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Inhibition of Alk signaling promotes the induction of human salivary gland-derived organoids.

Hyposalivation and xerostomia are the cause of several conditions of morbidities such as dental caries, painful mucositis, oral fungal infections, sialadenitis and dysphagia. For these reasons, preservation of normal saliva secretion is critical for the maintenance of functionally normal oral homeostasis and finally for keeping good health. Several strategies for restoring salivary gland hypofunction have been reported from different points of view based on such salivary gland-derived epithelial stem/progenitor cells and tissue engineering approaches to induce organoids mimicking in vivo salivary glands. In this study, we clarified that inhibition of Activin receptor-like kinase (Alk) signaling was essential for the induction of human salivary gland-derived organoids and showed their usefulness as an inflammatory disease model. In the inflammatory conditions like sialadenitis, in general, pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) are upregulated but their function is still unclear. In our established human salivary gland-derived organoid culture system, we successfully induced an organoid swelling revealing the function of saliva secretion by the stimulation of carbachol, a non-selective cholinergic agonist, and forskolin, an activator of cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, we found that this organoid swelling was inhibited by TNF-α. From these results, we could clarify the inhibitory function of TNF-α on the saliva secretion in vitro. Thus, our established human salivary gland-derived organoids would be able to be useful for the in vitro analyses of the morphological and functional changes of salivary gland dysfunctions in several research fields such as pathobiology, inflammation and regenerative medicine.