Mesenchymal stem cells reverse disease-specific abnormalities in nociceptive regions of the brain

Neuropathic pain is characterized by hyperalgesia, allodynia or spontaneous pain arising from lesions or pathology in the somatosensory nervous system. Multiple mechanisms contribute to this pain following peripheral nerve and spinal cord injuries. Evidence shows that injury-induced changes in dendritic spine morphology in the dorsal horn may contribute to neuropathic pain presentation. Dendritic spines, critical postsynaptic structures for synaptic transmission, undergo remodelling from filopodia-like structures to mature, mushroom-shaped spines in nociceptive spinal cord regions after injury. Recent evidence indicates that peripheral nerve and spinal cord injuries affect local tissues and also lead to pathology in supraspinal brain regions. Interestingly, different injuries appear to target specific brain regions, potentially causing corresponding remodelling of dendritic spines. To investigate this, we examined whether spared nerve injury, as a peripheral nerve injury model, and spinal cord injury induce morphological changes in dendritic spines in different brain regions and whether systemic administration of mesenchymal stem cells could alleviate neuropathic pain by altering dendritic spine morphology. Our results demonstrate that both injuries induce significant morphological changes in dendritic spines in the brain and spinal cord. Specifically, the peripheral nerve injury model increases the density of mushroom-shaped spines in superficial Lamina II of the dorsal horn, whereas spinal cord injury induces similar changes in deeper Lamina V. In the brain, the peripheral nerve injury model showed increased mushroom-shaped spines in the sensory cortex and ventral posterior complex of the thalamus. In contrast, the spinal cord injury model showed these changes primarily in the thalamic intralaminar nuclei. Infused mesenchymal stem cells partially alleviated neuropathic pain in both models and reduced the density of mushroom-shaped spines in the respective affected regions. Gene expression analysis of cytoskeletal genes related to actin associated with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AKAP5, ACTR2, and SORBS2) revealed upregulation of these genes in the sensory cortex (in the peripheral nerve injury model) and the thalamus (in the spinal cord injury model). Mesenchymal stem cells suppressed these upregulations, which were associated with reduced neuropathic pain. These findings suggest that infused mesenchymal stem cells can protect against the abnormal remodelling of dendritic spines, thereby contributing to pain alleviation regardless of injury type or affected region. The systemic administration of mesenchymal stem cells thus offers a promising therapeutic approach for treating multiple neuropathic pain conditions through structural and molecular alterations in dendritic spines.