000K utf8 1100 2023$c2023-11-27 1500 eng 2050 urn:nbn:de:hbz:465-20240731-151237-3 2051 10.1186/s12974-023-02961-0 3000 Labusek, Nicole 3010 Bendix, Ivo 3010 Diesterbeck, Eva 3010 Felderhoff-Müser, Ursula 3010 Ghari, Parnian 3010 Giebel, Bernd 3010 Hadamitzky, Martin 3010 Herz, Josephine 3010 Köster, Christian 3010 Mouloud, Yanis 4000 Hypothermia combined with extracellular vesicles from clonally expanded immortalized mesenchymal stromal cells improves neurodevelopmental impairment in neonatal hypoxic-ischemic brain injury [Labusek, Nicole] 4209 Background: Neonatal encephalopathy following hypoxia–ischemia (HI) is a leading cause of childhood death and morbidity. Hypothermia (HT), the only available but obligatory therapy is limited due to a short therapeutic window and limited efficacy. An adjuvant therapy overcoming limitations of HT is still missing. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have shown promising therapeutic effects in various brain injury models. Challenges associated with MSCs’ heterogeneity and senescence can be mitigated by the use of EVs from clonally expanded immortalized MSCs (ciMSCs). In the present study, we hypothesized that intranasal ciMSC-EV delivery overcomes limitations of HT. Methods: Nine-day-old C57BL/6 mice were exposed to HI by occlusion of the right common carotid artery followed by 1 h hypoxia (10% oxygen). HT was initiated immediately after insult for 4 h. Control animals were kept at physiological body core temperatures. ciMSC-EVs or vehicle were administered intranasally 1, 3 and 5 days post HI/HT. Neuronal cell loss, inflammatory and regenerative responses were assessed via immunohistochemistry, western blot and real-time PCR 7 days after insult. Long-term neurodevelopmental outcome was evaluated by analyses of cognitive function, activity and anxiety-related behavior 5 weeks after HI/HT. Results: In contrast to HT monotherapy, the additional intranasal therapy with ciMSC-EVs prevented HI-induced cognitive deficits, hyperactivity and alterations of anxiety-related behavior at adolescence. This was preceded by reduction of striatal neuronal loss, decreased endothelial, microglia and astrocyte activation; reduced expression of pro-inflammatory and increased expression of anti-inflammatory cytokines. Furthermore, the combination of HT with intranasal ciMSC-EV delivery promoted regenerative and neurodevelopmental processes, including endothelial proliferation, neurotrophic growth factor expression and oligodendrocyte maturation, which were not altered by HT monotherapy. Conclusion: Intranasal delivery of ciMSC-EVs represents a novel adjunct therapy, overcoming limitations of acute HT thereby offering new possibilities for improving long-term outcomes in neonates with HI-induced brain injury. 4950 https://doi.org/10.1186/s12974-023-02961-0$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:hbz:465-20240731-151237-3$xR$3Volltext$534 4961 https://duepublico2.uni-due.de/receive/duepublico_mods_00081661 5051 610 5550 Extracellular vesicles 5550 Hypothermia 5550 Long-term neurodevelopmental deficits 5550 Mesenchymal stem/stromal cells 5550 Neonatal encephalopathy 5550 Neonatal hypoxia–ischemia 5550 Neuroinflammation 5550 Neuroregeneration