PhD ceremony Ms. J.M.J. Stoffels: Multiple sclerosis, remyelination and the role of fibronectin

PhD ceremony: Ms. J.M.J. Stoffels

Dissertation: Multiple sclerosis, remyelination and the role of fibronectin

Promotor(s): prof. D. Hoekstra

Faculty: Medical Sciences

Our central nervous system functions, among other factors, as a result of myelin. Myelin is a fatty layer of insulation among nervous cells, which is produced by specific cells, the oligodendrocytes. Multiple sclerosis (MS) is a disease of damaged myelin. These myelin injuries (lesions) appear to be largely responsible for the disease burden of MS. Myelin injuries are often permanent in MS, but sometimes they recover spontaneously. This suggests that oligodendrocytes are capable of producing new myelin, but usually do not succeed. What signals prevent oligodendrocytes from producing new myelin in MS lesions?

In this thesis we investigated how the signal molecule fibronectin influences oligodendrocytes. We discovered that myelin injury ‘automatically’ leads to fibronectin production by neighbor cells, including cells called astrocytes. Fibronectin generally promotes recovery of myelin by attracting young progenitor cells of oligodendrocytes. When the progenitors mature to oligodendrocytes, fibronectin is degraded. In MS fibronectin is not degraded, but accumulates en binds to form aggregates. These fibronectin aggregates were found to impair myelin regeneration by oligodendrocytes. In accordance with this finding, fibronectin aggregates are not present in recovered MS lesions. Finally, fibronectin aggregates may stimulate inflammatory reactions of inflammatory cells, i.e. microglia and macrophages. The observations presented in this thesis suggest that interfering with fibronectin aggregation could contribute to promoting myelin regeneration in MS.