R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/β-catenin pathway

Abstract

R-Spondin1 (RSpo1) is a novel secreted protein that augments canonical Wnt/␤-catenin signaling. We injected recombinant RSpo1 protein into transgenic Wnt reporter TOPGAL mice and have identified the oral mucosa as a target tissue for RSpo1. Administration of RSpo1 into normal mice triggered nuclear translocation of ␤-catenin and resulted in increased basal layer cellularity, thickened mucosa, and elevated epithelial cell proliferation in tongue. We herein evaluated the therapeutic potential of RSpo1 in treating chemotherapy or radiotherapyinduced oral mucositis in several mouse models. Prophylactic treatment with RSpo1 dose-dependently overcame the reduction of basal layer epithelial cellularity, mucosal thickness, and epithelial cell proliferation in tongues of mice exposed to whole-body irradiation. RSpo1 administration also substantially alleviated tongue mucositis in the oral cavity of mice receiving concomitant 5-fluorouracil and x-ray radiation. Furthermore, RSpo1 significantly reduced the extent of tongue ulceration in mice receiving a single fraction, high dose head-only radiation in a dose-dependent manner. Moreover, combined therapy of RSpo1 and keratinocyte growth factor resulted in complete healing of tongue ulcers in mice subjected to snout-only irradiation. In conclusion, our results demonstrate RSpo1 to be a potent therapeutic agent for oral mucositis by enhancing basal layer epithelial regeneration and accelerating mucosal repair through upregulation of Wnt/␤-catenin pathway.RSpo1 ͉ tongue ulceration ͉ head-only radiation ͉ TOPGAL ͉ 5-FU

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis

“…Although many studies have generated RIOM [39,50,53,194] animal models, most of them were artificial models and the tight duration of OM resulted in limitation of the experimental procedures. The main objective of our experimentations this time was to generate a RIOM mouse model having the longest possible ulcer duration using the maximally tolerated RT dose, signifying the need to develop a self-resolving lesion.…”

“…RIOM mouse models have been developed in earlier studies for both fractionated [15,39,48,49] and single dose RT [1, [50][51][52][53]. Both models did not have a long enough inflammatory and ulceration phase of RIOM as needed.…”

The development and inflammatory features of radiotherapy-induced glossitis in rats

“…In the present model, a single instance of anesthesia and irradiation was employed to mitigate the previously observed high rates of experimental animal death. No accidental animal death was observed in the rat model developed in this study, despite that the irradiation dose of 30 Gy used herein is identical to that used in previous reports (5). The typical appearance and progression of oral mucositis were observed to occur at the local region of the anterior dorsal tongue of the irradiated rats, which appeared to be in a latent stage 1 to 4 days after irradiation, present gradual ulceration 5 to 14 days after irradiation, peak in ulcerification 15 to 20 days after irradiation, begin to gradually heal 15 days after irradiation, and be completely healed 35 days after irradiation.…”

“…Additionally, the dorsal surface of the tongue can be covered with keratinized epithelium and nonkeratinized epithelium and can adequately express the epithelium tissues of oral mucosae. In comparison to previous radiotherapy-induced oral mucositis animal models, the tongue can be easily observed on a daily schedule (5,14,19). In this study, we designed a 2-mm-thick, cone-shaped lead device that limited irradiation to a 1×1 cm2 area of anterior dorsal tissue, while the remainder of the rat body was effectively shielded from radiation (see Fig.…”

“…Tongue ulceration represents the mucosal damage seen in high-grade oral mucositis in cancer patients (1,5). The present study was designed to identify all possible alterations in tongue mucosae due to locally applied irradiation.…”