Valproic Acid Increases the Hepatic Differentiation Potential of Salivary Gland Cells

Abstract

The studies of cell plasticity and differentiation abilities are important problems in modern cellular biology. The use of histone deacetylase inhibitor - valproic acid is a promising approach to increasing the differentiation efficiency of various cell types. In this paper we investigate the ability of mouse submandibular salivary gland cells to differentiate into the hepatic direction and the effect of valproic acid on the efficiency of this differentiation. It was shown that the gene expression levels of hepatocyte markers (Aat, Afp, G6p, Pepck, Tat, Cyp3a13) and liver-enriched transcription factors (Hnf-3α, Hnf-3β, Hnf-4α, Hnf-6) were increased after differentiation in salivary gland cells. Valproic acid increases the specificity of hepatic differentiation, reducing the expression levels of the ductal (Krt19, Hhex1, Cyp7a1) and acinar (Ptf1a) markers. After valproic acid exposure, the efficiency of hepatic differentiation also increases, as evidenced by the increase in the gene expression level of Alb and Tdo, and increase in urea production by differentiated cells. No change was found in DNA methylation of the promoter regions of the genes; however, valproic acid treatment and subsequent hepatic differentiation largely affected the histone H3 methylation of liver-enriched genes. Thus, mouse submandibular salivary gland cells are capable of effective differentiation in the hepatic direction. Valproic acid increases the specificity and efficiency of the hepatic differentiation of these cells.

Valproic Acid Initiates Transdifferentiation of the Human Ductal Adenocarcinoma Cell-line Panc-1 Into α-Like Cells

“…One of the acknowledged HDACi is valproic acid (VPA), which acts through the enhanced acetylation of histones by inhibiting HDACs from class I and class II [32,33]. It was reported to increase the phenotypic plasticity of salivary gland cells and induce the pancreatic lineage transcription factors Ngn3, Pax4, Pdx1, and insulin (Ins)1 [34,35]. In zebrafish embryos, VPA treatment increased the pancreatic endoderm at the expense of hepatic endoderm [35], and in juvenile di-abetic rats, VPA improved β-cell proliferation and function as well as reduced β-cell apoptosis due to HDAC inhibition [36].…”