Mesenchymal derived exosomes enhance recovery of motor function in a monkey model of cortical injury

Abstract

Background: Exosomes from mesenchymal stromal cells (MSCs) are endosome-derived vesicles that have been shown to enhance functional recovery in rodent models of stroke. Objective: Building on these findings, we tested exosomes as a treatment in monkeys with cortical injury. Methods: After being trained on a task of fine motor function of the hand, monkeys received a cortical injury to the hand representation in primary motor cortex. Twenty-four hours later and again 14 days after injury, monkeys received exosomes or vehicle control. Recovery of motor function was followed for 12 weeks. Results: Compared to monkeys that received vehicle, exosome treated monkeys returned to pre-operative grasp patterns and latency to retrieve a food reward in the first three-five weeks of recovery. Conclusions: These results provide evidence that in monkeys exosomes delivered after cortical injury enhance recovery of motor function.

Extracellular vesicles from mesenchymal stem cells reduce microglial-mediated neuroinflammation after cortical injury in aged Rhesus monkeys

“…Previous studies have demonstrated the efficacy of MSC-derived EVs in enhancing neurorestorative events including neurogenesis, angiogenesis, and axonal sprouting, both in vivo and in vitro in rodent and porcine models of brain injury and stroke (Xin et al 2012(Xin et al , 2013Chopp and Zhang 2015;Casado et al 2017;Williams et al 2019). Recently, we showed that systemic administration of MSC-EVs enhanced motor recovery in aged rhesus monkeys with cortical injury that involved damage to the hand representation of the primary motor cortex (Moore et al 2019). Compared to aged monkeys that received phosphate-buffered saline (PBS) vehicle, aged monkeys treated with EVs showed remarkable recovery, exhibiting full restoration of fine motor functionality within the first 3-5 weeks of recovery (Moore et al 2019).…”

“…Brain tissue used in this study was from the nine aged female rhesus monkeys used in Moore et al 2019. They ranged in age from 16 to 26 years old (analogous to humans approximately 48 to 78 years old) (Tigges et al 1988).…”

“…Monkeys were acquired from a private vendor (WorldWide Primates, Inc.), trained on a fine motor task, then randomly assigned to a vehicle control or EV treatment group before receiving a targeted cortical injury in the hand representation of the motor cortex. Based on previous dosing studies using MSC-EVs (Xin et al 2013), EV treatment was administered intravenously at 4 × 10 11 particles/kg first at 24 hours after injury and again 14 days after injury, as described in (Moore et al 2019). Vehicle control (PBS) was administered IVat a similar volume at 24 hours after injury and 14 days after injury.…”

“…One therapeutic approach that may enhance recovery of function after stroke or cortical injury is treatment using mesenchymal stem cells (MSCs) (Chopp and Li 2002;Bang et al 2005;Chopp et al 2009;Liu et al 2010;Jeong et al 2014;Williams et al 2019). Previous studies have demonstrated that stem cells can enhance recovery, likely through immunomodulation and neurorestorative events (Chen et al 2001;Jeong et al 2014;Orczykowski et al 2019;Moore et al 2019). In terms of mechanism, MSCs release extracellular vesicles (EVs), which are membrane-bound nanovesicles that contain miRNA, RNA, and proteins important for cell signaling (Xin et al 2012;Phinney and Pittenger 2017).…”

“…Recently, we showed that systemic administration of MSC-EVs enhanced motor recovery in aged rhesus monkeys with cortical injury that involved damage to the hand representation of the primary motor cortex (Moore et al 2019). Compared to aged monkeys that received phosphate-buffered saline (PBS) vehicle, aged monkeys treated with EVs showed remarkable recovery, exhibiting full restoration of fine motor functionality within the first 3-5 weeks of recovery (Moore et al 2019).…”