Extracellular vesicles released from microglia-conditioned with mesenchymal stem cells positively regulate oligodendroglial progenitors proliferation in response to focal myelin lesion

In multiple sclerosis (MS), microglia (MG) have a key role in neuroinflammation. They participate in mechanisms of damage and, in response to injury, can acquire distinct phenotypes with opposite effects. The acquisition of different phenotypes depends on the nature and duration of environmental signals, and plays distinctive roles in remyelination. The proinflammatory phenotype is associated with a persistent inflammation that inhibits myelin regeneration, while the proregenerative one promotes remyelination by both secretion of anti-inflammatory factors and phagocytosis of myelin debris. We recently established that conditioning with mesenchymal stem cells (MSCs) is particularly effective in directing MG toward proregenerative functions. However, the modes of action of MG in fostering or inhibiting CNS repair are only partly known. Studies suggest that the distinct effects of MG phenotypes on remyelination may be mediated by extracellular vesicles (EVs), which are released from MG and can transfer multiple information. Furthermore, EVs have recently been proposed as transporters of toxic agents in neurodegenerative diseases, suggesting a role in both diffusion and progression of the pathology. Here, we are investigating whether EVs released from proregenerative phenotypes of MG had a beneficial impact on oligodendrocyte precursor cells (OPCs) in the lysolecithin mouse model of focal demyelination. To this aim EVs were isolated from MG exposed to IL-4 or to MSCs in the presence of inflammatory cytokines, and injected in focal demyelinated lesions of the corpus callosum. Artificial liposomes were employed as controls. Preliminary results indicate that proregenerative EVs increase the density of recruited OPCs, through their proliferation. These data unveil EVs as important players in microglia-OPCs cross-talk. Ongoing analyses will provide further insight on the action of MG EVs on OPC differentiation and remyelination.