R-spondin1 Protects Mice From Chemotherapy Orradiation-induced Oral Mucositis Through The Canonical Wnt/β-catenin Pathway

摘要

R-Spondin1 (RSpo1) is a novel secreted protein that augments canonical Wnt/β-catenin signaling. We injected recombinant RSpol protein into transgenic Wnt reporter TOPGAL mice and have identified the oral mucosa as a target tissue for RSpol. Administration of RSpol into normal mice triggered nuclear translocation of β-catenin and resulted in increased basal layer cellularity, thickened mucosa, and elevated epithelial cell proliferation in tongue. We herein evaluated the therapeutic potential of RSpol in treating chemotherapy or radiotherapy-induced oral mucositis in several mouse models. Prophylactic treatment with RSpol 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. RSpol administration also substantially alleviated tongue mucositis in the oral cavity of mice receiving concomitant 5-fluorouracil and x-ray radiation. Furthermore, RSpol 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 RSpol and keratinocyte growth factor resulted in complete healing of tongue ulcers in mice subjected to snout-only irradiation. In conclusion, our results demonstrate RSpol to be a potent therapeutic agent for oral mucositis by enhancing basal layer epithelial regeneration and accelerating mucosal repair through up-regulation of Wnt/β-catenin pathway.