Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation
| Autor: | Dharanipathy Rangaraj, Lizheng Qin, Bo Hai, Veera R. Gutti, Fei Liu, Qingguo Zhao |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Genetically modified mouse medicine.medical_specialty animal structures Genetic Vectors Submandibular Gland Saliva secretion Mice Transgenic Gene delivery Xerostomia Adenoviridae Mice 03 medical and health sciences Transduction Genetic Internal medicine Genetics medicine Animals Regeneration Hedgehog Proteins Progenitor cell Sonic hedgehog Molecular Biology Hedgehog Research Articles Radiation biology Gene Transfer Techniques Genetic Therapy Submandibular gland Hedgehog signaling pathway Disease Models Animal 030104 developmental biology medicine.anatomical_structure Endocrinology Microvessels embryonic structures Cancer research biology.protein Molecular Medicine Female Signal Transduction |
| Zdroj: | Human Gene Therapy. 27:390-399 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2016.005 |
| Popis: | Irreversible hypofunction of salivary glands is common in head and neck cancer survivors treated with radiotherapy and can only be temporarily relieved with current treatments. We found in an inducible sonic hedgehog (Shh) transgenic mouse model that transient activation of the Hedgehog pathway after irradiation rescued salivary gland function in males by preserving salivary stem/progenitor cells and parasympathetic innervation. To translate these findings into feasible clinical application, we evaluated the effects of Shh gene transfer to salivary glands of wild-type mice on irradiation-induced hyposalivation. Shh or control GFP gene was delivered by noninvasive retrograde ductal instillation of corresponding adenoviral vectors. In both male and female mice, Shh gene delivery efficiently activated Hedgehog/Gli signaling, and significantly improved stimulated saliva secretion and preserved saliva-producing acinar cells after irradiation. In addition to preserving parasympathetic innervation through induction of neurotrophic factors, Shh gene delivery also alleviated the irradiation damage of the microvasculature, likely via inducing angiogenic factors, but did not expand the progeny of cells responsive to Hedgehog/Gli signaling. These data indicate that transient activation of the Hedgehog pathway by gene delivery is promising to rescue salivary function after irradiation in both sexes, and the Hedgehog/Gli pathway may function mainly in cell nonautonomous manners to achieve the rescue effect. |
| Databáze: | OpenAIRE |
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