interest, FGF2 expression by astrocytes is increased in active MS lesions, and is known to downregulate myelin proteins, cause loss of mature OLs, and inhibit myelin formation150–152. ECM components are also important regulators of OL responses, and their dysregulation after injury contributes to remyelination failure153,154. Cell surface integrin receptors on OLs such as β1 integrin interact with ECM ligands on axons to amplify growth factor signaling, regulating the survival of pre-myelinating and myelinating OLs, increasing myelin membrane formation, influencing axonal selection for myelination in an diameter-dependent manner, and regulating myelin gene translation155–160. Astrocytes contribute to the ECM, as the main source of fibronectin after demyelination, which can inhibit OL differentiation and remyelination161; fibronectin is increased in the plasma of pre-symptomic and symptomatic people with MS, while low levels are observed in remyelinating MS lesions161. Astrocytes also produce hyaluronan during chronic demyelination, impairing remyelination by arresting OL differentiation via Toll-like receptor 2 ligation162–164; of note, hyaluronan is increased in several demyelinating diseases162,163,165. Moreover, ECM may influence OLs through regulation of tissue stiffness, which regulates OL differentiation166, and is increased in chronic demyelination yet decreased during remyelination167.
