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Fibulin-2 is an extracellular matrix inhibitor of oligodendrocytes relevant to multiple sclerosis
Samira Ghorbani, … , Mengzhou Xue, V. Wee Yong
Samira Ghorbani, … , Mengzhou Xue, V. Wee Yong
Published May 14, 2024
Citation Information: J Clin Invest. 2024;134(13):e176910. https://doi.org/10.1172/JCI176910.
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Research Article Neuroscience Article has an altmetric score of 10

Fibulin-2 is an extracellular matrix inhibitor of oligodendrocytes relevant to multiple sclerosis

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Abstract

Impairment of oligodendrocytes and myelin contributes to neurological disorders including multiple sclerosis (MS), stroke, and Alzheimer’s disease. Regeneration of myelin (remyelination) decreases the vulnerability of demyelinated axons, but this repair process commonly fails with disease progression. A contributor to inefficient remyelination is the altered extracellular matrix (ECM) in lesions, which remains to be better defined. We have identified fibulin-2 (FBLN2) as a highly upregulated ECM component in lesions of MS and stroke and in proteome databases of Alzheimer’s disease and traumatic brain injury. Focusing on MS, the inhibitory role of FBLN2 was suggested in the experimental autoimmune encephalomyelitis (EAE) model, in which genetic FBLN2 deficiency improved behavioral recovery by promoting the maturation of oligodendrocytes and enhancing remyelination. Mechanistically, when oligodendrocyte progenitors were cultured in differentiation medium, FBLN2 impeded their maturation into oligodendrocytes by engaging the Notch pathway, leading to cell death. Adeno-associated virus deletion of FBLN2 in astrocytes improved oligodendrocyte numbers and functional recovery in EAE and generated new myelin profiles after lysolecithin-induced demyelination. Collectively, our findings implicate FBLN2 as a hitherto unrecognized injury-elevated ECM, and a therapeutic target, that impairs oligodendrocyte maturation and myelin repair.

Authors

Samira Ghorbani, Cenxiao Li, Brian M. Lozinski, Dorsa Moezzi, Charlotte D’Mello, Yifei Dong, Frank Visser, Hongmin Li, Claudia Silva, Mohammadparsa Khakpour, Colin J. Murray, Marie-Ève Tremblay, Mengzhou Xue, V. Wee Yong

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Figure 1

FBLN2 is upregulated in lesions of MS and its animal models.

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FBLN2 is upregulated in lesions of MS and its animal models.
(A) Top: Lu...
(A) Top: Luxol fast blue (LFB) and H&E histologically stained tissues showing demyelinated lesions from 3 MS brain samples. White matter lesions were defined by loss of LFB staining (yellow rings). Bottom: Immunofluorescence images labeled with CD45 for immune cells and FBLN2. Scale bars: 2 mm. (B) Yellow dotted square specifies the area shown at higher magnification to the right. Scale bars: 1 mm (left), 200 μm (right). (C) Representative image of large area of longitudinal section of spinal cord from EAE mice. White dotted box indicates a region of interest (ROI) tracked by loss of myelin. (D) Representative images of spinal cord sections from EAE mice comparing the normal-appearing white matter (NAWM) and lesion area. Scale bars: 100 μm. (E) Colocalization of FBLN2 in GFAP+ astrocytes but rarely in CD45+ immune cells using Imaris 3D rendering. Scale bar: 10 μm. (F) Quantification comparing the percentage of FBLN2 in NAWM and EAE lesions at different time points. n = 6 mice total per group. Data were acquired from 2 separate experiments, and each dot represents mean of 5 lesions analyzed per mouse. (G) Representative images of coronal sections of NAWM and LPC-induced lesion (dotted line) 14 days after injury. Scale bars: 100 μm. (H) Bar graph comparing the percentage of FBLN2 area within the LPC lesion over the time after injury. n = 6 mice for days 3, 14, and 21; n = 9 mice for day 7, from 2 separate experiments. Images in A and C were obtained by slide scanner. Images in B, D, E, and G were acquired by immunofluorescence laser confocal microscope (Z-stack). Data in F and H are presented as mean ± SEM; 1-way ANOVA, Bonferroni post hoc.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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