Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure
Authors: Claudia Verderio
Marta Fumagalli
Maria P Abbracchio
Martina Gabrielli
Linda Chaabane
Elisabetta Bonfanti
Paola Giussani
Annalisa Buffo
Marta Lombardi
Federica Scaroni
Alice Gualerzi
Cecilia Garlanda
Paola Viani
Nicole Kerlero de Rosbo
Roberta Parolisi
Antonio Uccelli
Journal: Acta Neuropathologica (2019)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Astrocytes; Extracellular vesicles; Mesenchymal stem cells; Microglia; Myelin lesion
Affiliations: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy., CNR Institute of Neuroscience, via Vanvitelli 32, 20129, Milan, Italy., Department of Neuroscience Rita Levi-Montalcini and Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Regione Gonzole 10, 10043, Orbassano, Italy., Department of Excellence: Department of Pharmacological and Biomolecular Sciences (DiSFeB), University of Milan, via Balzaretti 9, 20133, Milan, Italy., IRCCS Fondazione Don Carlo Gnocchi, via Capecelatro 66, 20148, Milan, Italy., Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Paolo Daneo 3, 16132, Genoa, Italy., IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy., Department of Biotechnology and Translational Medicine, University of Milan, 20090, Segrate, Italy., Humanitas University, via Manzoni 56, 20089, Rozzano, Italy., Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Via Olgettina Milano 58, 20132, Milan, Italy., CNR Institute of Neuroscience, via Vanvitelli 32, 20129, Milan, Italy. .

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. 

Retracted: No

PubPeer comments:
 Figure 6e appears to have two images which overlap. *** ![file] , 
 Thank you for noticing the inconsistency in fig 6e. We checked the original images and realized that there was an error in the assembly of the representative images for the MSC-EVs condition. The representative image tagged as MSC-EVs shows by mistake a field taken from a IL-4-EVs coverslip, which partially overlaps the field shown in the IL-4-EVs image (see attached images tagged as vetrino 4 IL4-EVs 0016 and 0044). We here provide a right representative field from the MSC-EVs condition (vetrino 4 MSC-EVs 0040) and the revised figure 6e of our manuscript. ![file] ![file] ![file] ![file] , 
 Thank you for noticing the inconsistency in fig 6e. We checked the original images and realized that there was an error in the assembly of the representative images for the MSC-EVs condition. The representative image tagged as MSC-EVs shows by mistake a field taken from a IL-4-EVs coverslip, which partially overlaps the field shown in the IL-4-EVs image (see attached images tagged as vetrino 4 IL4-EVs 0016 and 0044). We here provide a right representative field from the MSC-EVs condition (vetrino 4 MSC-EVs 0040) and the revised figure 6e of our manuscript. ![file] ![file] ![file] ![file] ,