Plasticity in Differentiation of Salivary Glands: The Signaling Pathway That Induces Dedifferentiation of Parotid Acinar Cells

Abstract

Sjögren’s syndrome and therapeutic radiation for head and neck cancers result in atrophy of the salivary glands and consequent xerostomia (dry mouth). To clarify the mechanisms of salivary gland dysfunction, we have established a system for the primary culture of parotid acinar cells. We found that the expression patterns of claudins are remarkably changed during culture. These changes are considered a process of dedifferentiation since the expression levels of other differentiation markers also alter. Acinar markers, such as amylase and aquaporin-5, are decreased and, in contrast, duct markers such as claudin-4 and cytokeratin-14 are increased. In the late phase of culture, mesenchymal markers begin to be expressed. These results suggest that acinar cells transiently change to duct-like cells during epithelial mesenchymal transition. Inhibitors of Src and p38 MAP kinases suppress these changes and simultaneously increase the expression of acinar marker proteins. Activation of p38 MAP kinase occurs during cell isolation from the parotid glands, which is suppressed by Src kinase inhibitors. Therefore, cellular stresses caused by cell isolation trigger the signal that induces the transition to duct-like cells and dedifferentiation. There is a possibility that salivary acinar cells have differentiation plasticity, which is regulated by the Src-p38 MAP kinase signaling pathway.