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Updated: Jun 26, 2025
Rapid and Specific Immunomagnetic Isolation of Mouse Primary Oligodendrocytes
Published on: May 21, 2018
Fibulin-2 is an extracellular matrix inhibitor of oligodendrocytes relevant to multiple sclerosis
Samira Ghorbani1,2,3, Cenxiao Li1, Brian M Lozinski1
1Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
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.
Insights
Fibulin-2 (FBLN2), an extracellular matrix protein, hinders myelin repair in neurological diseases like multiple sclerosis. Reducing FBLN2 promotes oligodendrocyte maturation and enhances myelin regeneration, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Oligodendrocyte and myelin damage are central to neurological disorders such as multiple sclerosis (MS), stroke, and Alzheimer's disease.
- Myelin regeneration (remyelination) is crucial for protecting axons but often fails during disease progression.
- The extracellular matrix (ECM) within lesions is altered, contributing to remyelination failure, but its specific components remain poorly defined.
Purpose of the Study:
- To identify and characterize novel ECM components that impede myelin repair in neurological diseases.
- To investigate the role of fibulin-2 (FBLN2) in oligodendrocyte maturation and remyelination.
- To explore FBLN2 as a potential therapeutic target for enhancing myelin repair.
Main Methods:
- Identified FBLN2 as upregulated in MS, stroke, Alzheimer's disease, and traumatic brain injury lesions using proteomic analysis.
- Utilized the experimental autoimmune encephalomyelitis (EAE) model to assess the in vivo role of FBLN2 in myelin repair.
- Investigated the mechanism of FBLN2's action on oligodendrocyte progenitor cells (OPCs) in vitro, including Notch pathway engagement.
- Employed adeno-associated virus (AAV) mediated gene deletion of FBLN2 in astrocytes in the EAE model and in lysolecithin-induced demyelination models.
Main Results:
- Fibulin-2 (FBLN2) was found to be significantly upregulated in CNS injury lesions.
- Genetic deficiency of FBLN2 in the EAE model led to improved behavioral recovery, increased oligodendrocyte numbers, and enhanced remyelination.
- In vitro, FBLN2 inhibited OPC maturation by activating the Notch pathway, resulting in cell death.
- AAV-mediated deletion of FBLN2 in astrocytes improved functional recovery in EAE and promoted myelin repair after lysolecithin-induced demyelination.
Conclusions:
- Fibulin-2 (FBLN2) is a novel, injury-elevated ECM component that impairs oligodendrocyte maturation and myelin repair.
- Targeting FBLN2 presents a promising therapeutic strategy for promoting myelin regeneration in neurological disorders.
- Understanding the role of ECM components like FBLN2 is critical for developing effective treatments for demyelinating diseases.
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