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TISSUE-SPECIFIC STEM CELLS

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

^aSection Radiation and Stress Cell Biology and
^bSection Stem Cell Biology, Department of Cell Biology, and
^cDepartment of Radiation Oncology, University Medical Center Groningen, University of Groningen, The Netherlands

Key Words. Radiation • Salivary gland • Keratinocyte growth factor/palifermin • Stem/progenitor cell

Correspondence: Correspondence: R.P. Coppes, Ph.D., UMCG,Department of Cell Biology, Section Radiation and Stress Cell Biology, P.O. Box 196 9700 AD Groningen, The Netherlands. Telephone: +31503632709; Fax: +31502913; e-mail: r.p.coppes{at}med.umcg.nl

Received on December 7, 2007; accepted for publication on July 17, 2008.

First published online in STEM CELLS EXPRESS  July 31, 2008.

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 (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. 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 N23-KGF also improved gland function, and this effect was much more pronounced in N23-KGF pretreated animals. Post-treatment with 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 N23-KGF is a promising drug to enhance the number of salivary gland progenitor/stem cells and consequently prevent radiation-induced hyposalivation.

Disclosure of potential conflicts of interest is found at the end of this article.