Back to Search
Start Over
Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure
- Source :
- Acta Neuropathologica
- Publication Year :
- 2019
- Publisher :
- Springer, 2019.
-
Abstract
- Microglia are highly plastic immune cells which exist in a continuum of activation states. By shaping the function of oligodendrocyte precursor cells (OPCs), the brain cells which differentiate to myelin-forming cells, microglia participate in both myelin injury and remyelination during multiple sclerosis. However, the mode(s) of action of microglia in supporting or inhibiting myelin repair is still largely unclear. Here, we analysed the effects of extracellular vesicles (EVs) produced in vitro by either pro-inflammatory or pro-regenerative microglia on OPCs at demyelinated lesions caused by lysolecithin injection in the mouse corpus callosum. Immunolabelling for myelin proteins and electron microscopy showed that EVs released by pro-inflammatory microglia blocked remyelination, whereas EVs produced by microglia co-cultured with immunosuppressive mesenchymal stem cells promoted OPC recruitment and myelin repair. The molecular mechanisms responsible for the harmful and beneficial EV actions were dissected in primary OPC cultures. By exposing OPCs, cultured either alone or with astrocytes, to inflammatory EVs, we observed a blockade of OPC maturation only in the presence of astrocytes, implicating these cells in remyelination failure. Biochemical fractionation revealed that astrocytes may be converted into harmful cells by the inflammatory EV cargo, as indicated by immunohistochemical and qPCR analyses, whereas surface lipid components of EVs promote OPC migration and/or differentiation, linking EV lipids to myelin repair. Although the mechanisms through which the lipid species enhance OPC maturation still remain to be fully defined, we provide the first demonstration that vesicular sphingosine 1 phosphate stimulates OPC migration, the first fundamental step in myelin repair. From this study, microglial EVs emerge as multimodal and multitarget signalling mediators able to influence both OPCs and astrocytes around myelin lesions, which may be exploited to develop novel approaches for myelin repair not only in multiple sclerosis, but also in neurological and neuropsychiatric diseases characterized by demyelination. Electronic supplementary material The online version of this article (10.1007/s00401-019-02049-1) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Male
S1P
Pathology and Forensic Medicine
Corpus Callosum
Rats, Sprague-Dawley
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Myelin
0302 clinical medicine
Immune system
Cell Movement
medicine
Animals
Sphingosine-1-phosphate
Remyelination
Myelin Sheath
Inflammation
Oligodendrocyte Precursor Cells
Original Paper
Microglia
Multiple sclerosis
Mesenchymal stem cell
Astrocytes
Extracellular vesicles
Mesenchymal stem cells
Myelin lesion
Lysophosphatidylcholines
Cell Differentiation
medicine.disease
Coculture Techniques
Neuroprotection
Cell biology
Mice, Inbred C57BL
stomatognathic diseases
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
chemistry
nervous system
Neurology (clinical)
030217 neurology & neurosurgery
Astrocyte
Demyelinating Diseases
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica
- Accession number :
- edsair.doi.dedup.....b109c1997eecd6fe2ad5c9d4f298052a