Radiation therapy, the predominant treatment for head and neck cancers, causes irreversible damage to the salivary glands, due to the loss of secretory acinar cells. Recent data from our laboratory demonstrates that human and murine salivary glands initiate acinar cell regeneration after radiation treatment, but in contrast to injury by duct ligation, the salivary glands do not fully recover function. However, the regenerative potential exhibited in irradiated glands implies that therapeutic strategies may be developed to stimulate repair of radiation-induced damage. Emerging evidence suggests that cell plasticity, defined as the ability of differentiated cells to re-enter the cell cycle, is a means of supplying precursors for tissue regeneration. Evidence of cell plasticity has only recently been reported in salivary glands. In studies of glands injured by duct ligation or ionizing radiation, we have identified three specific cell populations that display plasticity. These include surviving regenerative cells that can repopulate duct-ligated glands, a heterogeneous population of cells co-expressing duct and acinar cell markers with unknown fate, and duct cells that can undergo lineage conversion to generate secretory acinar cells in irradiated glands. Cellular plasticity, and the ability to convert cells from another lineage in vivo, offer considerable potential for replacement of lost acinar cells. However, our knowledge of the mechanisms that induce, regulate, and constrain this process is limited. We propose to compare different injury models, for the response of salivary gland cells, and to define the conditions that induce plasticity. Lineage tracing, which heritably labels cells and their descendants, will be used to investigate how cells exhibiting plasticity contribute to regeneration, and the requirements for those cells to undergo lineage conversion. Single cell RNA sequencing will be used to characterize the cell types involved in regeneration, and gain insight into participating molecular pathways. The feasibility of stimulating regeneration of endogenous cells through the introduction of exogenous factors will be explored. These studies will determine how cellular plasticity and lineage conversion are involved in the response to injury and regeneration of the salivary glands. Identification of the cells involved and the conditions driving these processes may yield critical information for development of regenerative approaches to treat xerostomia.
Cellular Plasticity in Salivary Gland Regeneration Although radiation damage is often considered irreversible, we have found that irradiated salivary glands have regenerative potential. Furthermore, we demonstrated that under severe conditions, salivary gland cells undergo lineage conversion to replace lost cells. To explore whether this process can be harnessed as a therapeutic modality for treating patients living with permanent xerostomia, we will focus on characterizing the mechanism and regulation of cellular plasticity in salivary gland cells.
