Neural recovery after cortical injury: Effects of MSC derived extracellular vesicles on motor circuit remodeling in rhesus monkeys

Reorganization of motor circuits in the cortex and corticospinal tract are thought to underlie functional recovery after cortical injury, but the mechanisms of neural plasticity that could be therapeutic targets remain unclear. Recent work from our group have shown that systemic treatment with mesenchymal stem cell derived (MSCd) extracellular vesicles (EVs) administered after cortical damage to the primary motor cortex (M1) of rhesus monkeys resulted in a robust recovery of fine motor function and reduced chronic inflammation. Here, we used immunohistochemistry for cfos, an activity-dependent intermediate early gene, to label task-related neurons in the surviving primary motor and premotor cortices, and markers of axonal and synaptic plasticity in the spinal cord. Compared to vehicle, EV treatment was associated with a greater density of cfos⁺ pyramidal neurons in the deep layers of M1, greater density of cfos⁺ inhibitory interneurons in premotor areas, and lower density of synapses on MAP2+ lower motor neurons in the cervical spinal cord. These data suggest that the anti-inflammatory effects of EVs may reduce injury-related upper motor neuron damage and hyperexcitability, as well as aberrant compensatory re-organization in the cervical spinal cord to improve motor function.