The mood stabilizers valproic acid and lithium enhance mesenchymal stem cell migration via distinct mechanisms

Mesenchymal stem cells (MSCs) show high potential for the therapy of several human diseases; however, the effectiveness of MSC transplantation has been hampered by the relatively poor migratory capacity of these cells toward disease target sites. This study investigated whether treatment of MSCs with two mood stabilizers-valproic acid (VPA) and lithium-would enhance cell migration and, if so, to explore the mechanisms underlying their effects. Short-term (3 h) exposure of MSCs to a relatively high concentration (2.5 mM) of VPA markedly increased the transcript and protein levels of CXC chemokine receptor 4 (CXCR4). VPA-induced CXCR4 expression required inhibition of histone deacetylases (HDACs), including the HDAC1 isoform, and involved histone hyperacetylation at the promoter region of the CXCR4 gene. Notably, VPA treatment enhanced stromal cell-derived factor-1α (SDF-1α)-mediated MSC migration, which was completely blocked by AMD3100, a CXCR4 antagonist. Treatment of MSCs with lithium (2.5 mM for 1 day) selectively elevated the transcript and protein levels of matrix metalloproteinase-9 (MMP-9) and its enzymatic activity; these effects were mimicked by inhibition or gene silencing of glycogen synthase kinase-3β (GSK-3β). Lithium treatment also potentiated SDF-1α-dependent MSC migration across the extracellular matrix, which was suppressed by two MMP-9 inhibitors, doxycycline and GM6001. Combining VPA and lithium treatment further increased MSC migration. Overall, VPA and lithium stimulated MSC migration through distinct targets and mediators: HDAC-CXCR4 and GSK-3β-MMP-9, respectively.