when the inhibitory factor levels on the surface of the glial scar remain constant, the longitudinal size of the glial scar has greater influence on the average rate of axon growth than the transverse size. These results will provide theoretical guidance and reference for researchers to design efficient experiments.

Mesenchymal stem cells are involved in cellular responses in the injured brain after a stroke. The formation of a glial scar is a local response in the brain to damage, and mesenchymal stem cells may be involved in the processes of scar formation. Mesenchymal stem cells express a range of membrane markers, the expression profile of which obviously changes as they differentiate and depends on the microenvironment in which these cells are located. However, it is still unclear where the stem cells in the damaged brain originate from – whether they come from a resident source or from the bone marrow, although an increase in CD34+ cells in the blood of stroke patients is a well-known fact. In this study, we consider the hypothesis regarding the appearance of mesenchymal stem cells in the brain during a stroke and their potential involvement in the formation of a glial scar. The aim of the study is to investigate the involvement of CD44+, CD68+, CD90+, and CD146+ cells in the formation of a glial scar during hemorrhagic stroke and the changes in their representation under the effect of dexamethasone. To achieve this goal, we simulated hemorrhagic stroke in rats and compared the results of immunohistochemical detection of CD44+, CD68+, CD90+, and CD146+ cells in the area of glial scar formation against the dexamethasone administration. We obtained convincing results of differences in the activity and timing of migration of cells expressing CD44 compared to cells expressing CD68, CD90, and CD146. There is a tendency indicating a dependence between the detection of CD44+ cells and the extent of the damage, while the detection of CD68+, CD90+, and CD146+ cells is strongly correlated and increases under the effect of dexamethasone. Cells expressing CD44 were the main participants in the infiltrating pool of cells in the acute phase, but dexamethasone delayed the peak accumulation of CD44+ cells in the forming scar. There were some changes in the detection of these cells around the hemorrhage during dexamethasone treatment, which may indicate its modulating effect on mesenchymal stem cells during glial scar formation. The more frequent detection of CD68+, CD90+, and CD146+ cells can be considered a manifestation of the potential modification by dexamethasone of cellular reactions involved in glial scar formation in the brain after a stroke. The study of the roles of specific immunophenotypes of mesenchymal stem cells in the areas of glial scar formation following hemorrhagic stroke opens new perspectives in the study of brain recovery processes.

