Extracellular vesicles isolated from bone marrow mesenchymal stem cells induce an anti-inflammatory phenotype in microglia exposed to human Aβ

In Alzheimer’s disease (AD), the presence of brain senile plaques, neurofibrillary tangles and activated microglial cells strongly contribute to generate an inflammatory environment. The aim of the project is to investigate a possible anti-inflammatory effect of bone marrow derived mesenchymal stem cell microvesicles (BM-MSC MVs) in microglia cultures exposed to human beta Amyloid peptide 1-42 (h-Aβ1-42). BM-MSCs isolated from 4-12 week old C57BL/6 mice were expanded in vitro and tested for their ability to differentiate into specific mesenchymal lineages. MVs were isolated from the culture medium of BM-MSCs by a protocol which consists of a series of centrifugation and were characterized by FACS and western blot analysis for specific surface markers. Primary culture of murine microglial cells derived from cortices of P2 mice were treated with h-Aβ1-42 peptide, in the presence of MVs or culture supernatant deprived of MVs, to evaluate by immunocytochemistry the expression of different inflammatory or anti-inflammatory markers and by ELISA cytokine production in different conditions. BM-MSC MVs down-regulate the inflammatory processes induced by exposure of microglia to h Aβ1-42 peptide in vitro. In fact, microglial cells, following MV treatment, assume an amoeboid phenotype becoming less ramified and releasing anti-inflammatory cytokines without significantly affecting the release of the pro-inflammatory ones. Moreover, MVs lead to a decreased expression of MHC II, associated with a pro-inflammatory phenotype. As in AD the chronic proinflammatory environment is postulated to contribute to the cognitive deficits and neuronal loss that characterize the disease, the immunomodulatory properties of BM-MSC MVs may represent a powerful tool to modulate this aberrant process.