Neural Progenitor-Like Cells Induced from Human Gingiva-Derived Mesenchymal Stem Cells Regulate Myelination of Schwann Cells in Rat Sciatic Nerve Regeneration

Abstract

Regeneration of peripheral nerve injury remains a major clinical challenge. Recently, mesenchymal stem cells (MSCs) have been considered as potential candidates for peripheral nerve regeneration; however, the underlying mechanisms remain elusive. Here, we show that human gingiva‐derived MSCs (GMSCs) could be directly induced into multipotent NPCs (iNPCs) under minimally manipulated conditions without the introduction of exogenous genes. Using a crush‐injury model of rat sciatic nerve, we demonstrate that GMSCs transplanted to the injury site could differentiate into neuronal cells, whereas iNPCs could differentiate into both neuronal and Schwann cells. After crush injury, iNPCs, compared with GMSCs, displayed superior therapeutic effects on axonal regeneration at both the injury site and the distal segment of the injured sciatic nerve. Mechanistically, transplantation of GMSCs, especially iNPCs, significantly attenuated injury‐triggered increase in the expression of c‐Jun, a transcription factor that functions as a major negative regulator of myelination and plays a central role in dedifferentiation/reprogramming of Schwann cells into a progenitor‐like state. Meanwhile, our results also demonstrate that transplantation of GMSCs and iNPCs consistently increased the expression of Krox‐20/EGR2, a transcription factor that governs the expression of myelin proteins and facilitates myelination. Altogether, our findings suggest that transplantation of GMSCs and iNPCs promotes peripheral nerve repair/regeneration, possibly by promoting remyelination of Schwann cells mediated via the regulation of the antagonistic myelination regulators, c‐Jun and Krox‐20/EGR2. Stem Cells Translational Medicine 2017;6:458–470

Gingiva-Derived Mesenchymal Stem Cell-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration

“…41 A cell/EV-scaffold combined product was developed using either GMSCs (5 • 10 5 cells in 20 mL PBS) or GMSC-derived EVs (40 mg in 20 mL PBS) mixed with Gelfoam (4 • 4 • 3 mm). 30 The cell/EVscaffold product was transplanted and wrapped around the injury site of the sciatic nerve immediately after nerve crush injury. Mice with sciatic nerve injury and treated with Gelfoam only served as controls.…”

“…In our previous study, we observed that transplanted GMSCs delivered in Gelfoam wrapped at the crush-injury site of the peripheral rat sciatic nerve did not cross the epineurium into the neural fiber compartment and appeared to exert their neurogenic effect via a paracrine mechanism. 30 In this study, we further explore the effect of GMSC-derived EVs in the repair/regeneration of PNI as an alternative therapeutic approach. Both immunofluorescence studies showed a significant decrease in b-tubulin III expression, a neuronal marker (Fig.…”

“…Most recently, we have shown that GMSCs could promote repair/regeneration of rat sciatic nerve injuries possibly via paracrine effects. 30 In this study, we explored whether EVs released by GMSCs could promote peripheral nerve regeneration using standard clinical approach with Gelfoam wrap embedded with these EVs and determined the potential underlying mechanisms.…”

In vitro study of neural stem cells and activated Schwann cells cocultured on electrospinning polycaprolactone scaffolds

“…In recent years, a variety of kinds of cells have been used for the neural repair. 2,[5][6][7][8] However, single-cell transplantation strategy cannot achieve a satisfying repair effect. In recent studies, combined strategy is widely used.…”

Advances of tooth‐derived stem cells in neural diseases treatments and nerve tissue regeneration

“…Once the sciatic nerve get injury, the motor function of leg would be affected. Gingiva-derived MSCs (GMSCs) have been shown to promote peripheral nerve repair as well by inducing remyelination by regulating the expression of the antagonistic myelination regulators, c-Jun and krox-20/ERG2 90. Studies showed that DPSCs could differentiate into Schwann cells in vitro.…”