The Interplay Between Neuromodulation and Stem Cell Therapy for Sensory-Motor Neuroplasticity After Spinal Cord Injury: A Perspective View.

Spinal Cord Injury (SCI) rehabilitation is undergoing a transformative shift with the emergence of new treatment strategies. Historically, treatment options were limited, and few offered meaningful recovery. Recent work in human models has shown that neuromodulation specifically with spinal cord epidural stimulation (SCES) paired with task-specific training (TsT) can partially restore motor function such as the ability to stand, step, and perform volitional movements. Despite these advances, the recovery has been shown to plateau even with the combination of therapies. The recovery process typically leads to partial rather than complete restoration of function. This limitation arises because current approaches primarily reactivate existing circuits rather than repair the disrupted pathways. Scar tissue and loss of descending and ascending connections remain major barriers to full recovery, restricting the transmission of neural signals. We argue that the next phase of research should be a synergistic strategy building upon the successes of neuromodulation and TsT while incorporating a regenerative therapy such as stem-cell-based interventions. Whereas neuromodulation and task-specific training increases excitability and reorganizes existing networks, stem cells have the potential to repair structural damage and re-establish communication across injured regions or facilitating the establishment of dormant pathways. The future of SCI recovery relies on multi-modal synergistic interventions that are likely to maximize long-term functional outcomes. In the current perspective, we summarized the basic findings on applications of SCES on restoration of sensory-motor functions. We then projected on current interventions on utilizing stem cell therapy intervention. We highlighted the outcomes of randomized clinical trials, and the major barriers for considering the synergistic approach between SCES and stem cell intervention. We are hopeful that this perspective may lead to roundtable scientific discussion to bridge the gap on how to conduct numerous clinical trials in the field.