Abstract
Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) promote neurological recovery after middle cerebral artery occlusion (MCAO) in young rodents. Ischemic stroke mainly affects aged humans. MSC-sEV effects on stroke recovery in aged rodents had not been assessed. In a head-to-head comparison, we exposed young (4–5 months) and aged (19–20 months) male Sprague–Dawley rats to permanent distal MCAO. At 24 h, 3 and 7 days post-stroke, vehicle or MSC-sEVs (2 × 106 or 2 × 107 MSC equivalents/kg) were intravenously administered. Neurological deficits, ischemic injury, brain inflammatory responses, post-ischemic angiogenesis, and endogenous neurogenesis were evaluated over 28 days. Post-MCAO, aged vehicle-treated rats exhibited more severe motor-coordination deficits evaluated by rotating pole and cylinder tests and larger brain infarcts than young vehicle-treated rats. Although infarct volume was not influenced by MSC-sEVs, sEVs at both doses effectively reduced motor-coordination deficits in young and aged rats. Brain macrophage infiltrates in periinfarct tissue, which were evaluated as marker of a recovery-aversive inflammatory environment, were significantly stronger in aged than young vehicle-treated rats. sEVs reduced brain macrophage infiltrates in aged, but not young rats. The tolerogenic shift in immune balance paved the way for structural brain tissue remodeling. Hence, sEVs at both doses increased periinfarct angiogenesis evaluated by CD31/BrdU immunohistochemistry in young and aged rats, and low-dose sEVs increased neurogenesis in the subventricular zone examined by DCX/BrdU immunohistochemistry. Our study provides robust evidence that MSC-sEVs promote functional neurological recovery and brain tissue remodeling in aged rats post-stroke. This study encourages further proof-of-concept studies in clinic-relevant stroke settings.
Highlights
Small extracellular vesicles obtained from mesenchymal stromal cells (MSCs) hold great promise as restorative stroke treatments
Following early reports of enhanced neuronal plasticity and neurological recovery following delivery of MSC-derived sEVs in rats exposed to middle cerebral artery occlusion (MCAO) [1, 2], our group previously showed that MSC-sEVs very effectively increased motor-coordination recovery, long-term neuronal survival, periinfarct angiogenesis, and neurogenesis as their parental MSCs when administered starting 24 h after MCAO in mice [3, 4]
To clarify if endogenous neurogenesis was elevated by sEVs in the distal rat MCAO model, we evaluated the number of B rdU+ newborn neurons adjacent to the subventricular zone (SVZ) that expressed the immature neuronal marker doublecortin (DCX)
Summary
Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) hold great promise as restorative stroke treatments. SEV-based therapies have various advantages over cell therapies [8]: sEVs are not selfreplicating and lack endogenous malignant transformation risks Due to their small size, sEV products can be sterilized by filtration, and their handling is much easier than that of cellular therapeutics. SEVs can hardly sense environmental conditions, and their biological activity can be predicted more precisely than that of cells. In view of their unique potential, MSC-sEVs are rapidly approaching clinical trials. MSC-sEV effects on stroke recovery have not yet been assessed in aged rodents. Our study provides first evidence that MSC-sEVs promote postischemic neurological recovery and brain remodeling in aged rats
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
