ABSTRACT
Mesenchymal stem cells have previously been shown to mediate brain repair after stroke; they secrete 50-100 nm complexes called extracellular vesicles (EVs), which could be responsible for provoking neurovascular repair and functional recovery. EVs have been observed by electron microscopy and NanoSight, and they contain associated proteins such as CD81 and Alix. This purified, homogeneous population of EVs was administered intravenously after subcortical stroke in rats. To evaluate the EVs effects, we studied the biodistribution, proteomics analysis, functional evaluation, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers. We found that a single administration of EVs improved functional recovery, fiber tract integrity, axonal sprouting and white matter repair markers in an experimental animal model of subcortical stroke. EVs were found in the animals' brain and peripheral organs after euthanasia. White matter integrity was in part restored by EVs administration mediated by molecular repair factors implicated in axonal sprouting, tract connectivity, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery. This novel role for EVs presents a new perspective in the development of biologics for brain repair.
Subject(s)
Extracellular Vesicles/transplantation , Mesenchymal Stem Cells/metabolism , Recovery of Function , Stroke/therapy , White Matter/metabolism , Animals , Axons/metabolism , Axons/ultrastructure , Biomarkers/metabolism , Brain/metabolism , Brain/ultrastructure , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Connectome , Disease Models, Animal , Extracellular Vesicles/chemistry , Gene Expression Regulation , Injections, Intravenous , Male , Nerve Regeneration/physiology , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neuronal Plasticity/physiology , Proteome/genetics , Proteome/metabolism , Rats , Rats, Sprague-Dawley , Stroke/genetics , Stroke/metabolism , Stroke/pathology , Tetraspanin 28/genetics , Tetraspanin 28/metabolism , Tissue Distribution , White Matter/ultrastructureABSTRACT
Ultrasound-targeted microbubble destruction (UTMD) has been shown to be a promising tool to deliver proteins to select body areas. This study aimed to analyze whether UTMD was able to deliver brain-derived neurotrophic factor (BDNF) to the brain, enhancing functional recovery and white matter repair, in an animal model of subcortical stroke induced by endothelin (ET)-1. UTMD was used to deliver BDNF to the brain 24 h after stroke. This technique was shown to be safe, given there were no cases of hemorrhagic transformation or blood brain barrier (BBB) leakage. UTMD treatment was associated with increased brain BDNF levels at 4 h after administration. Targeted ultrasound delivery of BDNF improved functional recovery associated with fiber tract connectivity restoration, increasing oligodendrocyte markers and remyelination compared to BDNF alone administration in an experimental animal model of white matter injury.
