Low dose of extracellular vesicles identified that promote recovery after ischemic stroke
Laura Otero‐Ortega, Fernando Laso-García, Mari Carmen Gómez-de Frutos, Luke Diekhorst, Arturo Martínez-Arroyo, Elisa Alonso‐López, Laura García‐Bermejo, Macarena Rodríguez‐Serrano, Mercedes Arrúe, Exuperio Díez‐Tejedor, Blanca Fuentes, María Gutiérrez‐Fernández
Abstract
BACKGROUND: Mesenchymal stem cell-derived extracellular vesicles (EVs) are one of the most promising therapeutics in protective and/or regenerative therapy in animal models of stroke using a dose of 100 μg. However, whether EVs dose is related to outcomes is not known. This study aimed to identify the optimal effective dose of EVs from adipose tissue-derived mesenchymal stem cells that promote functional recovery in subcortical stroke. MATERIALS AND METHODS: For this purpose, various doses of EVs were tested in an in vitro oxygen-glucose deprivation (OGD) model of oligodendrocytes and neuronal ischemia. At least 50 μg of EVs were necessary to induce proliferation and differentiation of oligodendrocyte and neurons in OGD conditions. For in vivo study, rats were subjected to subcortical stroke and various doses (50 μg, 100 μg, or 200 μg) of EVs were intravenously administered after 24 h. RESULTS: All the animals in the EV groups showed significant improvement in functional tests, with an increase in tract connectivity and brain repair-associated markers, and a decrease in cell death and in astrocyte-marker expression. Cell proliferation was increased in the groups receiving 50 μg and 100 μg doses. Only the 50-μg dose was associated with significant increases in brain-derived neurotrophic factor expression. CONCLUSION: In conclusion, 50 μg of EVs appears to be the minimal effective dose to enhance protection, brain repair, and recovery in subcortical ischemic stroke.