Anales RANF

S16-04 ACTIVATED MICROGLIA REGULATE THE RESPONSE OF OLIGODENDROCYTE PROGENITORS EXPRESSING THE P2Y- LIKE RECEPTOR GPR17 FOLLOWING CEREBRAL ISCHEMIA S. Raffaele 1 , E. Bonfanti 1 , P. Gelosa 2 , L. Castiglioni 1 , L. Sironi 1,2 , M. Cimino 3 , C. Verderio 4 , M. P. Abbracchio 1 , M. Fumagalli 1 1 . University of Milan, Milan, Italy; 2 . Centro Cardiologico Monzino, Milan, Italy 3 . University of Urbino, Urbino, Italy; 4 . CNR - Institute of Neuroscience, Milan, Italy. Cerebral ischemia is a neurological disease representing a main cause of death and disability worldwide. Oligodendrocytes, the myelin-forming cells of the brain, are strongly affected by ischemia, leading to axonal demyelination which contributes to stroke-associated deficits. On this basis, enhancing myelin repair has recently emerged as a new therapeutic strategy to improve post-stroke recovery. Recent data obtained performing permanent middle cerebral artery occlusion (pMCAo) in conditional GPR17-iCreER T2 xCAG-eGFP transgenic mice showed that the subpopulation of adult oligodendrocyte precursor cells (OPCs) expressing the P2Y-like receptor GPR17 (GFP + -OPCs) actively contributes to reparative mechanisms after ischemia by increasing both proliferation rate and migratory ability. However, at late stages of the disease only a small percentage of these cells reaches complete maturation, resulting in remyelination failure. This limited post-stroke repair is likely due to the local unfavorable inflammatory milieu mediated by resident microglia and blood-borne macrophages. Here, we aimed at understanding the time-dependent role of microglia/macrophages following cerebral ischemia and how these cells contribute to OPC responses after stroke. In this respect, our data showed that microglia/macrophages are activated early after ischemia and they assume both pro-inflammatory and pro-regenerative phenotypes; instead, at late stages after stroke the number of pro-regenerative cells remains stable while pro-inflammatory cells continue to increase and become prevalent. Furthermore, we exploited a gadolinium-based approach to deplete microglia/macrophages at different time points of the disease. Interestingly, partial depletion of microglia/macrophages during the early phase after ischemia exacerbates brain injury and reduces the amount of GFP + -OPCs in the peri-infarct region. On the other hand, late partial depletion of microglia/macrophages promotes GFP + -OPC reaction, but it is ineffective in fostering their differentiation. Taken together, our results suggest that microglia/macrophages exert different roles in the regulation of OPC-mediated regenerative response during the course of the disease. Supported by Fondazione Cariplo grant 2015-0910 to MF