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

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

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 8

FBLN2 deficiency enhances remyelination.

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FBLN2 deficiency enhances remyelination. (A) NG2CreER MAPTmGFP mice were...
(A) NG2CreER MAPTmGFP mice were used to identify newly formed oligodendrocytes and myelin as GFP+. (B) Representative images of LPC lesions 14 dpi from NG2CreER MAPTmGFP mice that had received AAVs 2 weeks before surgery. Images were acquired by immunofluorescence laser confocal microscope (Z-stack). Scale bars: 100 μm. The insets are magnified ×1.7. (C) Bar graph showing the extent of GFP in lesions (n = 6 mice over 2 separate experiments; 2-tailed, unpaired Student’s t test). (D) Electron micrographs of LPC-induced lesions from WT and Fbln2–/– mice at 14 dpi. Blue pseudocolored regions indicate examples of axons from myelinated axons. Scale bars: 1.5 μm. (E) Dot plot of percentage remyelinated axons. (F and G) Mean g-ratio (F) and scatterplot of g-ratio (y axis) in relation to axon diameter (x axis) (G) of individual fiber (n = 150 axons per mouse, 6 mice per group; simple linear regression of slopes). E–G: n = 6 mice per group; 2-tailed, unpaired Student’s t test; mean ± SEM.