Regeneration beyond the glial scar

Silver, Jerry; Miller, Jared H.

doi:10.1038/nrn1326

Cited by 2,654 publications

(2,289 citation statements)

References 142 publications

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“…At the same time, astrocytes are involved in the pathology of stroke by production of neurotoxic substances, release of reactive oxygen species and by being a part of the brain edema mechanism (Liu and Chopp, 2015; Zhao and Rempe, 2010). After the stroke, scar formation and expression of proteoglycans might impede neurite outgrowth and inhibit structural and functional recovery (Cregg et al, 2014; Silver and Miller, 2004). Glial scars represent powerful barriers for re‐growth of axons, also in the case of mechanical trauma where astrogliosis is seen as a contributor to post‐traumatic epilepsy (Robel, 2016; Verellen and Cavazos, 2010).…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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“…This glial scar is predominantly formed from extracellular matrix (ECM) molecules expressed by reactive astrocytes although macrophages, microglia, oligodendrocytes, invading Schwann cells and meningeal fibroblasts all contribute to production of the scar matrix (Fawcett and Asher, 1999). Chief of the many ECM molecules that serve to inhibit axonal regeneration are the chondroitin sulfate proteoglycans (CSPGs) (Eddleston and Mucke, 1993;Silver and Miller, 2004) that experience a great increase in expression following SCI (Lemons et al, 1999;McKeon et al, 1991). Both in vitro and in vivo studies have shown that axons do not extend into CSPG-rich ECM (Davies et al, 1997(Davies et al, , 1999McKeon et al, 1991;Meiners et al, 1995;Zuo et al, 1998), and specific CSPGs that inhibit neurite outgrowth have been identified including: aggrecan (Condic et al, 1999), neurocan , phosphocan , brevican (Yamada et al, 1997), versican (Schmalfeldt et al, 2000), and NG2 (Dou and Levine, 1994).…”

Section: Introductionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

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Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI.

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“…Key components of the extracellular environment are the chondroitin sulfate proteoglycans (CSPGs): these molecules are formed by a proteic scaffold supporting chondroitin sulfate glycosaminoglycan chains. Initially, it was recognized that CSPGs inhibit axonal sprouting as they are one of the main obstacles to axon regeneration [16][17][18] . It is now clear that the action of CSPG is multifaceted, as an inhibitory effect of CSPGs on axonal conduction and synaptic transmission in adult rat spinal cord has been recently reported 19 .…”

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confidence: 99%

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

et al. 2013

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Brain cells are immersed in a complex structure forming the extracellular matrix. The composition of the matrix gradually matures during postnatal development, as the brain circuitry reaches its adult form. The fully developed extracellular environment stabilizes neuronal connectivity and decreases cortical plasticity as highlighted by the demonstration that treatments degrading the matrix are able to restore synaptic plasticity in the adult brain. The mechanisms through which the matrix inhibits cortical plasticity are not fully clarified. Here we show that a prominent component of the matrix, chondroitin sulfate proteoglycans (CSPGs), restrains morphological changes of dendritic spines in the visual cortex of adult mice. By means of in vivo and in vitro two-photon imaging and electrophysiology, we find that after enzymatic digestion of CSPGs, cortical spines become more motile and express a larger degree of structural and functional plasticity.

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Regeneration beyond the glial scar

Cited by 2,654 publications

References 142 publications

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

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