Salivation restoration

Patients with cancers of the head and neck that have undergone radiation therapy often suffer from severe dry mouth (xerostomia) due to radiation-induced damage to the salivary glands. While current xerostomia therapies provide patients with temporary symptom relief, there are no treatments available to restore salivary gland function in these individuals. Nan Xiao and colleagues at Stanford University School of Medicine isolated submandibular glands from adult mice and identified a stem cell population in this tissue that that formed salispheres in vitro. Upon transplantation, these stem cells were able to incorporate into the secretory ducts of the submandibular gland and restore salivation in irradiated animals. Gene expression analysis revealed that these cells express high levels of glial cell line-derived neurotrophic factor (GDNF). Importantly, GDNF alone rescued saliva production in irradiated mice, but did not protect differentiated submandibular gland cells against radiation-mediated damage. In their companion Commentary, Adam Swick and Randall Kimple of the University of Wisconsin discuss how GDNF could potentially be used to improve xerostomia treatment. The accompanying image shows fluorescent staining a salisphere derived from murine submandibular gland stem cells. Embryonic stem cell marker keratin 5 (red) colocalizes with basal epithelial marker keratin 14 (green). Cell nuclei are labeled blue with DAPI.

Published July 18, 2014, by Corinne Williams

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Neurotrophic factor GDNF promotes survival of salivary stem cells
Nan Xiao, … , Maximilian Diehn, Quynh-Thu Le
Nan Xiao, … , Maximilian Diehn, Quynh-Thu Le
Published July 18, 2014
Citation Information: J Clin Invest. 2014;124(8):3364-3377. https://doi.org/10.1172/JCI74096.
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Research Article

Neurotrophic factor GDNF promotes survival of salivary stem cells

Abstract

Stem cell–based regenerative therapy is a promising treatment for head and neck cancer patients that suffer from chronic dry mouth (xerostomia) due to salivary gland injury from radiation therapy. Current xerostomia therapies only provide temporary symptom relief, while permanent restoration of salivary function is not currently feasible. Here, we identified and characterized a stem cell population from adult murine submandibular glands. Of the different cells isolated from the submandibular gland, this specific population, Lin–CD24+c-Kit+Sca1+, possessed the highest capacity for proliferation, self renewal, and differentiation during serial passage in vitro. Serial transplantations of this stem cell population into the submandibular gland of irradiated mice successfully restored saliva secretion and increased the number of functional acini. Gene-expression analysis revealed that glial cell line–derived neurotrophic factor (Gdnf) is highly expressed in Lin–CD24+c-Kit+Sca1+ stem cells. Furthermore, GDNF expression was upregulated upon radiation therapy in submandibular glands of both mice and humans. Administration of GDNF improved saliva production and enriched the number of functional acini in submandibular glands of irradiated animals and enhanced salisphere formation in cultured salivary stem cells, but did not accelerate growth of head and neck cancer cells. These data indicate that modulation of the GDNF pathway may have potential therapeutic benefit for management of radiation-induced xerostomia.

Authors

Nan Xiao, Yuan Lin, Hongbin Cao, Davud Sirjani, Amato J. Giaccia, Albert C. Koong, Christina S. Kong, Maximilian Diehn, Quynh-Thu Le

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Wetting the whistle: neurotropic factor improves salivary function
Adam Swick, Randall J. Kimple
Adam Swick, Randall J. Kimple
Published July 18, 2014
Citation Information: J Clin Invest. 2014;124(8):3282-3284. https://doi.org/10.1172/JCI77194.
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Commentary

Wetting the whistle: neurotropic factor improves salivary function

Abstract

Xerostomia, or dry mouth, is a common side effect of head and neck radiotherapy, Sjögren syndrome, diabetes, old age, and numerous medications. In this issue of the JCI, Xiao and colleagues identified glial cell line–derived neurotrophic factor (GDNF) as a potential stimulus for salivary stem cell growth. Due to its ability to promote neuronal growth, differentiation, and survival, GDNF is currently being used in clinical trials as a treatment for Parkinson disease; therefore, the findings of Xiao and colleagues may initiate a potential treatment for the millions of patients who suffer from xerostomia each year.

Authors

Adam Swick, Randall J. Kimple

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