Extracellular Vesicles Enhance The Coupling of Neurogenesis and Angiogenesis and Neurological Recovery By Transfer of Micrornas After Stroke

ABSTRACT

Intercellular communications underlying stroke‐induced angiogenesis and neurogenesis remain largely unknown. We tested the hypothesis that extracellular vesicles (EVs) derived from ischemic cerebral endothelial cells (ECs) and neural stem cells (NSCs) via their cargo microRNAs (miRNAs) mediate the coupling of angiogenesis and neurogenesis following stroke. Cell‐type‐specific EVs were isolated from conditioned media of cultured ECs and NSCs harvested from non‐ischemic and ischemic rats. EV cargo miRNA profile analyses revealed that ischemic EC‐EVs were enriched with miR‐125a and ‐146a, whereas ischemic NSC‐EVs were enriched with miR‐106b and ‐125b. In vitro, treatment of non‐ischemic NSCs with ischemic EC‐EVs significantly increased NSC proliferation and differentiation, and augmented their miR‐146a and ‐125a contents. Incubation of non‐ischemic ECs with ischemic NSC‐EVs robustly increased in vitro angiogenesis, with elevations of EC miR‐106b and ‐125b. To determine whether ischemic EV cargo miRNAs mediate these effects, we engineered non‐ischemic EC‐EVs and NSC‐EVs to carry specific miRNA mimics. Treatment of non‐ischemic NSCs with the engineered EC‐EVs containing miR‐125a or ‐146a mimics significantly increased neurogenesis, while treatment of non‐ischemic ECs with engineered NSC‐EVs containing miR‐106b or ‐125b mimics significantly promoted angiogenesis. Furthermore, intranasal administration of ischemic NSC‐EVs or EC‐EVs to rats subjected to 24‐h middle cerebral artery occlusion (MCAO), administered every other day for two consecutive weeks, markedly improved neurological and cognitive recovery. Collectively, our data suggest that ischemic EC‐ and NSC‐EV cargo, particularly miRNAs, facilitates the coupling of stroke‐induced neurogenesis and angiogenesis during stroke recovery.