The extracellular matrix: Focus on oligodendrocyte biology and targeting CSPGs for remyelination therapies

Abstract

The repair of myelin, termed remyelination, is a regenerative process that occurs within the central nervous system in conditions such as multiple sclerosis. Remyelination is enabled by oligodendrocytes that mature from oligodendrocyte precursor cells. Many factors influence the biology of oligodendrocytes and their capacity to reform myelin, and considerable evidence now implicates the extracellular matrix within the injured central nervous system as a major modifier of remyelination. Herein, we review current knowledge of components of the brain extracellular matrix that are beneficial or inhibitory for oligodendrocyte recruitment and maturation, and for their capacity to remyelinate where evidence exists. We highlight the detrimental roles of the chondroitin sulfate proteoglycans in remyelination and discuss approaches to alter the brain extracellular matrix for the wellbeing of oligodendrocytes and their capacity for myelin regeneration.

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

“…Remyelination commences within a week following lysolecithin demyelination (Jeffery & Blakemore, ), whereas oligodendrocyte remyelination is scant until at least the third week after SCI (Assinck, Duncan, Plemel, et al, ; Duncan, Manesh, et al, ; James et al, ). The speed of remyelination following SCI is likely affected by injury‐induced changes in the microenvironment, which have been recently reviewed elsewhere (Alizadeh & Karimi‐Abdolrezaee, ; Plemel et al, ; Pu, Stephenson, & Yong, ; Pukos, Goodus, Sahinkaya, & McTigue, ). Notably, remyelination may be slowed by cytotoxicity near the lesion, insufficient tissue oxygenation (Tsai et al, ; Yuen et al, ), or inhibitory factors in the glial scar and myelin debris (Buss & Schwab, ; Church, Milich, Lerch, Popovich, & McTigue, ; Dyck et al, ; Dyck, Kataria, Akbari‐Kelachayeh, Silver, & Karimi‐Abdolrezaee, ; Keough et al, ; Plemel, Manesh, Sparling, & Tetzlaff, ).…”

Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

“…Apart from cytokines, growth factors and neuropeptides, ECM molecules are also secreted by reactive astrocytes and highly modify the lesion environment in MS, consequently influencing the behavior of OPCs (Maier et al, 2005;van Horssen et al, 2005van Horssen et al, , 2006Clemente et al, 2011;Pu et al, 2018). Both the receptors present at the surface of OPCs and the ECM molecules secreted by reactive astrocytes are susceptible to change the environment from permissive to inhibitory for remyelination (de Castro et al, 2013).…”

Remodeling of the interstitial extracellular matrix in white matter multiple sclerosis lesions: Implications for remyelination (failure)

“…Moreover, CSPGs are cleared to enable remyelination. Deposition of CSPGs in MS lesion edges may lead to the formation of a barrier for OPC migration into the lesions, and loss of CSPGs in the center may preclude their beneficial actions after recovery (Keough et al, ; Lau et al, ; Pu et al, ; Sobel & Ahmed, ).…”