Valproic Acid Modulates the Multipotency in Periodontal Ligament Stem Cells via p53-Mediated Cell Cycle

Human periodontal ligament stem cells (PDLSCs), a type of mesenchymal stem cell, are a promising source for dental regeneration and are identified in human periodontal ligaments from extracted third molars. Valproic acid (VPA) is a histone deacetylase inhibitor that has been used as a wide-spectrum antiepileptic drug and a medication for mood disorders. VPA has shown several effects on increasing the pluripotency of embryonic stem cells and controlling osteogenic differentiation, besides the prevention of seizures. However, its effect on proliferation and osteogenesis depends on the cell type and concentration. The aim of this study was to investigate the effects of cyclic and constant VPA treatment on PDLSCs. Proliferation and apoptosis of PDLSCs were determined with cyclic and constant VPA treatment. In cemento/osteogenic differentiation, osteogenic markers decreased significantly after cyclic treatment with 0.5 mM VPA. In contrast, VPA enhanced osteogenic differentiation after constant treatment. With cyclic VPA treatment, p53 levels related to apoptotic pathway decreased to induce proliferation. These findings indicated that VPA has different roles in proliferation and differentiation of PDLSCs in vitro and in vivo via p53-related pathway.