Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons

Minor, Kenneth H.; Tang, Xian‐Liang; Kahrilas, Genevieve; Archibald, Simon J.; Davies, Jeannette E.; Davies, Stephen J.

doi:10.1016/j.nbd.2008.06.009

Cited by 52 publications

(40 citation statements)

References 76 publications

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“…However, results of previous studies have shown that infusion of human recombinant decorin core protein can promote axon growth across acute adult rat spinal cord injuries [6,23]. Based on our immunohistochemical and RT-PCR results, biglycan may have no role or a limited role in the retina.…”

Section: Discussionmentioning

confidence: 63%

Expression of Small Leucine-Rich Proteoglycans in the Developing Retina and Kainic Acid-Induced Retinopathy in ICR Mice

Ali

Hosaka

Uehara

2011

The Journal of Veterinary Medical Science

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ABSTRACT. The aim of this study was to determine the developmental changes of small leucine-rich proteoglycans (PGs), decorin, biglycan and fibromodulin, in ICR mouse retinas and to elucidate their role in the adult retina using kainic acid (KA)-induced retinal degeneration model. Retinas of prenatal, postnatal and adult mice were collected for histological and immunohistochemical staining to investigate the changes in distribution of these PGs. Decorin-and fibromodulin-immunostainings were diffusely distributed at prenatal and early postnatal stages and were stronger in the adult retina. However, biglycan was moderately distributed in the prenatal and early postnatal stages and was faint in the adult retina. Retinas were collected at 1, 3 and 7 days after intravitreal injection of KA. Retinas of KA injected eyes underwent shrinkage accompanied by serious damage in the inner layers. Decorin and fibromodulin were upregulated in the inner retinal layers of KA-injected eyes compared to the normal ones. Our results suggest that decorin and fibromodulin play key roles in retinal differentiation, and contribute to the retinal damage and repair process. However, biglycan may have no or only a limited role in the mouse retinal development or repair process.KEY WORDS: biglycan, decorin, fibromodulin, kainic acid, retinal development and damage.

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Section: Discussionmentioning

confidence: 63%

Expression of Small Leucine-Rich Proteoglycans in the Developing Retina and Kainic Acid-Induced Retinopathy in ICR Mice

Ali

Hosaka

Uehara

2011

The Journal of Veterinary Medical Science

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Section: Pharmacological Strategiesmentioning

confidence: 99%

“…in accord with these findings, decorin treatment in acute SCi induces the synthesis of plasminogen/plasmin by microglia, and these are known to play major roles in degrading the inhibitory components of the glial scar and promoting CNS plasticity [121] . More interestingly, a recent study showed that decorin has the ability to directly stimulate neurons to extend axons within CSPG-or myelin-rich environments, suggestive of a coherent pharmacological base that suppresses scarformation to facilitate axonal regrowth after SCi [122] .it is well established that anaerobic metabolism at the lesion site due to the loss of high-energy metabolites is an important contributor to secondary damage and neurological deficits [123] . Before undergoing a moderate spinal cord contusion, rats pretreated with creatine, a potent intracellular energy buffer, score better than controls…”

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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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“…the chondroitin sulfate proteoglycan (CSPG) aggrecan is known to inhibit axonal regrowth but also the growth promoting decorin, which antagonizes scar formation (46). USSC further secrete laminin subunits, which might promote neural differentiation and migration of neural precursor cells after CNS lesion and together with nidogen-1 could guide growth cone turning (71) as well as the heparan sulfate proteoglycan agrin, which is involved in synaptogenesis during regeneration (72).…”

Section: Secretion Of Proteins Involved In Extracellular Matrixmentioning

confidence: 99%

Characterization of Regenerative Phenotype of Unrestricted Somatic Stem Cells (USSC) from Human Umbilical Cord Blood (hUCB) by Functional Secretome Analysis

Schira¹,

Falkenberg

Hendricks

et al. 2015

Molecular & Cellular Proteomics

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Stem cell transplantation is a promising therapeutic strategy to enhance axonal regeneration after spinal cord injury. Unrestricted somatic stem cells (USSC) isolated from human umbilical cord blood is an attractive stem cell population available at GMP grade without any ethical concerns. It has been shown that USSC transplantation into acute injured rat spinal cords leads to axonal regrowth and significant locomotor recovery, yet lacking cell replacement. Instead, USSC secrete trophic factors enhancing neurite growth of primary cortical neurons in vitro. Here, we applied a functional secretome approach characterizing proteins secreted by USSC for the first time and validated candidate neurite growth promoting factors using primary cortical neurons in vitro. By mass spectrometric analysis and exhaustive bioinformatic interrogation we identified 1156 proteins representing the secretome of USSC. Using Gene Ontology we revealed that USSC secretome contains proteins involved in a number of relevant biological processes of nerve regeneration such as cell adhesion, cell motion, blood vessel formation, cytoskeleton organization and extracellular matrix organization. We found for instance that 31 well-known neurite growth promoting factors like, e.g. Injury to the spinal cord leads to a multiple damaging process including axonal contusion and transection with subsequent degeneration, massive apoptosis of oligodendrocytes and break-down of the blood-spinal cord barrier accompanied by invasion of immune cells resulting in sustained motoric and sensory impairments. Glial-fibrotic scarring and the lack of growth promoting factors impair axonal regrowth, which is currently the main target for therapeutic interventions to treat spinal cord injury. In addition, modulation of neuronal survival, remyelination of axons, and the immune reaction could promote functional regeneration (1-3). The inhibition of axonal regeneration might be overcome by exogenous application of growth factors or by transplantation of stem cells directly into the lesion site, which locally release trophic factors and thus support axonal regrowth. For clinical applications, stem cells should be ideally available on a clinical scale without ethical concerns or invasive interventions. Human umbilical cord blood (hUCB) 1 is

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Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons

Cited by 52 publications

References 76 publications

Expression of Small Leucine-Rich Proteoglycans in the Developing Retina and Kainic Acid-Induced Retinopathy in ICR Mice

Expression of Small Leucine-Rich Proteoglycans in the Developing Retina and Kainic Acid-Induced Retinopathy in ICR Mice

The glial scar in spinal cord injury and repair

Characterization of Regenerative Phenotype of Unrestricted Somatic Stem Cells (USSC) from Human Umbilical Cord Blood (hUCB) by Functional Secretome Analysis

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