Primary astrocytopathy has a detrimental effect on remyelination efficacy of parenchymal oligodendrocyte precursor cells

Background: Astrocytic impairment is a common feature of neuromyelitis optica and possibly also multiple sclerosis (MS) lesions and initiates even prior to demyelination. Repopulation of early active plaques with aquaporin 4-negative astrocyte precursors has been recorded, implying astrocytic loss in pre-active lesion stages.

Objectives: Therefore, we aimed at investigating effects of a primary astrocytic loss on lesion regeneration and remyelination.

Methods: Osmolytic shifts induce severe astrocytic loss in certain CNS regions, leading to a secondary oligodendrocyte loss and demyelination, in the absence of antigen-specific lymphocyte activation. In patients, this is referred to as central pontine myelinolysis (CPM). Studying autopsy material from patients with CPM, as well as an experimental rat model, we characterized the oligodendrocyte precursor cell (OPC) activation and differentiation. Using injections of the thymidine-analogue BrdU, we traced the maturation of OPCs activated in early lesions.

Results: Animal experiments revealed rapid activation of the parenchymal NG2+ OPC reservoir in the widely astrocyte-free lesion, leading to extensive OPC proliferation. One week after lesion initiation, most cells derived from parenchymal OPCs expressed breast carcinoma amplified sequence 1 (BCAS1), indicating the transition into a pre-myelinating state. Though, cells derived from the early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and without evidence for process extension, that were sparsely found among myelin producing or mature oligodendrocytes. Correspondingly, also early human CPM lesions showed reduced astrocyte numbers and non-myelinating BCAS1+ oligodendrocytes with dysfunctional morphology. In the animal model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already repopulated with OPCs, giving rise to nestin+ progenitors that partially generated oligodendroglial lineage cells in the lesion, that was finally successively refilled with astrocytes and remyelinated. Those nestin+ stem cell-derived progenitors were absent in human CPM cases possibly contributing to the rather inefficient lesion repair.

Conclusions: The present study underpins the importance of astrocyte-oligodendrocyte interactions for remyelination, thus stressing the necessity to further determine the impact of astrocyte dysfunction on remyelination efficiency in demyelinating disorders like MS.

Presenter: Melanie Lohrberg, University Medical Center Göttingen, Neuropathology, Robert-Koch-Straße 40, 37075, Göttingen, DE