Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression

Althoughtheinitialconceptsofstemcelltherapyaimedatreplacinglosttissue,morerecentevidence has suggested that stem and progenitor cells alike promote postischemic neurological recovery by secreted factors that restore the injured brain’s capacity to reshape. Specifically, extracellular vesicles (EVs) derived from stem cells such as exosomes have recently been suggested to mediate restorative stem cell effects.In order to define whether EVs indeedimprove postischemic neurologicalimpairmentandbrainremodeling,wesystematicallycomparedtheeffectsofmesenchymalstem cell(MSC)-derivedEVs(MSC-EVs)withMSCsthatwerei.v.deliveredtomiceondays1,3,and5(MSCEVs) or on day 1 (MSCs) after focal cerebral ischemia in C57BL6 mice. For as long as 28 days after stroke, motor coordination deficits, histological brain injury, immune responses in the peripheral bloodandbrain,andcerebralangiogenesisandneurogenesiswereanalyzed.Improvedneurological impairment and long-term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow-derived MSC lineages. MSC-EV administration closely resembled responses to MSCs and persisted throughout the observation period. Although cerebral immune cell infiltration was not affected by MSC-EVs, postischemic immunosuppression (i.e., B-cell, natural killer cell, and T-cell lymphopenia) was attenuated in the peripheral blood at 6 days after ischemia, providing an appropriate external milieu for successful brain remodeling. Because MSC-EVs have recently been shown to be apparently safe in humans, the present study provides clinically relevant evidence warranting rapid proof-of-concept studies in stroke patients. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1–13