Immune-derived mediators of salivary gland development and differentiation

Project Summary Irreversible damage to salivary glands (SGs) and their diverse cell types, is a debilitating condition caused by irradiation treatment for head and neck cancer, and the autoimmune disease Sjögrens Syndrome. Loss and remodeling of SG epithelial cells results in hyposalivation, leading to significant clinical issues including chronic dry mouth, increased dental caries, and oral infections. Currently, preventative and/or curative treatments do not exist, yet cell-based bioengineering therapies hold significant promise for SG regeneration. A significant hindrance to the progress of therapeutic optimization, however, is our incomplete understanding of the cellular cues that regulate SG progenitor dynamics, differentiation and the establishment of a functional secretory organ. The specialized branched architecture of the SG maximizes the total area of cell-cell contact between the epithelium and the components of its microenvironment. This project aims to elucidate how immune cells of the SG niche regulate coordinated epithelial cell processes. Our preliminary work using transgenic models defines intimate interactions between tissue-resident macrophages and SG epithelial cells during critical timepoints of SG formation, and preliminary cell depletion studies confirm the necessity of macrophages in guiding SG establishment. Here, we will leverage our expertise in SG development, discrete progenitor dynamics and niche- epithelial interactions to test the hypothesis that multiple aspects of SG morphogenesis are regulated by diverse functionalities of tissue-resident macrophages. Using genetic mouse models and transcriptomic approaches, we will determine how macrophages govern unique cell dynamics and the establishment of heterogenous SG cell identities. We will further test the hypothesis that macrophage-derived signaling factors govern SG progenitor cells and their directed cell expansion. Using biased cell-specific in vivo gene targeting and unbiased spatial single cell transcriptomic techniques, we will determine common immune-epithelial signaling networks, and potential species-specific differences, required for SG epithelial patterning across human and mouse development. Outcomes from this study will identify novel immune-specific mediators of multiple SG epithelial cellular and molecular processes and contribute at large to the advancement of therapeutic targets for salivary gland repair, regeneration, and restoration.