Human GMSCs Regulate Myelination of Schwann Cells via EGR2/Krox20 Pathway

Objectives: Peripheral nerve injury is debilitating and results in long-term disability and compromised quality of life. Currently, autologous nerve grafts remain the “gold standard”, however, the morbidity and limited supply of donor nerves have significantly impeded their clinical application. Our recent study showed that human gingiva-derived mesenchymal stem cells (hGMSCs) could promote the regeneration of rat sciatic nerve injuries. However, the exact mechanisms of nerve regeneration by MSCs remain elusive.In this study, we investigated whether human gingiva-derived mesenchymal stem cells (hGMSCs) could regulate myelination of Schwann cells and the potential mechanisms.
Methods: In vitro, hGMSCs were co-cultured with rat and human Schwann cells and the expression of key regulatory genes involved in Schwann cell myelination and dedifferentiation was determined by Western blot, qRT-PCR and immunocytochemical studies. Soluble factors secreted by hGMSCs involved in regulating Schwann cell myelination were identified by using siRNA transfection or neutralizing antibodies.
Results: We demonstrated that co-culture with hGMSCs or incubation with hGMSC-derived conditioned media significantly increased the expression of both EGR2/Krox20, a major transcription factor (TF) that governs the expression of myelin proteins, and c-Jun, one of the major negative regulators of myelination/differentiation, in Schwann cells. Our data showed that stimulation of Schwann cells with IL-6, an abundant cytokine secreted by hGMSCs, robustly increased the expression of c-Jun and Notch1, two negative regulators of myelination/differentiation. On the contrary, treatment with PGE2 and IL-8 consistently led to an increased expression of Krox-20/EGR2 and myelin protein P0.
Conclusions: Taken together, our findings suggest that hGMSCs regulate myelination/differentiation of Schwann cells via tuning the expression of the antagonistic myelination regulators, c-Jun/Notch1 and Krox-20/EGR2.