Chondroitin sulfate proteoglycans impede myelination by oligodendrocytes after perinatal white matter injury

Deng, Yingping; Sun, Yi; Hu, Lan; Li, Zhihua; Xu, Quanmei; Pei, Yi-Ling; Huang, Zhiheng; Yang, Zhengang; Chen, Chao

doi:10.1016/j.expneurol.2015.03.026

Cited by 25 publications

(26 citation statements)

References 48 publications

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“…Similar increases, however, have also been reported for CNS injuries known to affect myelin and OLGs, such as stroke (Carmichael et al, 2005), perinatal white matter injury (Deng et al, 2015) and MS (Sobel and Ahmed, 2001; van Horssen et al, 2006). Notably, chondroitin sulfate proteoglycans have been shown to also impair OLG process outgrowth and remyelination (Lau et al, 2012; Siebert et al, 2011; Siebert and Osterhout, 2011).…”

Section: Introductionsupporting

confidence: 72%

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

Wheeler

Fuss

2016

Experimental Neurology

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There is an increasing number of neurologic disorders found to be associated with loss and/or dysfunction of the CNS myelin sheath, ranging from the classic demyelinating disease, Multiple Sclerosis, through CNS injury, to neuropsychiatric diseases. The disabling burden of these diseases has sparked a growing interest in gaining a better understanding of the molecular mechanisms regulating the differentiation of the myelinating cells of the CNS, oligodendrocytes (OLGs), and the process of (re)myelination. In this context, the importance of the extracellular milieu is becoming increasingly recognized. Under pathological conditions, changes in inhibitory as well as permissive/promotional cues are thought to lead to an overall extracellular environment that is obstructive for the regeneration of the myelin sheath. Given the general view that remyelination is, even though limited in human, a natural response to demyelination, targeting pathologically ‘dysregulated’ extracellular cues and their downstream pathways is regarded as a promising approach toward the enhancement of remyelination by endogenous (or if necessary transplanted) OLG progenitor cells. In this review, we will introduce the extracellular cues that have been implicated in the modulation of (re)myelination. These cues can be soluble, part of the extracellular matrix (ECM) or mediators of cell-cell interactions. Their inhibitory and permissive/promotional roles with regard to remyelination as well as their potential for therapeutic intervention will be discussed.

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Section: Introductionsupporting

confidence: 72%

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

Wheeler

Fuss

2016

Experimental Neurology

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“…In demyelinating injury, they are locally upregulated by several cell types and deposited near the injury site [7][8][9][10][11][12][13]. CSPGs are potent inhibitors for regenerative processes such as axonal regeneration and remyelination [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…The biosynthetic process of CSPGs has largely been elucidated [20], and a number of pharmacological inhibitors of CSPG production have been examined for therapeutic effects, such as xylosides and fluorinated analogues that inhibit activity of CSPG biosynthesis enzymes [21,22]. Following CNS insult, chondroitinase ABC (ChABC)-mediated CSPG digestion improved axonal sprouting, remyelination, and cognitive recovery [14][15][16][23][24][25][26][27]. Perturbing CSPG signaling through antagonism of receptors (e.g., leukocytecommon antigen related and protein tyrosine phosphatase σ) also increased the population of alternatively activated macrophages following SCI [25].…”

Section: Introductionmentioning

confidence: 99%

The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination

Mishra

Dong

et al. 2020

J Neuroinflammation

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Background: Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of axonal regrowth and remyelination. More recently, they have also been highlighted as a modulator of macrophage infiltration into the central nervous system in experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. Methods: We interrogated results from single nucleotide polymorphisms (SNPs) lying in or close to genes regulating CSPG metabolism in the summary results from two publicly available systematic studies of multiple sclerosis (MS) genetics. A demyelinating injury model in the spinal cord of exostosin-like 2 deficient (EXTL2-/-) mice was used to investigate the effects of dysregulation of EXTL2 on remyelination. Cell cultures of bone marrowderived macrophages and primary oligodendrocyte precursor cells and neurons were supplemented with purified CSPGs or conditioned media to assess potential mechanisms of action. Results: The strongest evidence for genetic association was seen for SNPs mapping to the region containing the glycosyltransferase exostosin-like 2 (EXTL2), an enzyme that normally suppresses CSPG biosynthesis. Six of these SNPs showed genome-wide significant evidence for association in one of the studies with concordant and nominally significant effects in the second study. We then went on to show that a demyelinating injury to the spinal cord of EXTL2 −/− mice resulted in excessive deposition of CSPGs in the lesion area. EXTL2 −/− mice had exacerbated axonal damage and myelin disruption relative to wild-type mice, and increased representation of microglia/macrophages within lesions. In tissue culture, activated bone marrow-derived macrophages from EXTL2 −/− mice overproduce tumor necrosis factor α (TNFα) and matrix metalloproteinases (MMPs). Conclusions: These results emphasize CSPGs as a prominent modulator of neuroinflammation and they highlight CSPGs accumulating in lesions in promoting axonal injury.

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“…; Deng et al . ). It was suspected that this may be mediated via specific CSPG receptors or through non‐specific repulsion between CSPGs and axons because of charge differences (Sharma et al .…”

Section: Proteoglycansmentioning

confidence: 97%

Signaling pathways regulating neuron–glia interaction and their implications in Alzheimer's disease

Lian

Zheng

2015

Journal of Neurochemistry

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Astrocytes are the most abundant cells in the central nervous system. They play critical roles in neuronal homeostasis through their physical properties and neuron-glia signaling pathways. Astrocytes become reactive in response to neuronal injury and this process, referred to as reactive astrogliosis, is a common feature accompanying neurodegenerative conditions, particularly Alzheimer’s disease. Reactive astrogliosis represents a continuum of pathobiological processes and is associated with morphological, functional and gene expression changes of varying degrees. There has been a substantial growth of knowledge regarding the signaling pathways regulating glial biology and pathophysiology in recent years. Here we attempt to provide an unbiased review of some of the well-known players, namely calcium, proteoglycan, TGFβ, NFκB, and complement, in mediating neuron-glia interaction under physiological conditions as well as in Alzheimer’s disease.

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Chondroitin sulfate proteoglycans impede myelination by oligodendrocytes after perinatal white matter injury

Cited by 25 publications

References 48 publications

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination

Signaling pathways regulating neuron–glia interaction and their implications in Alzheimer's disease

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