Neurotrophic factor GDNF promotes survival of salivary stem cells

• Published in: The Journal of clinical investigation 2014-08, Vol.124 (8), p.3364-3377
• Main Authors: Xiao, Nan, Lin, Yuan, Cao, Hongbin, Sirjani, Davud, Giaccia, Amato J, Koong, Albert C, Kong, Christina S, Diehn, Maximilian, Le, Quynh-Thu
• Format: Article
• Language: English
• Subjects: Adult Stem Cells - drug effects; Adult Stem Cells - physiology; Adult Stem Cells - transplantation; Animals; Biomedical research; Cell Differentiation; Cell Proliferation; Cell Separation; Cell Survival - drug effects; Cell Survival - genetics; Cell Survival - physiology; Colleges & universities; Female; Gene expression; Gene Expression - radiation effects; Glial Cell Line-Derived Neurotrophic Factor - administration & dosage; Glial Cell Line-Derived Neurotrophic Factor - genetics; Glial Cell Line-Derived Neurotrophic Factor - physiology; Head and Neck Neoplasms - physiopathology; Head and Neck Neoplasms - radiotherapy; Humans; Kinases; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurotrophic functions; Physiological aspects; Population; Radiation Injuries - etiology; Radiation Injuries - physiopathology; Radiation Injuries - therapy; Recombinant Proteins - administration & dosage; Saliva - drug effects; Saliva - metabolism; Salivary glands; Salivary Glands - cytology; Salivary Glands - physiology; Salivary Glands - radiation effects; Spheroids, Cellular - cytology; Spheroids, Cellular - physiology; Stem cells; Submandibular Gland - cytology; Submandibular Gland - physiology; Submandibular Gland - radiation effects; Xerostomia - etiology; Xerostomia - physiopathology; Xerostomia - therapy
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci74096

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.