Objective: Mesenchymal stem cells (MSCs) and derived extracellular vesicles (MSC-EVs) have been reported to alleviate pain in humans with knee osteoarthritis (OA). Our objective was to determine whether MSCs and/or MSC-EVs reduce OA pain through influencing sensory neuron excitability in OA joints.
Methods: We induced knee OA in adult male C57BL/6J mice through the destabilization of the medial meniscus (DMM) surgery. Mice were divided into 4 experimental groups (N=9 per group): Sham, DMM, DMM+MSCs, DMM+MSC-EVs. Following surgery, MSCs were administered at 14-weeks, and MSC-EVs at 12-weeks and 14-weeks. Mouse behavior was evaluated by digging and rotarod tests, and the digital ventilated caging (DVC) system. After 16-weeks, mouse knee joints were harvested for histology and dorsal root ganglion (DRG) neurons were isolated for electrophysiology. Furthermore, we induced hyperexcitability in DRG neurons in vitro using nerve growth factor (NGF) and treated neurons with or without MSC-EVs and evaluated neuron excitability.
Results: MSC and MSC-EV treated DMM mice did not display pain-related behavioral changes (i.e. locomotion, digging and sleep) that occurred in untreated DMM mice. The absence of pain-related behaviors in MSC/MSC-EV treated mice was not the result of reduced joint damage, but rather a lack of knee-innervating sensory neuron hyperexcitability that was observed in untreated DMM mice (p < 0.01). Furthermore, we found that NGF-induced sensory neuron hyperexcitability is prevented by MSC-EV treatment (p < 0.05).
Conclusion: We conclude that MSCs and MSC-EVs may reduce pain in OA by direct action on peripheral sensory neurons.