L’accident vasculaire cérébral ischémique (AVCi) est une des pathologies les plus mortelles au monde. Le diabète de type II et l’obésité, qui représentent les deux maladies métaboliques les plus fréquentes, sont des facteurs de risque importants de la survenue d’un AVCi, et leur prévalence est augmentée à La Réunion. Par conséquent, le nombre d’AVCi à La Réunion par habitant est plus élevé que la moyenne nationale. Le diabète et l’obésité aggravent aussi les conséquences de l’ischémie cérébrale, via des mécanismes moléculaires et cellulaires qui ne sont pas encore élucidés. Au cours d’un AVCi, la souffrance et la mort cellulaire entraînent l’activation des microglies (microgliose) et des astrocytes (astrogliose). Cette gliose réactionnelle permet la formation d’une cicatrice gliale et fibrotique neuroprotectrice, isolant la région ischémiée du tissu cérébral intact. Cette fibrose devient délétère à moyen/long terme en entravant les processus de plasticité cérébrale. Notre hypothèse d’étude implique que les perturbations métaboliques altèrent la formation de la cicatrice gliale, accentuant les atteintes cérébrales post-AVC. L’objectif de cette présente thèse est donc d’étudier, dans le cadre de l’AVCi, les effets de perturbations métaboliques sur les dommages cérébraux, les processus de gliose réactionnelle, la fibrose ainsi que sur la récupération fonctionnelle. Pour ce faire, nous avons réalisé une ischémie cérébrale (technique MCAO) chez des souris diabétiques et obèses (modèle db/db). Nous avons ensuite décrit l’impact de cette condition métabolique sur la gliose réactionnelle. Nos résultats ont montré que les souris db/db présentaient un volume lésionnel, un œdème cérébral, une transformation hémorragique ainsi qu’une dysfonction de la barrière hématoencéphalique plus importants, en adéquation avec les données cliniques humaines. La gliose réactionnelle et la fibrose associée ont été exacerbées et persistent davantage chez les souris db/db. Forts de ces résultats, nous avons alors voulu explorer les mécanismes moléculaires et cellulaires impliqués dans l’astrogliose au cours d’une lésion ischémique dans une situation mimant un contexte de perturbation métabolique. Pour cela, nous avons mis en place plusieurs modèles afin de reproduire les conditions de l’AVCi in vitro : lésion mécanique du tapis cellulaire, déprivation en dioxygène et en glucose (OGD), et traitement avec des agents mimant les perturbations métaboliques. Des astrocytes de la lignée CLTT ont ainsi été traités au méthyglyoxal (MGO), un précurseur des produits avancés de glycation, reproduisant un des aspects des perturbations métaboliques au cours d’une situation d’hyperglycémie. Nos résultats ont révélé que le traitement au MGO altère le processus de « cicatrisation » à la suite d’une lésion mécanique. Malheureusement, des difficultés techniques ne nous ont pas permis de conclure quant à l’impact du MGO sur la réactivité/cicatrisation astrocytaire en situation d’OGD. Dans une dernière étude in vivo, nous avons étudié les possibles effets thérapeutiques de la modulation d’une voie de signalisation (voie adiponectine) à la suite d’une ischémie cérébrale chez la souris, sans pouvoir montrer d’effets probants. En conclusion, le travail réalisé au cours de cette thèse permet, pour la première fois à notre connaissance, de démontrer que les perturbations métaboliques accentuent la gliose réactionnelle et favorisent la persistance de la cicatrice gliale fibrotique au niveau de l’hémisphère ischémié. La modulation de la cicatrice gliale et de la fibrose permettrait de favoriser les mécanismes de réparation cérébrale et de récupération fonctionnelle des patients dans un contexte aussi bien normoglycémique qu’hyperglycémique
Ischemic stroke is the leading cause of death worldwide, with type II diabetes and obesity being significant risk factors. These metabolic diseases are particularly prevalent in Réunion Island, resulting in a higher incidence of stroke compared to the national average. Furthermore, diabetes and obesity worsen the outcomes of cerebral ischemia through unknown molecular and cellular mechanisms. During a stroke, cellular suffering and death trigger the activation of microglia (microgliosis) and astrocytes (astrogliosis), leading to the formation of a neuroprotective glial and fibrotic scar that isolates the damaged region from healthy brain tissue. However, this fibrosis can later hinder brain plasticity.Our research aimed to investigate the effects of metabolic disturbances on brain damage, reactive gliosis processes, fibrosis, and functional recovery in the context of stroke. For that, we induced cerebral ischemia in diabetic and obese mice (db/db model) and investigate the impact of their metabolic condition on reactive gliosis.Our findings clearly demonstrated that db/db mice exhibited an increased in lesion volume, cerebral oedema, hemorrhagic transformation, and blood-brain barrier dysfunction, in line with human clinical data. Furthermore, reactive gliosis and associated fibrosis were more severe and persistent in db/db mice. To identify the molecular and cellular mechanisms involved in astrogliosis during ischemic injury under disrupted metabolic conditions, we established several in vitro models: wound healing assay, oxygen and glucose deprivation (OGD), and treatment with agents mimicking some aspects of the metabolic dysfunction. Thus, astrocytes from the CLTT cell line were treated with methyglyoxal (MGO), a precursor of advanced glycation products which is elevated in diabetics. Our results clearly demonstrate that MGO treatment impairs the 'healing' process following mechanical injury. However, due to technical difficulties we were not able to draw any conclusions regarding the impact of MGO on astrocytic reactivity/healing in OGD condition. Finally, we tested the potential therapeutic effects of modulating the adiponectin pathway following cerebral ischemia in mice. However, our results showed no conclusive effects.In conclusion, our research provides compelling evidences that metabolic disturbances significantly exacerbate reactive gliosis and promote the persistence of fibrotic glial scarring in the ischemic hemisphere. Modulating glial scar and fibrosis may enhance brain repair mechanisms and functional recovery in both normoglycemic and hyperglycemic patients

Glaucoma is a multifactorial, polygenetic disease with a shared outcome of loss of retinal ganglion cells and their axons, which ultimately results in blindness. The most common risk factor of this disease is elevated intraocular pressure (IOP), although many glaucoma patients have IOPs within the normal physiological range. Throughout disease progression, glial cells in the optic nerve head respond to glaucomatous changes, resulting in glial scar formation as a reaction to injury. This chapter overviews glaucoma as it affects humans and the quest to generate animal models of glaucoma so that we can better understand the pathophysiology of this disease and develop targeted therapies to slow or reverse glaucomatous damage. This chapter then reviews treatment modalities of glaucoma. Revealed herein is the lack of non-IOP-related modalities in the treatment of glaucoma. This finding supports the use of animal models in understanding the development of glaucoma pathophysiology and treatments.

