Organoids generated from pluripotent stem cells are used in the development of organ replacement regenerative therapy by recapitulating the process of organogenesis. These processes are strictly regulated by morphogen signalling and transcriptional networks. However, the precise transcription factors involved in the organogenesis of exocrine glands, including salivary glands, remain unknown. Here, we identify a specific combination of two transcription factors (Sox9 and Foxc1) responsible for the differentiation of mouse embryonic stem cell-derived oral ectoderm into the salivary gland rudiment in an organoid culture system. Following orthotopic transplantation into mice whose salivary glands had been removed, the induced salivary gland rudiment not only showed a similar morphology and gene expression profile to those of the embryonic salivary gland rudiment of normal mice but also exhibited characteristics of mature salivary glands, including saliva secretion. This study suggests that exocrine glands can be induced from pluripotent stem cells for organ replacement regenerative therapy.

Lactic acid (LA) is short-chain fatty acid, such as butyric acid and propionic acid, that is produced as a metabolite of lactic acid bacteria, including periodontopathic bacteria. These short-chain fatty acids have positive effects on human health but can also have negative effects, such as the promotion of periodontal disease (PD), which is caused by periodontal pathogens present in the gingival sulcus. PD is characterized by apical migration of junctional epithelium, deepening of pockets, and alveolar bone loss. Thus, the junctional epithelial cells that form the bottom of the gingival sulcus are extremely important in investigating the pathophysiology of PD. The aim of this study was to investigate the effect of LA on wound healing, cell growth, cell cycle kinetics, and gene expression of cultured junctional epithelium cells. The results showed that stimulation with 10 mM LA slowed wound healing of the junctional epithelial cell layer and arrested the cell cycle in the G0/G1 (early cell cycle) phase, thereby inhibiting cell growth. However, cell destruction was not observed. LA also enhanced mRNA expression of integrin α5, interleukin (IL)-6, IL-8, intercellular adhesion molecule-1, and receptor activator of nuclear factor kappa-B ligand. The results of this study suggest that stimulation of junctional epithelial cells with high concentrations of LA could exacerbate PD, similarly to butyric acid and propionic acid.

Purpose: To elucidate the effects of butyric acid (BA), a metabolite of bacteria involved in periodontitis, and a possible enhancer of the junctional epithelial cells. Methods: A murine junctional epithelial cell line, JE-1, was used to assess the effects of sodium butyrate (NaB) as BA. Cell proliferation, migration and attachment were analyzed. Additionally, gene and promoter expression analysis was performed, i.e., cap analysis of gene expression (CAGE) and gene ontology (GO) term enrichment analysis. Results: NaB affected junctional epithelial cell proliferation, migration and attachment. A high concentration of NaB caused cell death and a low concentration tended to promote migration and adhesion. CAGE analysis revealed 75 upregulated and 96 downregulated genes in the cells after 0.2 mM NaB stimulation for 3 h. Regarding GO term enrichment, the genes upregulated >4-fold participated predominantly in cell migration and proliferation. The results of this study suggest that BA produced from periodontopathic bacteria is involved in periodontal tissue destruction at high concentrations. Furthermore, at low concentrations, BA potentially participates in periodontal disease progression by increasing proliferation, migration and attachment of the junctional epithelium and thereby increasing epithelial down-growth.