Separation of the Perivascular Basement Membrane Provides a Conduit for Inflammatory Cells in a Mouse Spinal Cord Injury Model

Takigawa, Tomoyuki; Yonezawa, Tomoko; Yoshitaka, Teruhito; Minaguchi, Jun; Kurosaki, Masae; Tanaka, Masato; Sado, Yoshikazu; Ohtsuka, Aiji; Ozaki, Toshifumi; Ninomiya, Yoshifumi

doi:10.1089/neu.2009.1111

Cited by 23 publications

(25 citation statements)

References 38 publications

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“…A similar detachment of blood vessel BM has been described as characteristic for tumor blood vessels, 72 diabetic retinopathy, 73 and Alzheimer disease. 74 Only very recently, Takigawa and associates 14 reported that after SCI, blood vessel walls can exhibit a separation of their BM in an inner endothelial, and an outer parenchymal part, although not all blood vessels are concerned.…”

Section: Discussionmentioning

confidence: 99%

“…12 For some of them, a separation of their BM into an inner endothelial and an outer perivascular BM layer was observed. 14 Laminin labeling intensity and the number of hypertrophied blood vessels decreased with time and distance from the injury site.…”

Section: Intrathecal Chabc Injections Induce Cspg Degradation At the mentioning

confidence: 96%

“…6,7 Moreover, secondary injuries and chronic functional deficits after SCI are associated with alterations of the microvasculature, 8 including increased BBB permeability, 9 modified vascular morphology, [10][11][12] and BM duplication. 13,14 Further, the giant protein AHNAK (700 kDa), expressed in an intact central nervous system (CNS) only by endothelial cells and pericytes, and specifically associated with tight junctions (TJ) of blood vessels belonging to the BBB, 15 is strongly expressed within the lesion site, both in blood vessels and in cells forming at later stages post-injury the inner border of cystic cavities, in front of the astrocytic scar. 12 Interestingly, after SCI, CSPG expression remains detectable at the interface of reactive astrocytes and AHNAK-positive cells even at long term.…”

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confidence: 99%

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Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

Milbreta

Boxberg

Mailly

et al. 2014

Journal of Neurotrauma

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Upregulation of extracellular chondroitin sulfate proteoglycans (CSPG) is a primary cause for the failure of axons to regenerate after spinal cord injury (SCI), and the beneficial effect of their degradation by chondroitinase ABC (ChABC) is widely documented. Little is known, however, about the effect of ChABC treatment on astrogliosis and revascularization, two important factors influencing axon regrowth. This was investigated in the present study. Immediately after a spinal cord hemisection at thoracic level 8-9, we injected ChABC intrathecally at the sacral level, repeated three times until 10 days post-injury. Our results show an effective cleavage of CSPG glycosaminoglycan chains and stimulation of axonal remodeling within the injury site, accompanied by an extended period of astrocyte remodeling (up to 4 weeks). Interestingly, ChABC treatment favored an orientation of astrocytic processes directed toward the injury, in close association with axons at the lesion entry zone, suggesting a correlation between axon and astrocyte remodeling. Further, during the first weeks post-injury, ChABC treatment affected the morphology of laminin-positive blood vessel basement membranes and vessel-independent laminin deposits: hypertrophied blood vessels with detached or duplicated basement membrane were more numerous than in lesioned untreated animals. In contrast, at later time points, laminin expression increased and became more directly associated with newly formed blood vessels, the size of which tended to be closer to that found in intact tissue. Our data reinforce the idea that ChABC injection in combination with other synergistic treatments is a promising therapeutic strategy for SCI repair.

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Section: Discussionmentioning

confidence: 99%

Section: Intrathecal Chabc Injections Induce Cspg Degradation At the mentioning

confidence: 96%

mentioning

confidence: 99%

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Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

Milbreta

Boxberg

Mailly

et al. 2014

Journal of Neurotrauma

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“…in the acute stage after SCi, the single-layer by glial scarring [100] . Moreover, disruption of astroglial scar formation using astrocytic STAT3-CKo mice to augment the spread of inflammation after SCi underscores the beneficial effect of glial scars on inflammatory restriction [70] .…”

Section: Regulation Of Neuro-inflammationmentioning

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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“…Pathological vascular changes and the subsequent events are crucial for the development of secondary injury [2][3][4] . Destruction of the blood-spinal cord barrier leads to massive leakage of blood components, initiating inflammation and gliosis [5] . Post-traumatic ischemia resulting from tissue compression, thrombosis and vasospasm causes progressive neuronal death, and shows a direct linear relationship with the severity of injury [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Protective effects of Batroxobin on spinal cord injury in rats

et al. 2013

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Expansion of the secondary injury following primary spinal cord injury is a major pathological event that increases destruction in the spinal cord, so measures to reduce secondary injury are needed. Our previous study demonstrated that, at the front of the expanding secondary injury in the spinal cord, there is an ischemic area in which many neurons can still be rescued. Therefore, enhancement of blood circulation in the cord may be helpful, and indeed, we found that a traditional Chinese medicine, shu-xue-tong, efficiently reduces the secondary injury. The aim of the present study was to investigate the effect of reducing fibrinogen with Batroxobin, a drug widely used clinically for ischemia, in rats with spinal cord contusion. We found that both 2 and 4 Batroxobin units (BU)/kg efficiently decreased the plasma fibrinogen, and 2 BU/kg significantly increased spinal blood flow, enhanced neuronal survival, mitigated astrocyte and microglia activation, and improved locomotor recovery. However, 4 BU/kg had no effect on the secondary spinal cord injury. These data suggest that Batroxobin has multiple beneficial effects on spinal cord injury, indicating a potential clinical application.

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Separation of the Perivascular Basement Membrane Provides a Conduit for Inflammatory Cells in a Mouse Spinal Cord Injury Model

Cited by 23 publications

References 38 publications

Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

The glial scar in spinal cord injury and repair

Protective effects of Batroxobin on spinal cord injury in rats

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