Abstract Multiple sclerosis (MS) is an inflammatory relapsing or progressive central nervous system (CNS) disorder characterized by focal areas of myelin destruction associated with astroglial scar formation (Figure 18.1). These lesions are scattered throughout the CNS with a predilection for the optic nerves, brainstem, spinal cord and periventricular white matter. The initial pathological descriptions of MS were reported in the first half of the 19th century (Cruveilhier, 1835; Carswell, 1838; Charcot, 1868). Later studies revealed that the classical clinico-pathological pattern of MS described in these early studies represented only one member of a family of closely related idiopathic inflammatory demyelinating diseases (IIDDs) (Weinshenker and Lucchinetti, 1998). These include fulminant demyelinating disorders such as the acute Marburg variant, Balo’s concentric sclerosis and acute disseminated encephalomyelitis (ADEM); the monosymptomatic IIDDs such as transverse myelitis or isolated optic neuritis or brainstem demyelination; and the recurrent disorders with a restricted topographical distribution including Devic’s neuromyelitis optica and relapsing myelitis. The literature is confusing with respect to the classification of these syndromes. Some studies emphasize specific clinical or pathological features to distinguish between these syndromes. However, there are examples of transitional cases which defy a specific terminology. For example, the typical concentric lesions ofBalo’s concentric sclerosis can be adjacent to more typical MS plaques (Marburg, 1906). In addition, there are patients with lesions demonstrating histological features of both ADEM and MS (Krucke, 1973). The presence of these transitional forms suggests a spectrum of inflammatory diseases which may share a pathogenetic relationship.

Microglia are the resident macrophages of the central nervous system (CNS). These cells of mesodermal/mesenchymal origin migrate into all regions of the CNS. Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways, they can communicate with macroglial cells (e.g. astrocytes) and neurons and with cells of the immune system. Under normal physiological conditions, microglia constantly monitor their microenvironment and survey neurons. Microglia have other functions including the participation in the formation of new blood vessels or angiogenesis, cognitive function, the regulation of synaptic plasticity, and neurogenesis and they play a crucial role in the CNS through communication with other brain cells. This chapter will provide an overview of the functions of microglial cells within the CNS.

The response of neural cells to mechanical cues is a critical component of the innate neuroprotective cascade aimed at minimizing the consequences of traumatic brain injury (TBI). Reactive gliosis and the formation of glial scars around the lesion site are among the processes triggered by TBI where mechanical stimuli play a central role. It is well established that the mechanical properties of the microenvironment influence phenotype and morphology in most cell types. It has been shown that astrocytes change morphology [1] and cytoskeletal content [2] when grown on substrates of varying stiffness, and that mechanically injured astrocyte cultures show alterations in cell stiffness [3]. Accurate estimates of the mechanical properties of central nervous system (CNS) cells in their in-vivo conditions are needed to develop multiscale models of TBI. Lu et al found astrocytes to be softer than neurons under small deformations [4]. In recent studies, we investigated the response of neurons to large strains and at different loading rates in order to develop single cell models capable of simulating cell deformations in regimes relevant for TBI conditions [5]. However, these studies have been conducted on cells cultured on hard substrates, and the measured cell properties might differ from their in-vivo counterparts due to the aforementioned effects. Here, in order to investigate the effects of substrate stiffness on the cell mechanical properties, we used atomic force microscopy (AFM) and confocal imaging techniques to characterize the response of primary neurons and astrocytes cultured on polyacrylamide (PAA) gels of varying composition. The use of artificial gels minimizes confounding effects associated with biopolymer gels (both protein-based and polysaccharide-based) where specific receptor bindings may trigger additional biochemical responses [1].