Background: Our recent work indicates that surviving oligodendrocytes (OLs) can contribute to myelin repair both in MS models and patients. However, their remyelination is often inefficient.

Hypothesis: We believe that surviving OLs can be integrated into the remyelination process if we target the molecular checkpoints determining their repair capacity in the inflamed CNS.

Strategy: We will use bioinformatic analysis to identify candidate checkpoints, modulate them in preclinical models where we can read out the repair response by in vivo microscopy and determine their potential to affect human OLs.


Multiple Sclerosis is a chronic inflammatory disease of the central nervous system (CNS) characterized by persistent myelin loss, contributing to neurodegeneration and disability. Current therapeutic strategies aim to promote myelin repair by improving differentiation of oligodendrocyte progenitor cells, however our recent work in MS patients (by S.J. and colleagues) and MS models (by M.K. and colleagues) suggests that surviving mature oligodendrocytes have the potential to contribute to myelin repair. Still, in vivo imaging of mature oligodendrocytes in the inflamed cortex reveals that remyelination by surviving oligodendrocytes is often inefficient. Notably, therapeutic approaches supporting remyelination of newly differentiating oligodendrocytes rather inhibit the repair capacity of surviving oligodendrocytes indicating that they are regulated by distinct molecular pathways. Here, we thus want to determine the molecular checkpoints governing the reparative response of surviving oligodendrocytes in inflammation which could represent novel targets for therapeutic intervention.We plan to employ a translational research approach combining single cell genomics, in vivo imaging of rodent models, human iPSC-derived in vitro models and the use of postmortem human brain tissue. Specifically, we want to make use of a model of cortical MS pathology, we recently developed, to characterize the molecular response of surviving oligodendrocytes on the single cell level and identify the mechanisms responsible for the initiation of remyelination. Next, we want to use this information to genetically modify the repair capacity of surviving oligodendrocytes which we can directly monitor by following individual genetically tagged cells in the inflamed cortex by time-lapse in vivomicroscopy. Finally, we want to assess the relevance of our findings for human oligodendrocytes responses by the integrative analysis of single cell genomics data from experimental and human cortical MS lesions and evaluatetheir therapeutic potential in newly-established human in vitro and human mouse-chimeric in vivo systems. We believe that the proposed work will allow us to resolve if and how mature oligodendrocytes that can survive long term both in experimental and human neuroinflammatory lesions can be recruited to support the myelin repair process.