Neural progenitor cell-derived extracellular vesicles enhance blood-brain barrier integrity in stroke mice

Abstract

Objective Extracellular vesicles (EVs) derived from neural progenitor cells (NPCs) enhance post-stroke neurological recovery, albeit the underlying mechanisms remain elusive. Since previous research described an enhanced post-stroke integrity of the blood-brain barrier (BBB) upon systemic transplantation of NPCs, we examined if NPC-derived EVs affect BBB integrity and which cellular mechanisms are involved in the process. Approach and Results Using in vitro models of primary brain endothelial cell (EC) cultures as well as co-cultures of brain endothelial cells (ECs) and astrocytes exposed to oxygen-glucose-deprivation (OGD), we examined the effects of EVs or vehicles on microvascular integrity. In vitro data were confirmed using a mouse transient middle cerebral artery occlusion model. Cultured ECs displayed increased ATP-binding cassette transporter B1 (ABCB1) levels when exposed to OGD, which was reversed by treatment with EVs. The latter was due to an EV-induced inhibition of the NF-κB pathway. Using a BBB co-culture model of ECs and astrocytes exposed to OGD, EVs stabilized the BBB and ABCB1 levels without affecting the transcellular electrical resistance (TER) of ECs. Likewise, EVs yielded reduced Evans blue extravasation, decreased ABCB1 expression as well as an inhibition of the NF-κB pathway and downstream matrix metalloprotease-9 activity in stroke mice. The EV-induced inhibition of the NF-κB pathway resulted in a post-stroke modulation of immune responses. Conclusions Our findings suggest that NPC-EVs enhance post-stroke BBB integrity via ABCB1 and MMP-9 regulation, attenuating inflammatory cell recruitment by inhibition of the NF-κB pathway.