Peripheral Nerve Regeneration by Secretomes of Stem Cells from Human Exfoliated Deciduous Teeth

Abstract

Peripheral nerve regeneration across nerve gaps is often suboptimal, with poor functional recovery. Stem cell transplantation-based regenerative therapy is a promising approach for axon regeneration and functional recovery of peripheral nerve injury; however, the mechanisms remain controversial and unclear. Recent studies suggest that transplanted stem cells promote tissue regeneration through a paracrine mechanism. We investigated the effects of conditioned media derived from stem cells from human exfoliated deciduous teeth (SHED-CM) on peripheral nerve regeneration. In vitro, SHED-CM-treated Schwann cells exhibited significantly increased proliferation, migration, and the expression of neuron-, extracellular matrix (ECM)-, and angiogenesis-related genes. SHED-CM stimulated neuritogenesis of dorsal root ganglia and increased cell viability. Similarly, SHED-CM enhanced tube formation in an angiogenesis assay. In vivo, a 10-mm rat sciatic nerve gap model was bridged by silicon conduits containing SHED-CM or serum-free Dulbecco's modified Eagle's medium. Light and electron microscopy confirmed that the number of myelinated axons and axon-to-fiber ratio (G-ratio) were significantly higher in the SHED-CM group at 12 weeks after nerve transection surgery. The sciatic functional index (SFI) and gastrocnemius (target muscle) wet weight ratio demonstrated functional recovery. Increased compound muscle action potentials and increased SFI in the SHED-CM group suggested sciatic nerve reinnervation of the target muscle and improved functional recovery. We also observed reduced muscle atrophy in the SHED-CM group. Thus, SHEDs may secrete various trophic factors that enhance peripheral nerve regeneration through multiple mechanisms. SHED-CM may therefore provide a novel therapy that creates a more desirable extracellular microenvironment for peripheral nerve regeneration.

Stem Cells from Human Exfoliated Deciduous Teeth: A Growing Literature

“…These data reaffirm the immunomodulatory potential of MSC and indicate that it is also shared by SHED [Silva et al, 2014]. Sugimura-Wakayama et al [2015] investigated the effects of conditioned media derived from SHED on peripheral nerve regeneration (rat sciatic nerve) and detected that some growth factors such as neural growth factor, brain-derived neurotrophic factor, neurotrophin-3, ciliary neurotrophic factor, glial cell-derived neurotrophic factor, vascular endothelial growth factor and hepatocyte growth factor, various cytokines and chemokines can enhance peripheral nerve regeneration, and the results indicate that they can regulate the mobilization of stem cells to the target tissue.…”

Stem Cells of Dental Origin: Current Research Trends and Key Milestones towards Clinical Application

“…The latter was primarily attributed to the combined secretion of MCP-1 and the Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 (ED-Siglec-9) among 28 proteins detected in SHED-CM [160]. These results have been also validated by other groups that used SHED-CM for peripheral nerve regeneration across nerve gaps on rat sciatic nerve gap models [161]. A recent study also investigated the neuroprotective role of SHED-derived exosomes, highlighting another mechanism of their paracrine-mediated action [162].…”

Dental Stem Cell-Derived Secretome/Conditioned Medium: The Future for Regenerative Therapeutic Applications

“…This neuroprotective effect was evident through the promotion of migration, proliferation, and differentiation of Schwann cells; blood vessel formation; and nerve fiber extension [111]. These in vitro results were confirmed in vivo [110,111]. SHED-CM administration in a rat nerve gap model induced axon regeneration and remyelination [110,111].…”

“…(Table 1). SHED-CM contains various cytokines and chemokines with the ability to improve peripheral nerve regeneration and functional recovery [110]. The unique combination of neurotrophic factors, MCP-1 and secreted ectodomain of sialic acid-binding Ig-like lectin-9 (sSiglec-9), were described as crucial for SHED-CM mediated functional recovery, following severe peripheral nerve injury.…”