Remodeling of the interstitial extracellular matrix in white matter multiple sclerosis lesions: Implications for remyelination (failure)

Jong, Jody M. de; Wang, Peng; Oomkens, Michelle; Baron, Wia

doi:10.1002/jnr.24582

Cited by 30 publications

(34 citation statements)

References 274 publications

(676 reference statements)

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“…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]. Differentiation of neural stem cells into OPCs and finally into mature myelinating OLGs is, in addition to ECM composition, also dependent on the stiffness of the ECM [254].…”

Section: Astrocyte Diversity and Remyelinationmentioning

confidence: 99%

“…Thus, in WM MS lesions, hMOLs populations were skewed to the transcriptionally different fully mature hMOL5 population and/or other populations were depleted. In favor of the latter is that in MS lesions adult OPCs lack the capability [120] and/or receive inhibitory signals [201,239] to form new hMOLs, which may represent the reduced abundance of the pre-myelinating hMOL6 [121]. In addition, increased transcript levels of myelin genes were observed in mature wmOLGs in MS [121], hinting to the involvement of mature OLGs in remyelination.…”

Section: Oligodendroglial Lineage Cell Diversity In White Matter Multmentioning

confidence: 99%

“…Although often used as a marker for OPCs, NG2-expressing cells can also become ASTRs in vivo [105], and in rodents also microglia initiate NG2 expression upon aging [298]. Other ECM proteins that impair OLG production and remyelination include hyaluronan and fibronectin [7,236,239,[299][300][301]. Hyaluronan and its receptor CD44 are significantly increased in the WM, but not in the GM part of leukocortical lesions [7].…”

Section: Astroglial Scar Formation White Matter Multiple Sclerosis Lementioning

confidence: 99%

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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%

Section: Oligodendroglial Lineage Cell Diversity In White Matter Multmentioning

confidence: 99%

Section: Astroglial Scar Formation White Matter Multiple Sclerosis Lementioning

confidence: 99%

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Macroglial diversity: white and grey areas and relevance to remyelination

Werkman

Lentferink

Baron

2020

Cell. Mol. Life Sci.

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“…In addition, wmOPCs are more susceptible to the detrimental effects of inflammatory mediators such as interferon‐γ (IFNγ, (Lentferink et al., 2018)). Astrocytes (ASTRs) play an important role in transient remodeling of the local signaling environment to facilitate remyelination upon CNS demyelination (Gudi, Gingele, Skripuletz, & Stangel, 2014; Jong, Wang, Oomkens, & Baron, 2020). Therefore, in addition to regional differences in OPCs, ASTRs from different brain regions may also contribute to regional differences in remyelination efficiency.…”

Section: Introductionmentioning

confidence: 99%

“…These ASTR subtypes are morphologically and functionally distinct, that is, protoplasmic ASTRs are morphological more complex and ensheath synapses, whereas fibrous ASTRs are specialized in providing structural support to myelinated axons and interact with the nodes of Ranvier (Oberheim et al., 2012). A dense astroglial scar is mainly formed in WM MS lesions and consists of persistent locally deposited extracellular matrix molecules, including proteoglycans and fibronectin that impair remyelination (reviewed in de Jong et al., 2020). While the role of ASTRs in remyelination in MS is still debated, a strong correlation exists between severe reactive glial scar formation and remyelination failure (Nair, Frederick, & Miller, 2008; Nash, Ioannidou, & Barnett, 2011).…”

Section: Introductionmentioning

confidence: 99%

Impairing committed cholesterol biosynthesis in white matter astrocytes, but not grey matter astrocytes, enhances in vitro myelination

Werkman

Kövilein

Jonge

et al. 2020

Journal of Neurochemistry

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Remyelination is a regenerative process that is essential to recover saltatory conduction and to prevent neurodegeneration upon demyelination. The formation of new myelin involves the differentiation of oligodendrocyte progenitor cells (OPCs) toward oligodendrocytes and requires high amounts of cholesterol. Astrocytes (ASTRs) modulate remyelination by supplying lipids to oligodendrocytes. Remarkably, remyelination is more efficient in grey matter (GM) than in white matter (WM), which may relate to regional differences in ASTR subtype. Here, we show that a feeding layer of gmASTRs was more supportive to in vitro myelination than a feeding layer of wmASTRs. While conditioned medium from both gmASTRs and wmASTRs accelerated gmOPC differentiation, wmOPC differentiation is enhanced by secreted factors from gmASTRs, but not wmASTRs. In vitro analyses revealed that gmASTRs secreted more cholesterol than wmASTRs. Cholesterol efflux from both ASTR types was reduced upon exposure to pro‐inflammatory cytokines, which was mediated via cholesterol transporter ABCA1, but not ABCG1, and correlated with a minor reduction of myelin membrane formation by oligodendrocytes. Surprisingly, a wmASTR knockdown of Fdft1 encoding for squalene synthase (SQS), an enzyme essential for the first committed step in cholesterol biosynthesis, enhanced in vitro myelination. Reduced secretion of interleukin‐1β likely by enhanced isoprenylation, and increased unsaturated fatty acid synthesis, both pathways upstream of SQS, likely masked the effect of reduced levels of ASTR‐derived cholesterol. Hence, our findings indicate that gmASTRs export more cholesterol and are more supportive to myelination than wmASTRs, but specific inhibition of cholesterol biosynthesis in ASTRs is beneficial for wmASTR‐mediated modulation of myelination.

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Identifying miRNAs in multiple sclerosis gray matter lesions that correlate with atrophy measures

Tripathi

Pandit

Perles

et al. 2021

Ann Clin Transl Neurol

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Objective: Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Though MS was initially considered to be a white matter demyelinating disease, myelin loss in cortical gray matter has been reported in all disease stages. We previously identified microRNAs (miRNAs) in white matter lesions (WMLs) that are detected in serum from MS patients. However, miRNA expression profiles in gray matter lesions (GMLs) from progressive MS brains are understudied. Methods: We used a combination of global miRNAs and gene expression profiling of GMLs and independent validation using real-time quantitative polymerase chain reaction (RT-qPCR), immuno-in situ hybridization, and immunohistochemistry. Results: Compared to matched myelinated gray matter (GM) regions, we identified 82 miRNAs in GMLs, of which 10 were significantly upregulated and 17 were significantly downregulated. Among these 82 miRNAs, 13 were also detected in serum and importantly were associated with brain atrophy in MS patients. The predicted target mRNAs of these miRNAs belonged to pathways associated with axonal guidance, TGF-b signaling, and FOXO signaling. Further, using state-of-the-art human protein-protein interactome network analysis, we mapped the four key GM atrophy-associated miRNAs (hsa-miR-149*, hsa-miR-20a, hsa-miR-29c, and hsa-miR-25) to their target mRNAs that were also changed in GMLs. Interpretation: Our study identifies miRNAs altered in GMLs in progressive MS brains that correlate with atrophy measures. As these miRNAs were also detected in sera of MS patients, these could act as markers of GML demyelination in MS.

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Remodeling of the interstitial extracellular matrix in white matter multiple sclerosis lesions: Implications for remyelination (failure)

Cited by 30 publications

References 274 publications

Macroglial diversity: white and grey areas and relevance to remyelination

Macroglial diversity: white and grey areas and relevance to remyelination

Impairing committed cholesterol biosynthesis in white matter astrocytes, but not grey matter astrocytes, enhances in vitro myelination

Identifying miRNAs in multiple sclerosis gray matter lesions that correlate with atrophy measures

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