F. Van Der Meer
University Medical Center Göttingen Institute of NeuropathologyAuthor Of 2 Presentations
LB01.01 - Primary astrocytopathy has a detrimental effect on remyelination efficacy of parenchymal oligodendrocyte precursor cells.
Abstract
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.
PS14.05 - Remyelinating satellite oligodendrocytes provide a rescue strategy to protect neurons after cortical demyelination in multiple sclerosis
Abstract
Background
Remyelination is observed in the white and grey matter of patients with multiple sclerosis (MS). However, whether remyelinating oligodendrocytes arise from newly formed oligodendrocyte progenitor cells (OPCs) or from preexisting OPCs generated during development is not known.
Objectives
The aim of the study is to investigate the origin of remyelinating oligodendrocytes in MS. Therefore, we intensively studied oligodendrocytes, oligodendrocyte-proliferation and differentiation in MS and demyelinating models of MS.
Methods
We performed immunohistochemistry in white and grey matter lesions of patients with early MS obtained at biopsy and late cortical lesions of patients with progressive MS obtained at autopsy. In comparison, we analyzed experimental models of MS, targeting the cortex or the white matter.
Results
In experimental demyelination as well as MS we found very little proliferation of oligodendrocytes and only single mature oligodendrocytes with BrdU incorporation indicating that newly formed oligodendrocytes did not participate in remyelination. Actively remyelinating, breast carcinoma amplified sequence 1 (BCAS1)-positive oligodendrocytes were to identify active remyelination and find that BCAS1 positive myelinating oligodendrocytes were generated immediately after experimental lesion induction and in early active MS lesions. In MS, the total number of oligodendrocytes in the cerebral cortex of early active MS lesions remained unchanged, but decreased with disease duration. This was associated with increased numbers of TPPP/p25 mature oligodendrocytes, suggesting oligodendrocyte differentiation. Furthermore, we identified that a fraction of BCAS1 positive oligodendrocytes in the cerebral cortex are perineuronal satellite cells. These cells obtain a myelinating morphology and express MAG after toxic demyelination and in early MS indicating that these cells participate in remyelination. In progressive MS and at late remyelination time-points in animal models we observed increased numbers of TPPP/p25 positive satellite oligodendrocytes.
Conclusions
Our data show that remyelination is predominantly performed by preexisting oligodendrocytes and is most efficient immediately after demyelination. Furthermore, we were able to demonstrate for the first time that BCAS1 positive perineuronal satellite cells in the cerebral cortex serve as a pool to generate remyelinating oligodendrocytes after experimental demyelination and in MS.
Presenter Of 1 Presentation
PS14.05 - Remyelinating satellite oligodendrocytes provide a rescue strategy to protect neurons after cortical demyelination in multiple sclerosis
Abstract
Background
Remyelination is observed in the white and grey matter of patients with multiple sclerosis (MS). However, whether remyelinating oligodendrocytes arise from newly formed oligodendrocyte progenitor cells (OPCs) or from preexisting OPCs generated during development is not known.
Objectives
The aim of the study is to investigate the origin of remyelinating oligodendrocytes in MS. Therefore, we intensively studied oligodendrocytes, oligodendrocyte-proliferation and differentiation in MS and demyelinating models of MS.
Methods
We performed immunohistochemistry in white and grey matter lesions of patients with early MS obtained at biopsy and late cortical lesions of patients with progressive MS obtained at autopsy. In comparison, we analyzed experimental models of MS, targeting the cortex or the white matter.
Results
In experimental demyelination as well as MS we found very little proliferation of oligodendrocytes and only single mature oligodendrocytes with BrdU incorporation indicating that newly formed oligodendrocytes did not participate in remyelination. Actively remyelinating, breast carcinoma amplified sequence 1 (BCAS1)-positive oligodendrocytes were to identify active remyelination and find that BCAS1 positive myelinating oligodendrocytes were generated immediately after experimental lesion induction and in early active MS lesions. In MS, the total number of oligodendrocytes in the cerebral cortex of early active MS lesions remained unchanged, but decreased with disease duration. This was associated with increased numbers of TPPP/p25 mature oligodendrocytes, suggesting oligodendrocyte differentiation. Furthermore, we identified that a fraction of BCAS1 positive oligodendrocytes in the cerebral cortex are perineuronal satellite cells. These cells obtain a myelinating morphology and express MAG after toxic demyelination and in early MS indicating that these cells participate in remyelination. In progressive MS and at late remyelination time-points in animal models we observed increased numbers of TPPP/p25 positive satellite oligodendrocytes.
Conclusions
Our data show that remyelination is predominantly performed by preexisting oligodendrocytes and is most efficient immediately after demyelination. Furthermore, we were able to demonstrate for the first time that BCAS1 positive perineuronal satellite cells in the cerebral cortex serve as a pool to generate remyelinating oligodendrocytes after experimental demyelination and in MS.