Cell Cycle Activation and Spinal Cord Injury

Wu, Junfang; Stoica, Bogdan A.; Faden, Alan I.

doi:10.1007/s13311-011-0028-2

Cited by 62 publications

(51 citation statements)

References 93 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%

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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%

“…The glial scar is in fact highly dependent upon the proliferation of reactive astrocytes and microglia/blood-derived macrophages as well as on the degree of cell death at the lesion site (Tian et al, 2006(Tian et al, , 2007Wu et al, 2011).…”

Section: P53mentioning

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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“…in the damaged cord, glial scar formation is markedly reduced, whereas the number of proliferative astrocytes decreases in an astrocyte culture scratch injury model after ethyl pyruvate administration. Moreover, ethyl pyruvate affects activated microglia and CD11b-positive inflammatory cells in an anti-inflammatory fashion.A recent study showed that the delayed expression of cell-cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion, suggesting that pharmacological agents against cell-cycle proteins ameliorate the non-permissive microenvironment [127] . Specifically, the use of olomoucine to inhibit cell cycle kinases (CDKs) 2 and 5 results in the persistent down-regulation of astroglia [128] and microglia [129] …”

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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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“…Importantly, this approach also promotes functional axon collateral and regenerative sprouting, as described in the article by Onifer, Smith, and Fouad [18]. Although there are other impediments to axon regeneration in the injured spinal cord environment and intrinsic to the axons themselves, the glial scar can also be attenuated with cell cycle inhibitors and matrix metalloproteinases inhibitors, which is discussed in the articles by Wu, Stoica, and Faden, as well as by Zhang, Chang, Hansen, Basso, and Noble-Haeusslein [10,11] respectively.…”

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confidence: 99%

“…This third review also describes the ongoing discovery of novel and selective matrix metalloproteinase inhibiting compounds for acute treatment of SCI. The fourth review, largely an inflammation-directed article, by Wu, Stoica, and Faden [11] presents the role of aberrant cell cycle activation in post-traumatic spinal cellular death mechanisms and microglial and astrocytic activation, and the neuroprotective effects of prototypical pharmacological cell cycle inhibitors.…”

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confidence: 99%