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

Abstract

Over 700 drugs have failed in stroke clinical trials, an unprecedented 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 cell signaling particles, were tested in a mouse thromboembolic (TE) stroke model. Neural stem cell (NSC) and mesenchymal 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 hanging 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 mediated by altering the systemic immune response. These data strongly support further preclinical development of a NSC EV-based stroke therapy and warrant their testing in combination with FDA-approved stroke therapies.Electronic supplementary materialThe online version of this article (10.1007/s12975-017-0599-2) contains supplementary material, which is available to authorized users.

Neural stem cell therapy for stroke: A multimechanistic approach to restoring neurological function

“…Recent studies have demonstrated that NSC culture‐conditioned media and purified media products inhibit apoptosis, reduce lesion size, and promote functional recovery in stroked preclinical models (Akerblom, Sachdeva, & Jakobsson, ; Delaloy et al, ; Madelaine et al, ; Stappert, Roese‐Koerner, & Brustle, ; Sutaria, Badawi, Phelps, & Schmittgen, ; Webb, Kaiser, Jurgielewicz et al, ; Webb, Kaiser, Scoville et al, ; Yang et al, ; Zhang et al, ). In a recent rat study utilizing NSC culture‐conditioned media directly, they showed a neuroprotective effect on tissue and functional improvement in a 21‐point behavioral test.…”

“…EVs derived from various cell sources have been shown to carry protein, DNA, and RNA cargoes that have therapeutic properties (Sutaria et al, ; Webb, Kaiser, Jurgielewicz et al, ; Zhang et al, ). Indeed, recent studies by Webb et al demonstrated that EVs derived from NSCs mitigated the systemic immune response, reduced infarct volume, inhibited hemorrhagic transformation, improved white matter integrity, and promoted functional recovery in two divergent preclinical stroke models‐ mouse thromboembolic and pig permanent middle cerebral artery occlusion stroke model (Webb, Kaiser, Jurgielewicz et al, ; Webb, Kaiser, Scoville et al, ). Although the exact molecular mechanism of NSC EV‐induced recovery is unknown, flow cytometry analysis illustrated that NSC EVs harbor CD29 and CD41b, which may have played a role in promoting BBB integrity and partially explain the therapeutic effect (Webb, Kaiser, Jurgielewicz et al, ).…”

“…Furthermore, comorbidities commonly encountered with stroke patients (e.g., diabetes and hypertension) as well as age effects and sex have not been or only limitedly assessed for their effects on NSC therapies in stroke. Indeed, only a handful of preclinical stroke studies are conducted in aged animals despite documented evidence of varying effectiveness of stroke therapeutics between young and aged animals (Popa‐Wagner, Filfan, Uzoni, Pourgolafshan, & Buga, ; Sandu et al, ; Webb, Kaiser, Scoville et al, ). Likewise, while animal models of diabetes, hypertension, and vascular dementia exist, they are rarely used to test NSC therapeutics in stroke in the preclinical setting.…”

Engineering Extracellular Vesicles as Nanotherapeutics for Regenerative Medicine

“…In a swine model of traumatic brain injury and hemorrhagic shock, animals that received bone marrow MSC-derived EVs via intravenous injection showed significantly lower neurologic impairment and had a faster full neurological recovery to baseline functions [47]. Similarly, intravenous administration of EVs from human embryonic stem cell-derived neural stem cells improved the functional and physical outcomes after thromboembolic stroke in middle-aged mice [48]. Mice that received EV treatment had greater improvements in motor functions and episodic memory while MRI analysis showed significantly less tissue loss.…”

Attack on stroke

“…4 The treatment, called AB126 uses extracellular vesicles, fluid-filled structures known as exosomes, which are generated from human neural stem cells. 4 The treatment, called AB126 uses extracellular vesicles, fluid-filled structures known as exosomes, which are generated from human neural stem cells.…”