Abstract
Stem cell therapy is one of the most promising candidate treatments for spinal cord injury. Research has shown optimistic results for this therapy, but clinical limitations remain, including poor viability, engraftment, and differentiation. Here, we isolated novel peripheral nerve-derived stem cells (PNSCs) from adult peripheral nerves with similar characteristics to neural-crest stem cells. These PNSCs expressed neural-crest specific markers and showed multilineage differentiation potential into Schwann cells, neuroglia, neurons, and mesodermal cells. In addition, PNSCs showed therapeutic potential by releasing the neurotrophic factors, including glial cell-line-derived neurotrophic factor, insulin-like growth factor, nerve growth factor, and neurotrophin-3. PNSC abilities were also enhanced by their development into spheroids which secreted neurotrophic factors several times more than non-spheroid PNSCs and expressed several types of extra cellular matrix. These features suggest that the potential for these PNSC spheroids can overcome their limitations. In an animal spinal cord injury (SCI) model, these PNSC spheroids induced functional recovery and neuronal regeneration. These PNSC spheroids also reduced the neuropathic pain which accompanies SCI after remyelination. These PNSC spheroids may represent a new therapeutic approach for patients suffering from SCI.
Highlights
Spinal cord injury (SCI) is mainly caused by external injuries, and by vascular disorders, tumors, and infections
In the peripheral nerve-derived stem cells (PNSCs)-transplanted groups, the expressions of the neuronal marker Tuj1 and the oligodendrocyte marker MBP increased, but expression of the astrocytic marker GFAP decreased (Figure 6C–F). This was especially true for the SCI/PNSC spheroids group which showed the most marked changes in all cell types; Tuj1 expression increased significantly to near-sham levels and the expressions of the other markers was closer to sham levels compared to the other groups (Figure 6C–F). These results indicate that PNSC viability is not sufficient; its paracrine effects are required for the enhancement of recovery and is improved by the formation of spheroids
We report on the development of PNSC spheroids that: (1) can form as stable spheres (100 ± 20 μm); (2) have immune expression characteristics similar to neural crest (NC) stem cells; (3) have the ability to differentiate into neuronal and mesenchymal cells; (4) consistently release several neurotrophic factors and anti-inflammatory factors; and (5) have improved therapeutic ability in a SCI model
Summary
Spinal cord injury (SCI) is mainly caused by external injuries, and by vascular disorders, tumors, and infections. Stem cell therapy is a major field of research for SCI treatment. MSCs have been mostly used in SCI clinical trials In these studies, the effects of MSCs were reported to be anti-inflammatory, immunomodulatory, anti-apoptotic, and paracrine, and included the release of neurotrophic factors. The origins of NSCs used for SCI research are from several sources: fetal and embryonic stem cells, iPSCs, and via trans-differentiation [14]. Ethical and safety concerns remain about potential tumorigenesis due to their sources [8] Due to these reasons, identification of other cell types for effective SCI therapies is needed, with the possibility of pre-conditioning them or modifying their genes to enhance both their survival and paracrine effect
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