Hypoxia-activated Adipose Mesenchymal Stem Cells Prevents Irradiation-induced Salivary Hypofunction by Enhanced Paracrine Effect through FGF10.

Hypoxia-activated Adipose Mesenchymal Stem Cells Prevents Irradiation-induced Salivary Hypofunction by Enhanced Paracrine Effect through FGF10.

Stem Cells. 2018 Mar 23;:

Authors: Shin HS, Lee S, Kim YM, Lim JY

Abstract
PURPOSE: To explore the effects and mechanisms of paracrine factors secreted from human adipose mesenchymal stem cells (hAdMSCs) that are activated by hypoxia on radioprotection against irradiation-induced salivary hypofunction in subjects undergoing radiotherapy for head and neck cancers.
MATERIALS AND METHODS: An organotypic spheroid coculture model to mimic IR-induced salivary hypofunction was set up for in vitro experiments. Human parotid gland epithelial cells were organized to form three-dimensional acinus-like spheroids on growth factor reduced (GFR)-Matrigel. Cellular, structural, and functional damage following irradiation were examined after cells were cocultured with hAdMSCs preconditioned with either normoxia (hAdMSCNMX ) or hypoxia (hAdMSCHPX ). A key paracrine factor secreted by hAdMSCsHPX was identified by high-throughput microarray-based enzyme-linked immunosorbent assay. Molecular mechanisms and signaling pathways on radioprotection were explored. Therapeutic effects of hAdMSCsHPX were evaluated after in vivo transplant into mice with irradiation-induced salivary hypofunction.
RESULTS: In our 3D coculture experiment, hAdMSCsHPX significantly enhanced radioresistance of spheroidal hPECs, and led to greater preservation of salivary epithelial integrity and acinar secretory function relative to hAdMSCsNMX . Coculture with hAdMSCsHPX promoted FGFR expression and suppressed FGFR diminished antiapoptotic activity of hAdMSCsHPX . Among FGFR-binding secreted factors, we found that FGF10 contributed to therapeutic effects of hAdMSCsHPX by enhancing antiapoptotic effect, which was dependent on FGFR-PI3K signaling. An in vivo transplant of hAdMSCsHPX into irradiated salivary glands of mice reversed IR-induced salivary hypofunction where hAdMSC-released FGF10 contributed to tissue remodeling.
CONCLUSION: Our results suggest that hAdMSCsHPX protect salivary glands from irradiation-induced apoptosis, and preserve acinar structure and functions by activation of FGFR-PI3K signaling via actions of hAdMSC-secreted factors, including FGF10. This article is protected by copyright. All rights reserved.

PMID: 29569790 [PubMed - as supplied by publisher]

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