Introduction: Treatment of rodents with bone marrow mesenchymal stromal cells (MSCs) enhances functional recovery after stroke. We have shown in a series of studies that much or all of this effect is mediated through release of exosomes--small, membrane bound vesicles that contain many biomolecules--by the MSCs, and that functional benefit is dependent on white matter remodeling.
Hypothesis: We hypothesize that exosomes derived from monkey MSCs enhance axonal growth and myelination.
Methods: We isolated MSCs from the bone marrow of a young adult rhesus monkey, and harvested their exosomes from MSC culture medium.
Results: We first investigated the effect of exosomes on cultured organotypic brain slices from the cerebrum of rat pups. Treatment of brain slices with exosomes markedly increased myelination in cortex and corpus callosum compared to control. Image analysis of 3D reconstructions showed that exosomes increased connections of oligodendrocyte processes with axons by 48%, suggesting enhancement of initiation of myelination. To examine the effect of exosomes directly on neurons and oligodendrocyte progenitor cells (OPCs), exosomes were applied to either cortical neurons cultured in a microfluidic chamber or OPCs. We found that exosomes significantly (p<0.05) increased axonal length (526±22μm vs. 320±15μm for control, n=75/group) and increased the number of NG2+ OPCs by twofold compared to control (P < 0.01). However, exosomes had no significant effect on mature, MBP expressing oligodendrocytes.
Conclusion: Our data suggest that exosomes enhance myelination by a two-pronged effect. First, they promote axonal growth, and second, they increase the number of available OPCs. Increased axonal growth may trigger OPCs to myelinate axons. This work is the first to demonstrate the therapeutic potential of monkey exosomes for axonal growth and myelination.