Imagine a small gland beneath the jaw that quietly produces saliva day after day suddenly “awakening” and expressing stem cell markers when its duct becomes blocked. That is what drg. Nunuk Purwanti, M.Kes., Ph.D., and a research team from The University of Tokushima, Japan, discovered in a study published in the Journal of Oral Pathology & Medicine in 2011. The research revealed that obstruction of the main duct of the submandibular gland—the second-largest salivary gland, located beneath the lower jaw—dramatically increased the expression of Sca-1, a stem cell marker, in cells of the glandular ducts.
The finding is important because it offers a new way of understanding how salivary glands may recover from injury, a question that has remained incompletely understood in dentistry and biomedicine.
What Is Sca-1, and Why Does It Matter to the Salivary Gland?
Sca-1, or Stem Cell Antigen-1, is an 18-kilodalton protein located on the cell surface. The protein was first identified in blood cells but was later shown to be expressed in various other tissues, including the prostate, heart, and mammary glands. Cells expressing Sca-1 are known to have greater regenerative potential than cells that do not express it.
The mouse submandibular gland provides an ideal model for this type of research. The gland contains at least six different types of epithelial cells, including acinar cells—the cells responsible for producing saliva—and several types of ductal cells, such as striated duct (SD), granular convoluted tubule (GCT), intercalated duct (ID), and excretory duct (ED) cells. Each has a distinct function and response to injury.
Under normal conditions, Sca-1 is present only at low levels in excretory duct cells. But what happens when the gland's main duct is tied off and obstructed?
Duct Ligation Triggers an Extraordinary Response from Ductal Cells
The researchers performed ligation—a procedure involving the tying of the main duct with surgical thread—on the submandibular glands of eight-week-old male mice. The results were examined on days 0, 1, 3, and 6 after the procedure using three methods: Western blotting to measure protein levels, immunohistochemistry to visualise the location of cells, and fluorescence-activated cell sorting (FACS) to quantify the stem cell population.
The results were surprising. Just one day after ligation, Sca-1 expression increased dramatically in the ligated glands. Even more surprisingly, the gland on the opposite, non-ligated side also showed an increase in Sca-1 expression, although the increase was less pronounced. This suggests the presence of chemical signals travelling throughout the body rather than a purely local response.
“Sca-1 was strongly expressed in most cells of the two major ductal systems, namely the striated ducts and granular convoluted tubules, but was not detected in acinar cells.”
This finding is consistent with previous knowledge that duct ligation causes acinar cells to undergo apoptosis, while ductal cells proliferate. Sca-1 appears to be part of this proliferative mechanism.
Side-Population Cells Increase Threefold
In addition to Sca-1, the study analysed the side population (SP)—a group of cells considered to possess stem cell-like properties because of their ability to efflux Hoechst 33342 dye. Under normal conditions, SP cells account for only approximately 0.2% of the total submandibular gland cell population.
However, one day after ligation, the number of SP cells increased threefold. The number then gradually declined on days 3 and 6. This pattern of increase and decline corresponded with changes in Sca-1 expression detected by Western blotting and immunohistochemistry, strengthening the possibility that the two phenomena are linked to the regenerative process.
The researchers noted that approximately 75–93% of SP cells in other tissues, such as the mammary gland, heart, and skin, also express Sca-1. Whether the same applies to the submandibular gland remains a question for further research.
Salivary Gland Regeneration: Promising Clinical Implications
Salivary gland damage caused by radiotherapy for head and neck cancer remains a clinical problem without a satisfactory solution. Patients undergoing radiation therapy in the head and neck region frequently develop xerostomia—chronic dry mouth—which can significantly reduce quality of life.
Understanding how salivary gland cells respond to injury and initiate regeneration is crucial for developing future stem cell-based therapies. The study by drg. Nunuk Purwanti and colleagues demonstrates that cells in the submandibular gland ducts, particularly SD, GCT, and ID cells, are not merely passive “pipes.” They may have the potential to act as active progenitor cells involved in tissue recovery.
Acinar cells that die following injury are not replaced by acinar cells themselves, but are likely regenerated from differentiating ductal cells. Sca-1 appears to be one of the factors that activates this process.
Of course, the journey from experiments in mice to clinical therapies for humans remains a long one. Yet every small step toward understanding the fundamental biology of salivary gland regeneration represents an important foundation—particularly for the millions of patients seeking relief from debilitating dry mouth.
Authors: Achmad Zam Zam Aghasy, DDS, M.Kes.; Hazra Alifia Muharam
Photo: Freepik
DOI Source: https://doi.org/10.1111/j.1600-0714.2011.01011.x