Epithelial Cleft Formation: The internal architecture of many embryonic organs is established by repetitive branching of epithelia. Epithelial clefts and outgrowths generate this internal branching of glands and other organs. Onodera et al. (p. 562 ) identify a gene, Btbd7 , as a regulator of epithelial dynamics and cleft formation, linking the extracellular matrix with morphogenesis. Btbd7 is induced by a matrix protein at sites of cleft progression and induces a transcription factor and suppresses cell adhesion. The resulting local cell separation and motility contribute to transient tissue gaps that contribute to clefts that help form branched organs.

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.

This report describes our initial attempt to regenerate salivary glands using induced pluripotent stem (iPS) cellsin vivoandin vitro. Glandular tissues that were similar to the adult submandibular glands (SMGs) and sublingual glands could be partially produced by the transplantation of iPS cells into mouse salivary glands. However, the tumorigenicity of iPS cells has not been resolved yet. It is well known that stem cells affect their microenvironment, known as a stem cell niche. We focused on the niche and the interaction between iPS cells and salivary gland cells in our study on salivary gland regeneration. Coculture of embryonic SMG cells and iPS cells have better-developed epithelial structures and fewer undifferentiated specific markers than monoculture of embryonic SMG cellsin vitro. These results suggest that iPS cells have a potential ability to accelerate differentiation for salivary gland development and regeneration.