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In this regard, the use of extracellular vesicles (EVs) represents a promising therapeutic approach. However, the molecular mechanisms by which EVs regulate microglial responses remain poorly understood. In the present study, we used EVs derived from human oral mucosa stem cells (OMSCs) to investigate the effects on the lipid raft formation and the phagocytic response of human microglial cells. Lipid raft labeling with fluorescent cholera toxin subunit B conjugates revealed that both EVs and lipopolysaccharide (LPS) by more than two times increased lipid raft formation in human microglia. By contrast, combined treatment with LPS and EVs significantly decreased lipid raft formation indicating possible interference of EVs with the process of LPS\u2010induced lipid raft formation. Specific inhibition of Toll\u2010like receptor 4 (TLR4) with anti\u2010TLR4 antibody as well as inhibition of purinergic P2X4 receptor (P2X4R) with selective antagonist 5\u2010BDBD inhibited EVs\u2010 and LPS\u2010induced lipid raft formation. Selective blockage of \u03b1v\u03b23\/\u03b1v\u03b25 integrins with cilengitide suppressed EV\u2010 and LPS\u2010induced lipid raft formation in microglia. Furthermore, inhibition of TLR4 and P2X4R prevented EV\u2010induced phagocytic activity of human microglial cells. We demonstrate that EVs induce lipid raft formation in human microglia through interaction with TLR4, P2X4R, and \u03b1V\u03b23\/\u03b1V\u03b25 signaling pathways. Our results provide new insights about the molecular mechanisms regulating EV\/microglia interactions and could be used for the development of new therapeutic strategies against neurological disorders.<\/jats:p>","DOI":"10.1002\/cbin.12111","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T18:34:34Z","timestamp":1702665274000},"page":"358-368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Extracellular vesicles from oral mucosa stem cells promote lipid raft formation in human microglia through TLR4, P2X4R, and \u03b1V\u03b23\/\u03b1V\u03b25 signaling pathways"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6642-6894","authenticated-orcid":false,"given":"Diana","family":"Romenskaja","sequence":"first","affiliation":[{"name":"Department of Stem Cell Biology State Research Institute Centre for Innovative Medicine Vilnius 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