Valproic acid preconditioning of bone marrow mesenchymal stem cells promotes remyelination of the corpus callosum in a cuprizone-induced demyelination model

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disorder that currently has no exact treatment. However, stem cell therapy shows promise in treating neurodegenerative disorders. One of the main challenges with this treatment is the high apoptosis rate and low migration capacity of the transplanted stem cells. In this study we used Valproic acid (VPA) for preconditioning of bone marrow mesenchymal stem cells (BM-MSCs) before transplantation into the cuprizone induced demyelination model in C57/BL6 mice. Cell viability and CXCR4 mRNA expression and protein levels were assessed after preconditioning of BM-MSCs with VPA. Homing of BM-MSCs into the corpus callosum and visceral organs (liver and lung) were assessed 48 h after intravenous transplantation. Also, myelin content and the number of oligodendrocytes and astrocytes were evaluated in the corpus callosum. Our results indicated that 3 h VPA (5 mM) preconditioning of BM-MSCs led to an increase in viability and CXCR4 mRNA and protein levels in BM-MSCs. After IV transplantation VPA preconditioned BM-MSCs had a greater homing ability into the CNS but not to the visceral organs than non-preconditioned BM-MSCs. Also, transplantation of VPA preconditioned BM-MSCs resulted in a significant increase in remyelination and the number of oligodendrocytes while decreasing the number of astrocytes. These findings suggest that VPA preconditioning enhances the therapeutic efficacy of BM-MSCs when applied to cuprizone induced demyelination model.