Treatment with Mesenchymal-Derived Extracellular Vesicles Reduces Injury-Related Pathology in Pyramidal Neurons of Monkey Perilesional Ventral Premotor Cortex

Abstract

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle-and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.

Molecular Mechanism of Bone Marrow Mesenchymal Stem Cell Derived Exosomes on Vascular Repair in Rats with Brain Injury

“…In previous studies, BMSCs have been injected into animals with central nervous system damage and it is found that BMSCs can survive and migrate into damaged tissues and finally improve the neural function [10] . After ischemic stroke forms blood clots, endothelial cells die due to lack of nutrition, which destroys blood-brain barrier, causes edema of brain tissue and aggravates disease progress [11] . Promoting the formation of new blood vessels in ischemic area is of great significance to improve the prognosis of cerebral infarction.…”

Therapeutic application of exosomes in ischaemic stroke

“…66 Further mechanism studies reveal that MSC exosomes not only reduced neuroinflammation and shift microglia into restorative functions in aged macaca mulatta, 85 but also hampered injury related hyperexcitability and restored excitatory-inhibitory balance. 86 These effects could be ascribed to functional miRNAs or proteins transferring and further downstream signalling pathway activation. Intranasal delivery of MSC exosomes before ischaemia reduced neuronal death, promoted oligodendroglia maturation and inhibited microglia-mediated neuro-inflammation possibly via Toll-like receptor 4/CD14/NF-kB signalling pathway.…”

Mechanism of White Matter Injury and Promising Therapeutic Strategies of MSCs After Intracerebral Hemorrhage

“…The BMSCs, injected from the jugular vein of ICH-bearing rats, attenuated the inflammatory response and decreased BBB disruption by secreting TSG-6 after being trapped in the lung ( Chen M. et al, 2015 ). Most recently, researchers have verified the MSC-derived EVs (MSC-EVs), which mediate cell-to-cell inflammation and trophic signaling, to be feasible therapeutic targets for functional recovery after cortical injury in a monkey model ( Medalla et al, 2020 ). Besides, MSC-EVs can also trigger macrophage polarization by increasing the formation of anti-inflammatory M2 phenotype over M1-like pro-inflammatory phenotype via downregulation of level of IL-23 and IL-22.…”