Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke

Robin L Webb, Erin E Kaiser*, Brian J Jurgielewicz, Samantha Spellicy, Shelley L. Scoville, Tyler A. Thompson, Raymond L Swetenburg, David C Hess, Franklin D West, Steven Stice

ArunA Biomedical, Athens, GA, Regenerative Bioscience Center and Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Rhodes Center for Animal and Dairy Science, Athens Department of Neurology, Augusta University, GA

Food and Drug approved therapies for stroke (tissue-type plasminogen activator and endovascular thrombectomy) are currently only available to a small population of stroke victims1,2. After a litany of failed treatments, assessment by the Stem Cell Emerging Paradigm in Stroke consortium meetings identified major needs, including (1) a regeneration therapy, and (2) testing in translational animal models more reflective of human pathology3,4. Similarly, the Stroke Therapy Academic Roundtable encouraged (1) testing in higher-order gyrenchephalic species, (2) evaluating clinically relevant routes of administration, and (3) longitudinal behavior assessment5,6. These recommendations prompted our therapeutic evaluation of intravenrously administered human neural stem cell extracellular vesicles (NSC EVs) in translational pig ischemic stroke model.


Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model

Robin L Webb1,2, Erin E Kaiser 2*, Shelley L Scoville 1, Tyler A Thompson 1, Sumbul Fatima3, Chirayukumar Pandya3, Chirayukumar Pandya3, Karishma Sriram2, Raymond L Swetenburg 1, Kumar Vaibhav3, Ali S Arbab4, Babak Baban5, Krishnan M Dhandapani6, David C Hess 7, MN Hoda3, Steven Stice1,2

1 Aruna Biomedical, Athens, GA 30602, USA 2 Regenerative Bioscience Center, Rhodes Center for Animal and Dairy Science, Bioscience, University of Georgia, Athens GA 30602, USA 3 Department of Medical Laboratory, Imaging and Radiologic Sciences, Augusta University, Augusta, GA 30912 4 Cancer Center, Augusta University, Augusta GA 30912, USA 5 Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta GA 30912, USA 6 Department of Neurosurgery, Augusta University, Augusta GA 30912, USA 7 Department of Neurology, Augusta University, Augusta GA 30912, USA

Over 700 drugs have failed in stroke clinical trials, an unprecendented rate thought to be attributed in part to limited and isolated testing often solely in "young" rodent models and focusing on a single secondary injury mechanism. Here, extracellular vesicles (EVs), nanometer-sized signaling particles, were tested in a mouse thromboembolic (TE) stroke model. Neural stem sell (NSC) and mesachysmal stem cell (MSC) EVs derived from the same pluripotent stem cell (PSC) line were evaluated for changes in infarct volume as well as sensorimotor function. NSC EVs improved cellular, tissue and functional outcomes in middle-aged rodents, whereas MSC EVs were less effective. Acute differences in lesion volume following NSC EV treatment were corroborated by MRI in 18-month-old aged rodents. NSC EV treatment has a positive effect on motor function in the aged rodent as indicated by beam walk, instances of foot faults, and strength evaluated by handing wire test. Increased time with a novel object also indicated that NSC EVs improved episodic memory formation in the rodent. The therapeutic effect of NSC EVs appears to be medicated by altering the systemic immune response. These data strongly support further preclinical development o fa NSC EV-based stroke therapy and warrant their testing in combination with FDA-approved stroke therapies.