Many extracellular factors have been implicated in regulating the responses of immature cells of the OL lineage, including IGF-1, LIF, CNTF, CSPGs, and laminins136–139. OLs are also influenced by neighbouring cells that shape the microenvironment by secreting growth factors and components of the extracellular matrix (ECM). For instance, platelet-derived growth factor (PDGF) can prevent apoptosis of newly formed OLs to support myelination and remyelination, while also supporting OPC proliferation and differentiation140–145. However, expression of its receptor PDGFRα needs to be tightly controlled, as it is normally downregulated with OL maturation and preventing this via overexpression drives myelin defects146. Fibroblast growth factor (FGF) signaling also regulates OLs, with FGFR2 ligation stimulating process outgrowth and regulating myelin thickness via ERK1/2 MAPK signaling147,148. Knockout of FGFR1 in mature OLs increases their numbers and promotes remyelination in EAE, while promoting myelination in vitro149,150. Of 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
