Extracellular vesicles from mesenchymal stem cells reduce microglial-mediated neuroinflammation after cortical injury in aged Rhesus monkeys
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Cortical injury, such as injuries after stroke or age-related ischemic events, triggers a cascade of degeneration accompanied by inflammatory responses that mediate neurological deficits. Therapeutics that modulate such neuroinflammatory responses in the aging brain have the potential to reduce neurological dysfunction and promote recovery. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) are lipid-bound, nanoscale vesicles that can modulate inflammation and enhance recovery in rodent stroke models. We recently assessed the efficacy of intravenous infusions of MSC-EVs (24-h and 14-days post-injury) as a treatment in aged rhesus monkeys (Macaca mulatta) with cortical injury that induced impairment of fine motor function of the hand. Aged monkeys treated with EVs after injury recovered motor function more rapidly and more fully than aged monkeys given a vehicle control. Here, we describe EV-mediated inflammatory changes using histological assays to quantify differences in markers of neuroinflammation in brain tissue between EV and vehicle-treated aged monkeys. The activation status of microglia, the innate macrophages of the brain, is critical to cell fate after injury. Our findings demonstrate that EV treatment after injury is associated with greater densities of ramified, homeostatic microglia, along with reduced pro-inflammatory microglial markers. These findings are consistent with a phenotypic switch of inflammatory hypertrophic microglia towards anti-inflammatory, homeostatic functions, which was correlated with enhanced functional recovery. Overall, our data suggest that EVs reduce neuroinflammation and shift microglia towards restorative functions. These findings demonstrate the therapeutic potential of MSC-derived EVs for reducing neuroinflammation after cortical injury in the aged brain.
KeywordsExtracellular vesicles Cortical injury Rhesus Monkeys
Mesenchymal stem cells
Perilesional gray matter
Sublesional white matter
We would like to acknowledge our staff, Penny Schultz and Karen Slater, and graduate students, Karen Bottenfield, Katelyn Trecartin, Samantha Calderazzo, and Ajay Uprety, for their invaluable assistance with this study.
This work was supported by the NIH grants R21-NS102991, R21NS111174, and U01-NS076474 and the National Center for Advancing Translational Sciences, National Institutes of Health, through BU-CTSI Grant Number 1UL1TR001430.
Compliance with ethical standards
The authors declare that they have no competing interests.
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