Mesenchymal stromal cell-derived small extracellular vesicles promote neurological recovery and brain remodeling after distal middle cerebral artery occlusion in aged rats

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.

Hippocampal neuroprotection mediated by secretome of human mesenchymal stem cells against experimental stroke

“…In line with our findings, Cho et al have shown that CM derived from human MSCs elevates number of CD31‐positive microvessels in the penumbra following MCAO 16 . Recently, it has been reported that three times systemic injections of EVs derived from human BM‐MSCs could increase number of CD31 + /BrdU + microvessels and promote angiogenesis in the peri‐infarct cortex of ischemic rats 51 . It should be noted the newly generated capillaries may also pose major concerns including edema formation, hemorrhagic transformation, and BBB damage.…”

“…Furthermore, we also showed that rats receiving three injections of hESC‐MSC‐CM exhibit decreased mRNA level of IL‐6 as well as increased mRNA level of IL‐10 relative to ischemic rats. Similarly, intravenous injection of EVs obtained from MSCs has been shown to induce anti‐inflammation properties and reduce infiltration of immune cells in ischemic brains of aged mice on 7‐day post‐MCAO as well as microglia accumulation in the peri‐infarct cortex of young rats on 28‐day post‐MCAO 51,60 . Moreover, in several studies strong anti‐inflammatory and immunomodulatory properties of ESC‐MSC have been revealed.…”

“… 16 Recently, it has been reported that three times systemic injections of EVs derived from human BM‐MSCs could increase number of CD31 + /BrdU + microvessels and promote angiogenesis in the peri‐infarct cortex of ischemic rats. 51 It should be noted the newly generated capillaries may also pose major concerns including edema formation, hemorrhagic transformation, and BBB damage. For instance, although VEGF is the most potent trigger for inducing angiogenesis, it also enhances vascular permeability.…”

“…Similarly, intravenous injection of EVs obtained from MSCs has been shown to induce anti‐inflammation properties and reduce infiltration of immune cells in ischemic brains of aged mice on 7‐day post‐MCAO as well as microglia accumulation in the peri‐infarct cortex of young rats on 28‐day post‐MCAO. 51 , 60 Moreover, in several studies strong anti‐inflammatory and immunomodulatory properties of ESC‐MSC have been revealed. They secrete higher anti‐inflammatory cytokines IL‐10 while releasing lower pro‐inflammatory cytokine IL‐6 than fetal MSCs or BM‐MSCs.…”

Microvesicle-camouflaged biomimetic nanoparticles encapsulating a metal-organic framework for targeted rheumatoid arthritis therapy

“…Extracellular vesicles with lipid bilayer structures, such as exosomes and microvesicles (MVs), are secreted by mesenchymal stromal cells [ 25 ], neural stem cells [ 26 ], microglia [ 27 ] and other cell types. These vesicles can fuse with the cell membrane, providing a way for the vesicle contents to be transported between cells and for the vesicles to escape phagocytosis by endothelial reticular cells, thereby stabilizing them in the circulation [ 28 , 29 ].…”