Do-Hun Kim

Background: Spinal cord injury (SCI) results in permanent impairment of motor and sensory functions at and below the lesion site. There is no therapeutic option to the functional recovery of SCI involving diverse injury responses of different cell types in the lesion that limit endogenous nerve regeneration. In this regard, cell replacement therapy utilizing stem cells or their derivatives has become a highly promising approach to promote locomotor recovery. For this reason, the demand for a safe and efficient multipotent cell source that can differentiate into various neural cells is increasing. In this study, we evaluated the efficacy and safety of human polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive neural precursor cells (hNPCs^PSA-NCAM+) as a treatment for SCI. Methods: One hundred thousand hNPCs^PSA-NCAM+ isolated from human embryonic stem cell-derived NPCs were transplanted into the lesion site by microinjection 7 days after contusive SCI at the thoracic level. We examined the histological characteristics of the graft and behavioral improvement in the SCI rats 10 weeks after transplantation. Results: Locomotor activity improvement was estimated by the Basso–Beattie–Bresnahan locomotor rating scale. Behavioral tests revealed that the transplantation of the hNPCs^PSA-NCAM+ into the injured spinal cords of rats significantly improved locomotor function. Histological examination showed that hNPCs^PSA-NCAM+ had differentiated into neural cells and successfully integrated into the host tissue with no evidence of tumor formation. We investigated cytokine expressions, which led to the early therapeutic effect of hNPCs^PSA-NCAM+, and found that some undifferentiated NPCs still expressed midkine, a well-known neurotrophic factor involved in neural development and inflammatory responses, 10 weeks after transplantation. Conclusion: Our results demonstrate that hNPCs^PSA-NCAM+ serve as a safe and efficient cell source which has the potential to improve impaired motor function following SCI.

Previous studies have shown that early therapeutic events of neural precursor cells (NPCs) transplantation to animals with acute ischemic stroke readily protected neuronal cell damage and improved behavioral recovery through paracrine mechanisms. In this study, we tested the hypothesis that administration of conditioned medium from NPCs (NPC-CMs) could recapitulate the beneficial effects of cell transplantation. Rats with permanent middle cerebral artery occlusion (pMCAO) were randomly assigned to one of the following groups: PBS control, Vehicle (medium) controls, single (NPC-CM(S)) or multiple injections of NPC-CM(NPC-CM(M)) groups. A single intravenous injection of NPC-CM exhibited strong neuroregenerative potential to induce behavioral recovery, and multiple injections enhanced this activity further by suppressing inflammatory damage and inducing endogenous neurogenesis leading to histopathological and functional recovery. Proteome analysis of NPC-CM identified a number of proteins that are known to be associated with nervous system development, neurogenesis, and angiogenesis. In addition, transcriptome analysis revealed the importance of the inflammatory response during stroke recovery and some of the key hub genes in the interaction network were validated. Thus, our findings demonstrated that NPC-CM promoted functional recovery and reduced cerebral infarct and inflammation with enhanced endogenous neurogenesis, and the results highlighted the potency of NPC-CM in stroke therapy.