Thomi, Gierin FlorenceGierin FlorenceThomi0000-0003-4607-2889Surbek, DanielDanielSurbekHaesler, ValérieValérieHaeslerJörger, MarianneMarianneJörgerSchoeberlein, AndreinaAndreinaSchoeberlein0000-0002-6716-95512024-10-082024-10-082019-03-21https://boris-portal.unibe.ch/handle/20.500.12422/65865BACKGROUND Preterm newborns are at high risk of developing neurodevelopmental deficits caused by neuroinflammation leading to perinatal brain injury. Human Wharton's jelly mesenchymal stem cells (hWJ-MSC) derived from the umbilical cord have been suggested to reduce neuroinflammation, in part through the release of extracellular vesicle-like exosomes. Here, we studied whether exosomes derived from hWJ-MSC have anti-inflammatory effects on microglia-mediated neuroinflammation in perinatal brain injury. METHODS Using ultracentrifugation, we isolated exosomes from hWJ-MSC culture supernatants. In an in vitro model of neuroinflammation, we stimulated immortalized BV-2 microglia and primary mixed glial cells with lipopolysaccharide (LPS) in the presence or absence of exosomes. In vivo, we introduced brain damage in 3-day-old rat pups and treated them intranasally with hWJ-MSC-derived exosomes. RESULTS hWJ-MSC-derived exosomes dampened the LPS-induced expression of inflammation-related genes by BV-2 microglia and primary mixed glial cells. The secretion of pro-inflammatory cytokines by LPS-stimulated primary mixed glial was inhibited by exosomes as well. Exosomes interfered within the Toll-like receptor 4 signaling of BV-2 microglia, as they prevented the degradation of the NFκB inhibitor IκBα and the phosphorylation of molecules of the mitogen-activated protein kinase family in response to LPS stimulation. Finally, intranasally administered exosomes reached the brain and reduced microglia-mediated neuroinflammation in rats with perinatal brain injury. CONCLUSIONS Our data suggest that the administration of hWJ-MSC-derived exosomes represents a promising therapy to prevent and treat perinatal brain injury.enBV-2 Exosomes Extracellular vesicles Hypoxia-ischemia Intranasal Mesenchymal stem cells Microglia Neuroinflammation Perinatal brain damage Preterm birth Umbilical cord White matter injury600 - Technology::610 - Medicine & health500 - Science::570 - Life sciences; biologyarticle10.7892/boris.1293353089815410.1186/s13287-019-1207-z