Author:
Kano Fumiya,Hashimoto Noboru,Liu Yao,Xia Linze,Nishihara Takaaki,Oki Wakana,Kawarabayashi Keita,Mizusawa Noriko,Aota Keiko,Sakai Takayoshi,Azuma Masayuki,Hibi Hideharu,Iwasaki Tomonori,Iwamoto Tsutomu,Horimai Nobuyasu,Yamamoto Akihito
Abstract
AbstractRadiation therapy for head and neck cancers is frequently associated with adverse effects on the surrounding normal tissue. Irreversible damage to radiation-sensitive acinar cells in the salivary gland (SG) causes severe radiation-induced xerostomia (RIX). Currently, there are no effective drugs for treating RIX. We investigated the efficacy of treatment with conditioned medium derived from stem cells from human exfoliated deciduous teeth (SHED-CM) in a mouse RIX model. Intravenous administration of SHED-CM, but not fibroblast-CM (Fibro-CM), prevented radiation-induced cutaneous ulcer formation (p < 0.0001) and maintained SG function (p < 0.0001). SHED-CM treatment enhanced the expression of multiple antioxidant genes in mouse RIX and human acinar cells and strongly suppressed radiation-induced oxidative stress. The therapeutic effects of SHED-CM were abolished by the superoxide dismutase inhibitor diethyldithiocarbamate (p < 0.0001). Notably, quantitative liquid chromatography-tandem mass spectrometry shotgun proteomics of SHED-CM and Fibro-CM identified eight proteins activating the endogenous antioxidant system, which were more abundant in SHED-CM than in Fibro-CM (p < 0.0001). Neutralizing antibodies against those activators reduced antioxidant activity of SHED-CM (anti-PDGF-D; p = 0.0001, anti-HGF; p = 0.003). Our results suggest that SHED-CM may provide substantial therapeutic benefits for RIX primarily through the activation of multiple antioxidant enzyme genes in the target tissue.
Funder
Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan
Joint research fund from Yushinkai Medical Cooperation
Publisher
Springer Science and Business Media LLC
Cited by
1 articles.
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