Anales RANF

S16-01 EFFECTS OF ATP-INDUCED MICROGLIAL EXTRACELLULAR VESICLES ON OLIGODENDROCYTE PROGENITORS IN CEREBRAL ISCHEMIA E. Bonfanti 1 , S. Raffaele 1 , M. Lombardi 2 , P. Gelosa 3 , L. Castiglioni 1 , L. Sironi 1,3 , M. Cimino 4 , M. P. Abbracchio 1 , C. Verderio 4 , M. Fumagalli 1 1 . University of Milan, Milan, Italy; 2 . IRCCS Humanitas, Milan, Italy; 3 .Centro Cardiologico Monzino, Milan, Italy; 4 .University of Urbino, Urbino, Italy; 4 . CNR - Institute of Neuroscience, Milan, Italy. Microglia are very plastic cells that can acquire multiple activated phenotypes in response to brain insults, participating not only in mechanisms of injury, but also in tissue remodeling. A dualistic role for distinct polarized cell populations has been associated with several neuropathological conditions, including ischemic stroke. In particular, during the acute phase of brain ischemia, microglia assume a protective phenotype, but at late stages, they acquire a prominent detrimental role that hinders the post-stroke reparative response sustained by oligodendrocyte progenitors (OPCs), the glial cell type able to generate myelinating oligodendrocytes. However, the mode(s) of action of microglia in supporting or inhibiting myelin repair is still unclear. Our in vitro data showed that extracellular vesicles (EVs) released from activated microglia promote OPC myelination, highlighting EVs as key players in microglia-OPCs cross-talk. Whether EVs shed from activated microglia could improve the endogenous remyelination capability of OPCs after brain ischemia is still not known. Here, we investigated in vivo the effects of ATP-induced EVs isolated from primary microglia polarized toward pro-inflammatory or pro-regenerative phenotypes in a murine model of permanent middle cerebral artery occlusion (pMCAo). Briefly, pMCAo was performed in GPR17-iCreERT2:CAG-eGFP mice in order to visualize the sub-population of GPR17-expressing OPCs thanks to GFP expression following tamoxifen administration. Then, EVs produced by microglia with diverse activation state were infused in the ipsilateral corpus callosum of ischemic mice two weeks after MCAo, when proinflammatory cells dominate the injured area, in order to analyze their effects on GFP + -OPC by immunohistochemistry. Results pointed out that only EVs derived from pro-regenerative microglia increase OPC maturation in vivo . Globally our results unveil EVs as a tool to implement tissue repair in brain ischemia. Dissecting microglial EVs content will be indispensable to design engineered-EVs for therapeutic purposes. Supported by Fondazione Cariplo grant 2015-0910 to MF