Therapeutic benefits of factors derived from stem cells from human exfoliated deciduous teeth for radiation-induced mouse xerostomia

Abstract

Radiation 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.

Current developments and opportunities of pluripotent stem cells-based therapies for salivary gland hypofunction

“…However, this therapeutic effect was not found in the BMSC-derived conditioned medium group, which may be related to the fact that the DPSC-derived conditioned medium contains more cytokines that regulate cell proliferation, antiinflammatory and immunomodulatory effects than the BMSCderived conditioned medium. Another subsequent study used conditioned medium of human SHEDs for prophylactic treatment of radiotherapy-injured mice (Kano et al, 2023). SHED-derived conditioned medium was found to effectively upregulate the expression of antioxidant genes in mouse salivary glands and human acinar cells damaged by radiotherapy and strongly inhibit the radiotherapy-induced oxidative stress, thereby maintaining the salivary gland function (Kano et al, 2023).…”

“…Another subsequent study used conditioned medium of human SHEDs for prophylactic treatment of radiotherapy-injured mice (Kano et al, 2023). SHED-derived conditioned medium was found to effectively upregulate the expression of antioxidant genes in mouse salivary glands and human acinar cells damaged by radiotherapy and strongly inhibit the radiotherapy-induced oxidative stress, thereby maintaining the salivary gland function (Kano et al, 2023). There are still few reports of conditioned medium of iMSCs origin for disease treatment.…”