Inhibiting cell proliferation during formation of the glial scar: effects on axon regeneration in the CNS

Rhodes, Kate; Moon, Lawrence; Fawcett, James W.

doi:10.1016/s0306-4522(03)00285-9

Cited by 73 publications

(61 citation statements)

References 67 publications

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“…The increased proliferation of activated microglia/macrophages at the lesion site after SCI in p53 Ϫ/Ϫ mice could lead to an aberrant inflammatory response, exacerbated secondary degeneration, and the formation of a more aggressive inhibitory environment, contributing to a more pronounced motor impairment. The inhibition of glial proliferation by several pharmacological strategies including the use of cell cycle inhibitors (Wu et al, 2011), such as Ara-C and Flavopiridol (Rhodes et al, 2003;Di Giovanni et al, 2005c;Byrnes et al, 2007), or the depletion of hematogenous macrophages by liposomeencapsulated clodronate (Popovich et al, 1999), has been shown to enhance axonal sprouting and functional recovery after both brain and spinal cord injury.…”

Section: Discussionmentioning

confidence: 99%

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

et al. 2012

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Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53 Ϫ/Ϫ versus wild-type mice. p53 Ϫ/Ϫ spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss-and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53 Ϫ/Ϫ mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53 Ϫ/Ϫ mice, while, similarly, p53 expression in p53 Ϫ/Ϫ cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.

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Section: Discussionmentioning

confidence: 99%

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

et al. 2012

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“…To determine whether the AQP4-dependent astroglial cell migration in culture models might occur in the brain in vivo, we studied reactive gliosis and glial scar formation using a well-established cortical-stab-injury model (Bush et al, 1999;Hampton et al, 2004;Rhodes et al, 2003;Wang et al, 2004). The stab-injury mouse model, unlike other brain-injury models (tumor, infection, trauma), is not associated with significant brain swelling, which could confound interpretation of results.…”

Section: Reactive Gliosis In Vivomentioning

confidence: 99%

Involvement of aquaporin-4 in astroglial cell migration and glial scar formation

Saadoun

Papadopoulos

Watanabe

et al. 2005

Journal of Cell Science

422

386

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Aquaporin-4, the major water-selective channel in astroglia throughout the central nervous system, facilitates water movement into and out of the brain. Here, we identify a novel role for aquaporin-4 in astroglial cell migration, as occurs during glial scar formation. Astroglia cultured from the neocortex of aquaporin-4-null mice had similar morphology, proliferation and adhesion, but markedly impaired migration determined by Transwell migration efficiency (18±2 vs 58±4% of cells migrated towards 10% serum in 8 hours; P<0.001) and wound healing rate (4.6 vs 7.0 μm/hour speed of wound edge; P<0.001) compared with wild-type mice. Transwell migration was similarly impaired (25±4% migrated cells) in wild-type astroglia after ∼90% reduction in aquaporin-4 protein expression by RNA inhibition. Aquaporin-4 was polarized to the leading edge of the plasma membrane in migrating wild-type astroglia, where rapid shape changes were seen by video microscopy. Astroglial cell migration was enhanced by a small extracellular osmotic gradient, suggesting that aquaporin-4 facilitates water influx across the leading edge of a migrating cell. In an in vivo model of reactive gliosis and astroglial cell migration produced by cortical stab injury, glial scar formation was remarkably impaired in aquaporin-4-null mice, with reduced migration of reactive astroglia towards the site of injury. Our findings provide evidence for the involvement of aquaporin-4 in astroglial cell migration, which occurs during glial scar formation in brain injury, stroke, tumor and focal abscess.

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“…Astrocytes, derived from ependymal stem cells, migrate into the lesion to participate in glial scar formation after spinal cord injury in the adult . Proliferation of resident or migrating astrocytes is also involved in astrogliosis, but to a lesser extent (Rhodes et al, 2003;Hampton et al, 2004). Alterations in the intermediate filament cytoskeleton have been implicated in astrocyte motility.…”

Section: Glial Scar Formation and Mmp-2mentioning

confidence: 99%

Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

Hsu¹,

McKeon²,

Goussev³

et al. 2006

J. Neurosci.

204

184

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Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in both injury and repair mechanisms in the CNS. Pharmacological blockade of MMPs, limited to the first several days after spinal cord injury, improves locomotor recovery. This beneficial response is, however, lost when treatment is extended beyond the acutely injured cord to include wound healing and tissue remodeling. This suggests that some MMPs play a beneficial role in wound healing. To test this hypothesis, we investigated the role of MMP-2, which is actively expressed during wound healing, in white matter sparing and axonal plasticity, the formation of a glial scar, and locomotor recovery after spinal cord injury. MMP-2 increased between 7 and 14 d after injury, where it was immunolocalized in reactive astrocytes bordering the lesion epicenter. There was reduced white matter sparing and fewer serotonergic fibers, caudal to the lesion in injured MMP-2 null animals. MMP-2 deficiency also resulted in increased immunoreactivity to chondroitin sulfate proteoglycans and a more extensive astrocytic scar. Most importantly, locomotion in an open field, performance on a rotarod, and grid walking were significantly impaired in injured MMP-2 null mice. Our findings suggest that MMP-2 promotes functional recovery after injury by regulating the formation of a glial scar and white matter sparing and/or axonal plasticity. Thus, strategies exploiting MMPs as therapeutic targets must balance these beneficial effects during wound healing with their adverse interactions in the acutely injured spinal cord.

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Inhibiting cell proliferation during formation of the glial scar: effects on axon regeneration in the CNS

Cited by 73 publications

References 67 publications

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

Involvement of aquaporin-4 in astroglial cell migration and glial scar formation

Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

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