Multiple sclerosis (MS) is a multi-factorial central nervous system disease with heterogeneity at the clinical, pathological and molecular level. In MS, different demyelinated lesion types exist, ranging from active to mixed active-inactive to remyelinated lesions. The aim of the experiments described in this thesis of Marion Wijering was to examine between- and within lesion heterogeneity during de- and remyelination to gain more insights into the factors responsible/contributing to these processes and to elucidate the processes behind lesion progression. Therefore, we analyzed spatial gene expression profiles of different lesion types and the effect of MS astrocytes on myelin membrane formation.
Using spatial transcriptomics, we detected a transcriptional rim around active lesions. Using a computational analysis, we could predict lesion evolution, revealing that rim areas precede lesion core formation, emphasizing an important role for the rim in driving lesion expansion. Furthermore, using an experimental MS model, our findings showed that astrocytes in distinct brain regions in the mouse brain are differently affected by demyelination. Furthermore, the secretome of iPSC-derived astrocytes derived from relapsing-remitting MS patients arrested myelin membrane formation in immature OLs. These findings are paving the way towards modulating or preventing lesion progression and to astrocyte-directed strategies to overcome remyelination failure.
