Background: Cortical demyelination has been linked to disease progression in multiple sclerosis. Thus, identifying the factors contributing to cortical remyelination is an important goal.
Hypothesis: We hypothesize neuronal activity and microglia-derived signals act as checkpoint in promoting remyelination by perineuronal satellite oligodendrocytes.
Strategy: We will pursue an integrative cross-species approach using transcriptome analysis, fate-mapping, in vivo imaging and chemogenetics to determine the relevance of satellite oligodendrocytes for grey matter remyelination in mice and humans.
Summary
Cortical demyelination is a pathological hallmark of multiple sclerosis (MS) that can even exceed white matter demyelination in postmortem analyses. Neuronal pathology is a frequent feature of such lesions closely associating with clinical severity. Even if signs of remyelination can be detected, widespread cortical areas are demyelinated in chronic MS. We previously identified breast carcinoma-amplified sequence 1 (BCAS1)-positive cells in the mouse and human cortex that represent a subpopulation of pre- and actively myelinating cells. We now find that a relatively large fraction of BCAS1-positive oligodendrocytes are closely apposed to the neuronal soma, defining them as satellite oligodendrocytes, a cell population that has so far only received little attention. In our preliminary work, we obtained evidence that BCAS1-positive satellite oligodendrocytes respond to neuronal activity and to demyelinating injury. In this proposal, we therefore plan to determine the role of satellite oligodendrocytes in recovery from demyelinating injury in toxic and autoimmune models of MS in mice, as well as in human MS biopsy and autopsy tissue. We plan to perform a detailed characterization of satellite oligodendrocytes using multifluorescent immunohistochemistry, spatial transcriptomics, fate-mapping of newly generated and mature oligodendrocytes, and chronic in vivo imaging. We will explore their role in recovery from a demyelinating injury by pulse-chase experiments, spatial transcriptomics and chronic in vivo imaging of virus-labelled oligodendrocytes. This will reveal their lifecycle, their relation to the neuronal cell body during remyelination, and a potential exchange with non-satellite oligodendrocytes. To determine whether satellite oligodendrocytes respond to neuronal activity, we will use chemogenetic techniques to assess whether and how neuronal activity regulates the recruitment of satellite oligodendrocytes and thus impacts on myelination and remyelination. In addition, we will analyze whether satellite oligodendrocytes respond to inflammatory cytokine signalling in experimental demyelinated lesions and in a human iPSC-derived oligodendrocyte culture system.Together, our proposal will allow us to define neuronal activity and inflammatory signals as a possible checkpoint in the function of satellite oligodendrocytes in recovery from demyelinating damage.
