Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: Microglia-derived extracellular vesicles (EVs) effects in glioma

Extracellular vesicles (EVs), such as microvesicles (MVs) and exosomes (EXO) provide a new type of inter-cellular communication, directly transferring a ready to use box of information, consisting of proteins, lipids and nucleic acids. The content of EVs, considered true metabolic units, is released into the cytoplasm of receiving cells, where they mediate several functional effects (Iraci et al., 2017). In the nervous system, EVs participate to neuron-glial cross-talk, a bidirectional communication important to preserve brain homeostasis and, when dysfunctional, involved in several CNS diseases. They modulate synaptic activity and neuronal communication (Korkut et al., 2013; Chivet et al., 2014), and contribute to spreading disease in several CNS pathologies, such as multiple sclerosis (Carandini et al., 2015), Alzheimer’s disease (Aguzzi and Rajendran, 2009; Gouwens et al., 2018), prion disease (Fevrier et al., 2004), and Huntington’s disease (Zhang et al., 2016). EVs released by microglia, similarly to EVs released by macrophages, recapitulate, in their cargo, the inflammatory information of the donor cell (Garzetti et al., 2014). In the instauration of a brain tumor, microglia assume a pro-inflammatory phenotype that protects brain parenchyma exerting an anti-tumor function; whereby in the context of a persistent glioma, microglial cells modify their phenotype and local microenvironment toward a pro-tumor, anti-inflammatory state supporting tumor cell proliferation, survival, and invasion. These cells are called tumor associated myeloid cells (TAMs) (da Fonseca and Badie, 2013). The principal aim of the project was to investigate whether enrichment of microglia-derived EVs (MVs and EXO) could be used to transfer a protective phenotype to dysfunctional microglia and other cells in brain parenchyma in a tumoral context. At this aim EVs, both MVs and EXO released by microglia, were isolated and analyzed for their in vitro and in vivo effects on glioma cells and in glioma bearing mice respectively. Results show that the enrichment of microglia-derived EVs exert anti-tumoral effects depending on the inflammatory cargo for MVs and on miR124 for EXO. Part of this thesis it was published in 2019 on the journal “Frontiers in Cellular Neuroscience” (Grimaldi and Serpe et al., 2019). Other results are going on submission.