Tailored multipotent mesenchymal stromal cell harvested exosomes carrying elevated miR-17-92 cluster enhance neurovascular remodeling & improve functional recovery after stroke in rats
Xin H, Katakowski M, Wang F, Qian J, Santra M, Liu XS, Ali MM, Buller B, Zhang ZG, and Chopp M. Tailored multipotent mesenchymal stromal cell harvested exosomes carrying elevated miR-17-92 cluster enhance neurovascular remodeling & improve functional recovery after stroke in rats. Stroke 2017; 48 (Suppl 1).
Introduction: MSC generated exosomes mediate therapeutic benefits of MSCs for stroke, which are at least in-part attributed to their miRNA contents. In vitro, the miR-17-92 cluster promotes oligodendrogenesis, neurogenesis and axonal outgrowth, and tailored MSC exosomes enriched with the miR-17-92 cluster promote axonal outgrowth of primary cortical neurons. We therefore investigated whether the miR-17-92 cluster enriched exosomes (Exo-miR-17-92+) harvested from MSCs enhance neurological recovery compared to control MSC derived exosomes (Exo-Con).Methods: Rats (n=8/group) subjected to 2 hours of transient MCAO were intravenously administered ExomiR-17-92+, Exo-Con, or liposomes, and were sacrificed 28 days post MCAO. Foot-fault test, and a modified neurologic severity score (mNSS) were carried out at 1, 3, 7, 14, 21 and 28 days after MCAO by an investigator blinded to the treatments. Histochemistry, immunohistochemistry and Golgi-Cox staining were used to assess dendritic, axonal, synaptic and myelin remodeling. Expression of PTEN and activation of its downstream proteins, Akt, mTOR and GSK-3β in the peri-infarct region were measured by means of Western blots. Results: Compared with the liposome treatment, both exosome treatment groups exhibited significant improvement of functional recovery (P<0.05, respectively), but Ex-miR-17-92+ treatment had more robust effects on improvement of neurological function (P<0.05), and enhancements of oligodendrogenesis, neurogenesis and neurite remodeling/neuronal dendrite plasticity in the ischemic boundary zone (IBZ) than the Ex-Con treatment (P<0.05, respectively). Moreover, Ex-miR-17-92+ treatment substantially inhibited PTEN, a validated miR-17-92 cluster target gene, and subsequently increased the phosphorylation of PTEN downstream proteins, Akt, mTOR, and decreased the activity of GSK-3β by phosphorylating GSK-3β in neurons compared to Ex-Con treatment (P<0.05, respectively). Conclusions: Our data suggest that treatment of stroke with tailored exosomes enriched with the miR-17- 92 cluster increases neural plasticity and functional recovery after stroke, possibly via targeting PTEN to activate the PI3K/Akt/mTOR/GSK-3β signaling pathway.