title: Rescue Effects and Underlying Mechanisms of Intragland Shh Gene Delivery on Irradiation-Induced Hyposalivation.
abstract: 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.
authors.affiliation: 1 Institute for Regenerative Medicine, College of Medicine, Texas A&M Health Science Center , Temple, Texas.
authors.forename: Bo
authors.initials: B
authors.lastname: Hai
authors.affiliation: 1 Institute for Regenerative Medicine, College of Medicine, Texas A&M Health Science Center , Temple, Texas.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: 1 Institute for Regenerative Medicine, College of Medicine, Texas A&M Health Science Center , Temple, Texas.|2 Beijing Stomatological Hospital, Capital Medical University , Beijing, China .
authors.forename: Lizheng
authors.initials: L
authors.lastname: Qin
authors.affiliation: 3 Department of Radiation Oncology, Baylor Scott & White Hospital , Temple, Texas.
authors.forename: Dharanipathy
authors.initials: D
authors.lastname: Rangaraj
authors.affiliation: 3 Department of Radiation Oncology, Baylor Scott & White Hospital , Temple, Texas.
authors.forename: Veera R
authors.initials: VR
authors.lastname: Gutti
authors.affiliation: 1 Institute for Regenerative Medicine, College of Medicine, Texas A&M Health Science Center , Temple, Texas.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D011827:Radiation; D012038:Regeneration; D015398:Signal Transduction; D013363:Submandibular Gland / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D014161:Transduction, Genetic; D014987:Xerostomia / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse