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Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination

dc.contributor.authorLohrberg, Melanie
dc.contributor.authorWinkler, Anne
dc.contributor.authorFranz, Jonas
dc.contributor.authorvan der Meer, Franziska
dc.contributor.authorRuhwedel, Torben
dc.contributor.authorSirmpilatze, Nikoloz
dc.contributor.authorDadarwal, Rakshit
dc.contributor.authorHandwerker, Ronja
dc.contributor.authorEsser, Daniel
dc.contributor.authorWiegand, Kerstin
dc.contributor.authorHagel, Christian
dc.contributor.authorGocht, Andreas
dc.contributor.authorKönig, Fatima B.
dc.contributor.authorBoretius, Susann
dc.contributor.authorMöbius, Wiebke
dc.contributor.authorStadelmann, Christine
dc.contributor.authorBarrantes-Freer, Alonso
dc.date.accessioned2020-12-27T05:04:06Z
dc.date.available2020-12-27T05:04:06Z
dc.date.issued2020
dc.identifier.urihttp://resolver.sub.uni-goettingen.de/purl?gs-1/17715
dc.description.abstractDemyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2+ OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1+ oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin+ progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin+ stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.
dc.description.sponsorshipOpen-Access-Publikationsfonds 2020
dc.language.isoen
dc.publisherBioMed Central
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleLack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination
dc.typejournalArticle
dc.identifier.doi10.1186/s40478-020-01105-2
dc.type.versionpublishedVersion
dc.date.updated2020-12-27T05:04:06Z
dc.rights.holderThe Author(s)
dc.bibliographicCitation.volume8
dc.bibliographicCitation.issue1
dc.bibliographicCitation.firstPage1
dc.bibliographicCitation.lastPage24
dc.type.subtypejournalArticle
dc.bibliographicCitation.articlenumber224
dc.bibliographicCitation.journalActa Neuropathologica Communications


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