Keratinocyte Growth Factor Prevents Radiation Damage to Salivary Glands by Expansion of the Stem/Progenitor Pool

Irradiation of salivary glands during radiotherapy treatment of patients with head and neck cancer evokes persistent hyposalivation. This results from depletion of stem cells, which renders the gland incapable of replenishing saliva to produce acinar cells. The aim of this study was to investigate whether it is possible to expand the salivary gland stem/progenitor cell population, thereby preventing acinar cell depletion and subsequent gland dysfunction after irradiation. To induce cell proliferation, keratinocyte growth factor (Delta N23-KGF, palifermin) was administered to C57BL/6 mice for 4 days before and/or after local irradiation of salivary glands. Salivary gland vitality was quantified by in vivo saliva flow rates, morphological measurements, and a newly developed in vitro salisphere progenitor/stem cell assay. Irradiation of salivary glands led to a pronounced reduction in the stem cells of the tissues, resulting in severe hyposalivation and a reduced number of acinar cells. Delta N23-KGF treatment for 4 days before irradiation indeed induced salivary gland stem/progenitor cell proliferation, increasing the stem and progenitor cell pool. This did not change the relative radiation sensitivity of the stem/progenitor cells, but, as a consequence, an absolute higher number of stem/progenitor cells and acinar cells survived after radiation. Postirradiation treatment with Delta N23-KGF also improved gland function, and this effect was much more pronounced in Delta N23-KGF pretreated animals. Post-treatment with Delta N23-KGF seemed to act through accelerated expansion of the pool of progenitor/stem cells that survived the irradiation treatment. Overall, our data indicate that Delta N23-KGF is a promising drug to enhance the number of salivary gland progenitor/stem cells and consequently prevent radiation-induced hyposalivation. STEM CELLS 2008; 26: 2595-2601