Salivary gland progenitor cell biology provides a rationale for therapeutic salivary gland regeneration

Abstract

An irreversible loss of salivary gland function often occurs in humans after removal of salivary tumors, after therapeutic radiation of head and neck tumors, as a result of Sjögren's syndrome and in genetic syndromes affecting gland development. The permanent loss of gland function impairs the oral health of these patients and broadly affects their quality of life. The regeneration of functional salivary gland tissue is thus an important therapeutic goal for the field of regenerative medicine and will likely involve stem/progenitor cell biology and/or tissue engineering approaches. Recent reports demonstrate how both innervation of the salivary gland epithelium and certain growth factors influence progenitor cell growth during mouse salivary gland development. These advances in our understanding suggest that developmental mechanisms of mouse salivary gland development may provide a paradigm for postnatal regeneration of both mice and human salivary glands. Herein, we will discuss the developmental mechanisms that influence progenitor cell biology and the implications for salivary gland regeneration.

Figure 1. Localization of nerves and K5 progenitor cells in a mouse SMG

a. Bright field image of an E13 SMG. b. Whole-mount staining for K5 (green) and neuronal tubulin (Tubb3, red) highlights the localization of K5 cells in the SMG ducts and end buds with the nerves surrounding both ductal and end bud epithelia. c. Higher power image of a single end bud shows the nerves (red) wrapping around the end bud, which contains K5+ cells (green). Images were taken with a confocal laser-scanning microscope and are a single projection of a stack of images.

Figure 2. The K5 population expresses the self-renewal-mediating transcription factor Sox2

a. Whole mount staining of Sox2, K5, and K19 in an E13 SMG duct demonstrates the expression of Sox2+ (red) in K5+ (green), K19+ (blue) and K5+K19+ (cyan) cells. b. Histogram showing the percentage of Sox2-expressing cells in an E13 SMG (3±1%). Data was obtained via Fluorescent Activated Cell Sorting (FACS) analysis by staining single SMG cells with an isotype antibody (depicted as the area defined by the dotted line) to offset the background against cells stained with anti-Sox2 antibody (Santa Cruz, polyclonal goat, gray area). The horizontal line represents positive cells. c. A diagram showing the percentage of the Sox2+ cell population that are also K5+ (7±2%), K5+K19+ (19±5%), K19+ (23±6%), and K5-K19− (51±11%). Single SMG cells were stained for Sox2, K5 and K19 and evaluated by FACS analysis.