Acute and chronic demyelinated CNS lesions exhibit opposite elastic properties

Urbanski, Mateusz M.; Brendel, Matthew; Melendez‐Vasquez, Carmen V.

doi:10.1038/s41598-018-37745-7

Cited by 53 publications

(53 citation statements)

References 56 publications

(65 reference statements)

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“…Another feature of reactive ASTRs is increased deposition of ECM proteins. Upon toxin-induced demyelination, ASTRs transiently deposit several ECM proteins, including CSPGs and fibronectin, which add to resolve injury and promote recovery [221,[235][236][237][238][239]. The composition of the ECM affects OPC behavior; fibronectin increases OPC proliferation and migration and inhibits OPC differentiation [236,[239][240][241][242][243][244][245][246][247][248], while CSPGs inhibit OPC proliferation, migration and differentiation [239,[249][250][251][252][253].…”

Section: Astrocyte Diversity and Remyelinationmentioning

confidence: 99%

Macroglial diversity: white and grey areas and relevance to remyelination

Werkman

Lentferink

Baron

2020

Cell. Mol. Life Sci.

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Macroglia, comprising astrocytes and oligodendroglial lineage cells, have long been regarded as uniform cell types of the central nervous system (CNS). Although regional morphological differences between these cell types were initially described after their identification a century ago, these differences were largely ignored. Recently, accumulating evidence suggests that macroglial cells form distinct populations throughout the CNS, based on both functional and morphological features. Moreover, with the use of refined techniques including single-cell and single-nucleus RNA sequencing, additional evidence is emerging for regional macroglial heterogeneity at the transcriptional level. In parallel, several studies revealed the existence of regional differences in remyelination capacity between CNS grey and white matter areas, both in experimental models for successful remyelination as well as in the chronic demyelinating disease multiple sclerosis (MS). In this review, we provide an overview of the diversity in oligodendroglial lineage cells and astrocytes from the grey and white matter, as well as their interplay in health and upon demyelination and successful remyelination. In addition, we discuss the implications of regional macroglial diversity for remyelination in light of its failure in MS. Since the etiology of MS remains unknown and only disease-modifying treatments altering the immune response are available for MS, the elucidation of macroglial diversity in grey and white matter and its putative contribution to the observed difference in remyelination efficiency between these regions may open therapeutic avenues aimed at enhancing endogenous remyelination in either area.

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Section: Astrocyte Diversity and Remyelinationmentioning

confidence: 99%

Macroglial diversity: white and grey areas and relevance to remyelination

Werkman

Lentferink

Baron

2020

Cell. Mol. Life Sci.

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“…4 c). Of interest, transient ECM remodeling plays an important role in successful remyelination [ 5 , 57 , 74 , 75 ]. The extracellular matrix proteome, or the “matrisome” consists of core and associated proteins [ 76 ] and a heatmap of abundantly expressed matrisome-core and matrisome-associated genes that differed significantly (FDR < 0.05) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional heterogeneity between primary adult grey and white matter astrocytes underlie differences in modulation of in vitro myelination

Werkman

Dubbelaar

Vlies

et al. 2020

J Neuroinflammation

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Background Multiple sclerosis (MS) is an inflammation-mediated demyelinating disease of the central nervous system that eventually results in secondary axonal degeneration due to remyelination failure. Successful remyelination is orchestrated by astrocytes (ASTRs) and requires sequential activation, recruitment, and maturation of oligodendrocyte progenitor cells (OPCs). In both MS and experimental models, remyelination is more robust in grey matter (GM) than white matter (WM), which is likely related to local differences between GM and WM lesions. Here, we investigated whether adult gmASTRs and wmASTRs per se and in response to MS relevant Toll-like receptor (TLR) activation differently modulate myelination. Methods Differences in modulation of myelination between adult gmASTRs and wmASTRs were examined using an in vitro myelinating system that relies on a feeding layer of ASTRs. Transcriptional profiling and weighted gene co-expression network analysis were used to analyze differentially expressed genes and gene networks. Potential differential modulation of OPC proliferation and maturation by untreated adult gmASTRs and wmASTRs and in response to TLR3 and TLR4 agonists were assessed. Results Our data reveal that adult wmASTRs are less supportive to in vitro myelination than gmASTRs. WmASTRs more abundantly express reactive ASTR genes and genes of a neurotoxic subtype of ASTRs, while gmASTRs have more neuro-reparative transcripts. We identified a gene network module containing cholesterol biosynthesis enzyme genes that positively correlated with gmASTRs, and a network module containing extracellular matrix-related genes that positively correlated with wmASTRs. Adult wmASTRs and gmASTRs responding to TLR3 agonist Poly(I:C) distinctly modulate OPC behavior, while exposure to TLR4 agonist LPS of both gmASTRs and wmASTRs results in a prominent decrease in myelin membrane formation. Conclusions Primary adult gmASTRs and wmASTRs are heterogeneous at the transcriptional level, differed in their support of in vitro myelination, and their pre-existing phenotype determined TLR3 agonist responses. These findings point to a role of ASTR heterogeneity in regional differences in remyelination efficiency between GM and WM lesions.

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“…These lesions, as suggested by the name of the disease, are stiffer than the normal CNS (sclerotic). [ 24 ] The effect that this increased stiffness might have on the generation of OLs from resident OPCs has been addressed in a number of studies. [ 4,20 ] These have shown that OPCs are mechanosensitive, with substrate stiffness altering differentiation via signaling through the YAP/transcriptional coactivator with PDZ‐binding motif (TAZ) pathway.…”

Section: Discussionmentioning

confidence: 99%

Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP‐Dependent Regulation

Ong

Marinval

Lin

et al. 2020

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A key hallmark of many diseases, especially those in the central nervous system (CNS), is the change in tissue stiffness due to inflammation and scarring. However, how such changes in microenvironment affect the regenerative process remains poorly understood. Here, a biomimicking fiber platform that provides independent variation of fiber structural and intrinsic stiffness is reported. To demonstrate the functionality of these constructs as a mechanotransduction study platform, these substrates are utilized as artificial axons and the effects of axon structural versus intrinsic stiffness on CNS myelination are independently analyzed. While studies have shown that substrate stiffness affects oligodendrocyte differentiation, the effects of mechanical stiffness on the final functional state of oligodendrocyte (i.e., myelination) has not been shown prior to this. Here, it is demonstrated that a stiff mechanical microenvironment impedes oligodendrocyte myelination, independently and distinctively from oligodendrocyte differentiation. Yes‐associated protein is identified to be involved in influencing oligodendrocyte myelination through mechanotransduction. The opposing effects on oligodendrocyte differentiation and myelination provide important implications for current work screening for promyelinating drugs, since these efforts have focused mainly on promoting oligodendrocyte differentiation. Thus, the platform may have considerable utility as part of a drug discovery program in identifying molecules that promote both differentiation and myelination.

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Acute and chronic demyelinated CNS lesions exhibit opposite elastic properties

Cited by 53 publications

References 56 publications

Macroglial diversity: white and grey areas and relevance to remyelination

Macroglial diversity: white and grey areas and relevance to remyelination

Transcriptional heterogeneity between primary adult grey and white matter astrocytes underlie differences in modulation of in vitro myelination

Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP‐Dependent Regulation

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