Background: The factors that contribute to poor regeneration in multiple sclerosis are unknown.
Hypothesis: We hypothesize that inflammatory cytokine signalling, such as TNF-, is as a checkpoint for efficient generation and survival of oligodendrocytes in experimental demyelinated lesions.
Strategy: Here, we plan to pursue an integrative, trans-species approach by bringing together work in zebrafish, mice and humans.
Multiple sclerosis lesions are frequently characterized by oligodendrocyte loss and persistent demyelination. However, in a proportion of lesions, remyelination takes place either at the lesion margin or in the form of fully remyelinated shadow plaques. Differentiation of oligodendrocyte progenitor cells (OPC) into actively myelinating cells is necessary to generate new myelin sheaths. However, this process is insufficient in the majority of multiple sclerosis lesions and it is therefore essential to understand the causes of remyelination failure. In this proposal, we hypothesize that microglia/macrophage activation status is a key determinant for successful remyelination. We propose that microglia/macrophage activation is necessary to promote the secretion of growth factors that promote the generation and/or the survival of new myelin-forming oligodendrocytes. In recent studies we identified a marker protein of pre-myelinating and actively myelinating oligodendrocytes, breast cancer-amplified sequence 1 (BCAS1). This protein allows high-precision identification of lesion areas with ongoing remyelination in human and mouse tissue. Preliminary data obtained in brain lesions of patients with multiple sclerosis indicate a correlation of BCAS1+ cells with the density of CD68-positive macrophages/activated microglia. In addition, we found an increase in the number of BCAS1+ cells not only after demyelination, but also in relation to inflammatory cytokine exposure. The present proposal aims at testing inflammatory cytokine signalling as a relevant checkpoint for efficient generation and/or survival of oligodendrocytes in experimental demyelinated lesions.
