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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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 5

FBLN2 impairs maturation of oligodendrocytes and induces cell death.

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FBLN2 impairs maturation of oligodendrocytes and induces cell death. (A)...
(A) Mouse OPCs stained for O4 24 hours after plating onto PBS (control) or FBLN2. (B and C) Fold change in mean process outgrowth (B) and number of O4+ cells (C) of mouse OPCs cultured on control and different concentrations of FBLN2 for 24 hours. n = 5 independent experiments for FBLN2 (10 μg/mL), n = 3 for FBLN2 (1 and 5 μg/mL); 1-way ANOVA, Bonferroni post hoc. (D and E) Representative images (D) and number of MAG+ cells (E) from human OPCs cultured on control and FBLN2 (10 μg/mL). n = 3 independent experiments; 2-tailed, unpaired Student’s t test. (F and G) Mean process outgrowth (F) and number of O4+ cells (G) of mouse OPCs cultured on coated wells with different members of FBLN family (10 μg/mL). n = 3 independent experiments; 1-way ANOVA, Bonferroni post hoc. (H–K) Mouse OPCs (H) and fold change in mean process outgrowth (I), number of total cells (J), and number of O4+ cells (K) at 6, 12, and 24 hours after plating onto control or FBLN2 (10 μg/mL). n = 3 independent experiments; 2-way ANOVA, Bonferroni post hoc. (L) Representative images of mature mouse oligodendrocytes stained for O4 and MBP at 72 hours. (M) Quantification comparing number of O4+MBP+ cells. n = 3 independent experiments; 1-way ANOVA, Bonferroni post hoc. (N) Live imaging of mouse OPCs plated on control and FBLN2 (10 μg/mL) in the presence of propidium iodide (PI) at different time points. (O) Proportion of PI+ OPCs after 24 hours. n = 3 independent experiments; 2-tailed, unpaired Student’s t test. Each experiment (dot) included 3–4 replicates. (P) Ratio of Bax to Bcl2 mRNA expression in mouse OPCs using real-time PCR. n = 6 replicates over 2 separate experiments; 2-tailed, unpaired Student’s t test. Scale bars: 100 μm. Data are presented as mean ± SEM.