Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation

Abstract

Although adipose derived stem cells (ADSCs) exert their therapeutic potential in ischemic stroke, the migration of ADSCs in injured area is not apparently observed after intravenous administration. ADSCs are an important source of exosomes which hold great promise as an endogenous drug delivery system for the treatment of cerebral ischemia given their ability to cross the blood-brain barrier. Here we investigated whether ADSCs-derived exosomes mediated miRNAs transfer and thus promoted neurological recovery after stroke. We first proved that miR-126 levels were reduced in patients’ plasma with acute ischemic stroke and in rat plasma and brain tissue after ischemia. To test the effect of exosomal miR-126, we employed overexpression and knock-down technologies to up-regulate or inhibit miR-126 level in ADSCs and thus acquired miR-126 ⁺ exosomes and miR-126 ^- exosomes, respectively. Compared with control, systemic administration of ADSCs-derived exosomes significantly increased the expression of von Willebrand factor (an endothelia cell marker) and doublecortin (a neuroblasts marker) and improved functional recovery in stroke rats. ADSCs-derived exosomes also resulted in a decrease of neuron cell death and an increase of cell proliferation compared with control. Importantly, these outcomes were further enhanced with miR-126 ⁺ exosomes treatment and were significantly decreased with miR-126 ^- exosomes treatment, compared to naïve exosomes treatment. MiR-126 ⁺ exosomes also inhibited microglial activation and the expression of inflammatory factors in vivo and in vitro. Our results suggest that intravenous administration of miR-126 ⁺ exosomes post stroke improves functional recovery, enhances neurogenesis, inhibits neuroinflammation, and represents a novel treatment for stroke.