Human Pluripotent Stem Cells and Organoids for Salivary Gland Regeneration

Project Summary There are three major salivary glands (SG): the parotid, the submandibular, and the sublingual. These glands produce approximately 90% of the total saliva in the oral cavity, with the remaining 10% being produced by minor salivary glands under normal conditions. Dysfunction of the salivary glands occurs due to autoimmune disorders such as Sjögren's syndrome and most commonly due to cancer therapies aimed at the craniofacial region and result in the limited or complete loss of saliva production, a condition called xerostomia, or “dry-mouth”. Without saliva, patients experience loss of lubrication in the mouth, impaired digestion and taste, as well as tooth decay and tissue loss as there is no saliva to protect the oral surfaces from bacteria. Current treatments remain superficial, as drugs allow for artificial saliva to provide temporary relief. Regenerative medicine approaches may allow a path for a more permanent solution to this problem in terms of regaining SG function. Previous research in our lab demonstrated growth of SG progenitor cells and organoids from human embryonic and induced pluripotent stem cells (hiPSCs) through an approach that mimics SG development. The overarching hypothesis of the proposed work is that salivary gland progenitor cells (SGEPs) can be derived from hiPSCs, and used to produce mature and functional SG organoids (SGOs). The resulting progenitor cells and organoids may have the potential to regenerate the SG upon implantation in vivo. We will address this hypothesis in three specific aims. In Aim 1, we will apply our approach to generate SGEPs and SGOs from multiple hiPSC lines to ensure that our strategy is broadly applicable. In Aim 2, we will test the hypothesis that activation of the Erbb3 receptor and downstream signaling may lead to SGO maturation and development of SG function. Finally, in Aim 3 we will examine the potential of SGEPs and SGOs to regenerate SG upon transplantation into the mouse SMG. Successful completion of the proposed work will facilitate development of 3D cell culture systems for understanding of salivary gland biology as well as development of drug screening platforms and cell therapies for SG regeneration to treat hyposalivation disorders.