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The myoepithelium of the salivary gland demonstrates smooth muscle properties, and the myoepithelium-rich pleomorphic adenomas (PA) exhibit various cytological guises and frequently produce chondroid tissues. We recently reported that gene expression of myocyte enhancer factor 2 C (MEF2C) was up-regulated in myoepithelial cell lines established from mouse salivary glands. This transcription factor is known to regulate the development of smooth muscle cells and chondrocytes. These findings have led us to postulate that MEF2C may be a new marker of the myoepithelium and thus be of help for exploring myoepithelial participation in PA. The immunoreactivity of MEF2C was semi-quantitatively analyzed in normal salivary glands and in different types of cell in PA. The pattern of staining was also compared with that of α-smooth muscle actin (αSMA) and calponin. In the parenchyma of mouse and human submandibular glands, MEF2C expression was exclusive to the nuclei of myoepithelial cells. In the neoplastic myoepithelium of PA, epithelioid and stellate cells were consistently positive, but spindle and plasmacytoid cells exhibited selective staining. Although variability/loss of expression was evident, αSMA tended to show limited expression, whereas calponin tended to show extensive expression. Intense and uniform immunoreactivity for MEF2C was observed in lacunar cells in chondroid areas of PA. This is the first reported study to have demonstrated MEF2C immunoexpression in normal and neoplastic myoepithelial cells. Among the heterogeneously differentiated elements, MEF2C may be useful to define the myoepithelial/mesenchymal phenotypes of PA cells. Along with other relevant immunohistochemical markers, it may become another standard. [ABSTRACT FROM AUTHOR]

Although stem cell aging leads to a decline in tissue homeostasis and regenerative capacity, it remains unclear whether salivary gland stem cell function changes during this process. However, the salivary glands are gradually replaced by connective tissue during aging. Here, we show a decline in the stem cell ability of CD133-positive stem/progenitor cells in the salivary glands of aged mice. The CD133-positive cells were isolated from young, adult, and aged mice. The number of CD133-positive cells was significantly decreased in aged mice. They also showed a lower sphere formation capacity compared to young and adult mice. RNA sequencing revealed that CD133-positive cells in aged mice exhibited lower gene expression of several aging-related genes, including FoxO3a, than those in young and adult mice. Salivary gland cells infected with a recombinant lentivirus encoding the FoxO3a gene showed a reduction in oxidative stress induced by hydrogen peroxide compared with those infected with a control virus. Thus, FoxO3a may inhibit stem cell aging via oxidative stress. [Display omitted] • The function of CD133-positive cells changes with age and is expected to be one of the causative factors associated with salivary gland aging. [ABSTRACT FROM AUTHOR]

Exocrine glands share a common morphology consisting of ductal, acinar, and basal/myoepithelial cells, but their functions and mechanisms of homeostasis differ among tissues. Salivary glands are an example of exocrine glands, and they have been reported to contain multipotent stem cells that differentiate into other tissues. In this study, we purified the salivary gland stem/progenitor cells of adult mouse salivary glands using the cell surface marker CD133 by flow cytometry. CD133+ cells possessed stem cell capacity, and the transplantation of CD133+ cells into the submandibular gland reconstituted gland structures, including functional acinar. CD133+ cells were sparsely distributed in the intercalated and exocrine ducts and expressed Sox9 at higher levels than CD133– cells. Moreover, we demonstrated that Sox9 was required for the stem cell properties CD133+ cells, including colony and sphere formation. Thus, the Sox9-related signaling may control the regeneration salivary glands. • Lin–/CD133+ cells distribute in the intercalated and striated ducts. • Lin–/CD133+ cells have stem/progenitor features. • Sox9 contributes to stem/progenitor activity in salivary gland cells. [ABSTRACT FROM AUTHOR]