Abstract Body: Exosomes have been used for therapeutic purposes to target stroke and other disorders. Repeated administration of mesenchymal stem cell (MSC)-derived exosomes in rats showed improved functionality and reduced stroke injury. However, exosomes from endothelial progenitor cells (EPCs) have not been tested in any stroke model, and in vivo bio-distribution study is lacking.
Targeted delivery of IV-administered exosomes has been a great challenge. Modifying the exosomal surface to carry different ligands or peptides has been tried to increase delivery to target tissues. However, the overall results are not encouraging. Delivery of exosomes to the brain is a daunting task, and a blood-brain barrier(BBB)-penetrable peptide is being considered. However, a method that can deliver naïve (unmodified) exosomes to the site of stroke without destroying host tissues, disrupting BBB, or the membranes of the delivery vehicles (such as exosomes) will be a breakthrough.
Low-intensity pulsed ultrasound (LIPUS) is approved for clinical use in musculoskeletal and physiotherapy clinics. The use of focused LIPUS to deliver exosomes has yet to be explored in stroke. The objectives of the proposed studies were to determine whether LIPUS-mediated increased delivery of EPC exosomes enhances stroke recovery and functional improvement in mice with tMCAo stroke. In this study, we used EPC-derived exosomes for stroke treatment. To enhance exosome delivery to the stroke area, we utilized focused LIPUS, which temporarily disrupts BBB. We evaluated stroke volume with MRI at different time points. We also conducted behavioral studies in parallel to MRI to determine the recovery. In the end, we studied the brain tissue with immunohistochemistry studies to evaluate the extent of stroke and tissue regeneration.
In vivo, imaging showed a higher accumulation of EPC exosomes following focused LIPUS without any damage to the underlying brain tissues. Four groups (Vehicle, LIPUS only, EPC-exosomes only, and LIPUS+EPC-exosomes) of aged animals were enrolled in the studies. The focused LIPUS + EPC exosomes group showed a decreased stroke volume (p=0.08) on day 7, decreased FluoroJade+ cells, and significantly higher numbers of neovascularization in and around the stroke areas although rCBF was not increased compared to that of other groups. There were no differences in the white matter tract volumes, ventricular volumes, astrogliosis, or neurobehavioral functions among the treated groups.