The Wnt/β-catenin signaling pathway is one of several key conserved intercellular signaling pathways in animals, and plays fundamental roles in the proliferation, regeneration, differentiation, and function of many cell and tissue types. This pathway is activated in a dynamic manner during the morphogenesis of oral organs, including teeth, taste papillae, and taste buds, and is essential for these processes to occur normally. Conversely, forced activation of Wnt/β-catenin signaling promotes the formation of ectopic teeth and taste papillae. In this review, we discuss our current understanding of the roles of Wnt/β-catenin signaling in oral tissue development and in related human diseases, and the potential of manipulating this pathway for therapeutic purposes.

β-Catenin signaling is required for hair follicle development, but it is unknown whether its activation is sufficient to globally program embryonic epidermis to hair follicle fate. To address this, we mutated endogenous epithelial β-catenin to a dominant-active form in vivo. Hair follicle placodes were expanded and induced prematurely in activated β-catenin mutant embryos, but failed to invaginate or form multilayered structures. Eventually, the entire epidermis adopted hair follicle fate, broadly expressing hair shaft keratins in place of epidermal stratification proteins. Mutant embryonic skin was precociously innervated, and displayed prenatal pigmentation, a phenomenon never observed in wild-type controls. Thus,β -catenin signaling programs the epidermis towards placode and hair shaft fate at the expense of epidermal differentiation, and activates signals directing pigmentation and innervation. In transcript profiling experiments, we identified elevated expression of Sp5, a direct β-catenin target and transcriptional repressor. We show that Sp5 normally localizes to hair follicle placodes and can suppress epidermal differentiation gene expression. We identified the pigmentation regulators Foxn1, Adamts20 and Kitl, and the neural guidance genes Sema4c, Sema3c, Unc5b and Unc5c, as potential mediators of the effects of β-catenin signaling on pigmentation and innervation. Our data provide evidence for a new paradigm in which, in addition to promoting hair follicle placode and hair shaft fate, β-catenin signaling actively suppresses epidermal differentiation and directs pigmentation and nerve fiber growth. Controlled downregulation of β-catenin signaling is required for normal placode patterning within embryonic ectoderm, hair follicle downgrowth, and adoption of the full range of follicular fates.

Significance: Mesenchymal stem or stromal cells (MSCs) offer great promise as potential therapies for cancers and other diseases. However, applications of MSCs for cancer therapy are hindered by their protumor potential under certain conditions, considerable donor variations, and limited expandability. Here we report generation of induced pluripotent stem cells (iPSC)-derived MSCs with same tumor homing capacity but much less protumor potential using a modified protocol with high derivation efficiency. Starting from iPSCs with almost unlimited expandability, the protocol can be readily scaled up to provide huge amounts of MSCs with uniform biological properties for multicenter evaluation, large animal experiments, and potential clinical trial. Moreover, therapeutic transgenes can be inserted into safe-harbor loci of iPSCs before derivation of MSCs to eliminate insertional mutation and guarantee stable expression of transgenes during prolonged expansion.