Salivary gland dysfunction occurs as a result of pathological injury after radiotherapy for head and neck cancer and significantly compromises the oral health and quality of life of patients. A potential regenerative approach for restoring salivary function is stem cell therapy, where autologous stem/progenitor cells are transplanted into the injured organ or stem cells within the tissue are reactivated. However, the identity of human stem/progenitors and how they are regulated are unknown. In this application we propose to determine the contributions of putative progenitors in the mouse and human salivary gland to tissue repair and regeneration and to determine the influence of neuronal signals on their behavior. Parasympathetic nerves are essential to salivary function and regeneration, as well as the maintenance of epithelial progenitor cells, and are severely reduced in human salivary glands after radiotherapy. We hypothesize that discrete epithelial progenitor cells in the adult mouse and human salivary gland regenerate acini during homeostasis and injury in response to neuronal signals. Thus, the Specific Aims of this project are to: 1) Define the mechanisms by which parasympathetic nerves regulate progenitor cell fate, 2) Determine the contribution of salivary progenitor cells and neuronal signaling to adult homeostasis and repair and 3) Identify epithelial progenitor cells in the human salivary gland.
These aims will be achieved using a combination of human salivary glands and mouse genetics in conjunction with genetic, biochemical, immunochemical, and fluorescence imaging techniques. Our rationale for investigating this hypothesis is that understanding progenitor cell identity in the salivary gland and the mechanisms that regulate salivary tissue regeneration will enable the design of targeted regenerative approaches to reverse salivary dysfunction.
Salivary glands are irreversibly damaged after treatment with radiotherapy for head and neck cancer, and this substantially reduces oral health and quality of life. Stem cell therapy is a promising strategy to regenerate damaged tissue but the identity of stem cells and the mechanisms that regulate their behavior are not known. This project aims to identify salivary gland stem/progenitor cells that contribute to repair and regeneration after damage as well as the signals that control these events in order to develop targeted regenerative approaches to reverse salivary dysfunction.