Theranostics 2018; 8(16):4321-4331. doi:10.7150/thno.26509

Research Paper

Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model

Liang Hu1, Zhao Zhu1, Bo Hai2, Shimin Chang1, Linsha Ma1, Yipu Xu1, Xiangchun Li1, Xiaoyu Feng1, Xiaoshan Wu1, Qingguo Zhao2, Lizheng Qin1, Jingsong Wang3, Chunmei Zhang1, Fei Liu2✉, Songlin Wang1,3✉

1. Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing 100050, PR China
2. Institute for Regenerative Medicine, Molecular and Cellular Medicine Department, Texas A&M University Health Science Center, College Station, Texas 77843, USA
3. Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing 100069, P. R. China

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 recently in mouse models that transient activation of Hedgehog pathway following irradiation rescued salivary gland function by preserving salivary stem/progenitor cells, parasympathetic innervation and microvessels. Due to huge differences between salivary glands of rodents and humans, to examine the translational potential of this approach, we evaluated effects of Shh gene transfer in a miniature pig model of irradiation-induced hyposalivation.

Methods: The right parotid of each pig was irradiated with a single dose of 20 Gray. Shh and control GFP genes were delivered into irradiated parotid glands by noninvasive retrograde ductal instillation of corresponding adenoviral vectors 4 or 16 weeks after irradiation. Parotid saliva was collected every two weeks. Parotid glands were collected 5 or 20 weeks after irradiation for histology, Western blot and qRT-PCR assays.

Results: Shh gene delivery 4 weeks after irradiation significantly improved stimulated saliva secretion and local blood supply up to 20 weeks, preserved saliva-producing acinar cells, parasympathetic innervation and microvessels as found in mouse models, and also activated autophagy and inhibited fibrogenesis in irradiated glands.

Conclusion: These data indicate the translational potential of transient activation of Hedgehog pathway to preserve salivary function following irradiation.

Keywords: hyposalivation, Hedgehog signaling, radiotherapy, gene therapy, pig model

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How to cite this article:
Hu L, Zhu Z, Hai B, Chang S, Ma L, Xu Y, Li X, Feng X, Wu X, Zhao Q, Qin L, Wang J, Zhang C, Liu F, Wang S. Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model. Theranostics 2018; 8(16):4321-4331. doi:10.7150/thno.26509. Available from http://www.thno.org/v08p4321.htm