A new extracellular matrix inhibitor of oligodendrocyte maturation: Fibulin-2
Impairment of oligodendrocytes and myelin contributes to neurological disorders including multiple sclerosis (MS). 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 that remains to be better defined. We have identified fibulin-2 (FBLN2) as a highly upregulated ECM component in lesions of MS. The inhibitory role of FBLN2 was suggested in the experimental autoimmune encephalomyelitis (EAE) model in which genetic FBLN2 deficiency alleviated disease severity. Single-cell RNA sequencing of EAE-afflicted spinal cord with FBLN2-deficiency showed a profound myelination profile in oligodendrocytes of FBLN2 deficient mice following neuroinflammation.Mechanistically, when oligodendrocyte progenitors were cultured in differentiation media, 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 novel therapeutic target, that impairs oligodendrocyte maturation and myelin repair.