Salivary glands are critical for oral health, and loss of normal function results in adverse secondary conditions in affected patients. Radiation therapy, used to treat head and neck cancers, as well as autoimmune diseases, cause irreversible damage to the salivary glands, specifically to the acinar cells primarily responsible for salivary secretion. Current therapies for salivary gland dysfunction are pallative and short term. Potential strategies for permanent restoration of gland function include cell replacement. Although evidence suggests that salivary glands have stem cells, they have not yet been isolated. Moreover, the extent of stem cell contribution to salivary gland maintenance is unclear, as it is also reported that, in adults, acinar cells are renewed by self-duplication. We have identified a salivary gland progenitor cell that is marked by expression of Ascl3. Lineage tracing shows that these progenitors generate duct cells and a subset of acinar cells, but not the majority of serous acinar cells in the submandibular and parotid glands. We propose that Ascl3-expressing cells, located in the ducts, are transient intermediate progenitor cells involved in salivary gland maintenance. As the majority of serous acinar cells in the submandibular and parotid glands are not derived from Ascl3- expressing cells, we hypothesize that serous acinar cells are specified by a separate distinct progenitor population. This proposal will establish the differentiation potential of salivary gland progenitor cells and investigate the ability of these cells to contribute to regeneration of an atrophic gland. We have three specific aims: (1) To examine the potential of Ascl3-expressing progenitor cells to contribute to the maintenance and regeneration of the salivary gland. (2) To determine the role of serious acinar progenitors in the salivary gland. (3) To test the ability of cultured progenitor cells to contribute to salivary gland regeneration following transplantation. The identification and characterization of progenitor cell types in the salivary gland is a critical step in the path to cell replacement therapies.

Public Health Relevance

Salivary gland function is dramatically reduced by radiation treatment for head and neck cancers, by drug therapy and in autoimmune diseases such as Sjogren's syndrome. This has a significant impact on the oral health of affected patients. Possible permanent cures include cell transplantation into the damaged gland. This proposal will examine the ability of salivary gland progenitor cells to contribute to gland repair following transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018896-05
Application #
8427390
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$362,247
Indirect Cost
$127,022
Name
University of Rochester
Department
Genetics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Rugel-Stahl, Anastasia; Elliott, Marilyn E; Ovitt, Catherine E (2012) Ascl3 marks adult progenitor cells of the mouse salivary gland. Stem Cell Res 8:379-87
Arany, Szilvia; Xu, Qingfu; Hernady, Eric et al. (2012) Pro-apoptotic gene knockdown mediated by nanocomplexed siRNA reduces radiation damage in primary salivary gland cultures. J Cell Biochem 113:1955-65
Arany, Szilvia; Catalan, Marcelo A; Roztocil, Elisa et al. (2011) Ascl3 knockout and cell ablation models reveal complexity of salivary gland maintenance and regeneration. Dev Biol 353:186-93