Inhibition of Ape1 Redox Activity Promotes Odonto/osteogenic Differentiation of Dental Papilla Cells.

Tian Chen,Yang Xu,Xianrui Yang,Wenhua Sun,Weidong Tian,Guoqing Chen,Mei Yu,Ding Bai,Jingyu Li,Zhi Liu,Yan Liang

doi:10.1038/srep17483

Abstract

Dentinogenesis is the formation of dentin, a substance that forms the majority of teeth, and this process is performed by odontoblasts. Dental papilla cells (DPCs), as the progenitor cells of odontoblasts, undergo the odontogenic differentiation regulated by multiple cytokines and paracrine signal molecules. Ape1 is a perfect paradigm of the function complexity of a biological macromolecule with two major functional regions for DNA repair and redox regulation, respectively. To date, it remains unclear whether Ape1 can regulate the dentinogenesis in DPCs. In the present study, we firstly examed the spatio-temporal expression of Ape1 during tooth germ developmental process, and found the Ape1 expression was initially high and then gradually reduced along with the tooth development. Secondly, the osteo/odontogenic differentiation capacity of DPCs was up-regulated when treated with either Ape1-shRNA or E3330 (a specific inhibitor of the Ape1 redox function), respectively. Moreover, we found that the canonical Wnt signaling pathway was activated in this process, and E3330 reinforced-osteo/odontogenic differentiation capacity was suppressed by Dickkopf1 (DKK1), a potent antagonist of canonical Wnt signaling pathway. Taken together, we for the first time showed that inhibition of Ape1 redox regulation could promote the osteo/odontogenic differentiation capacity of DPCs via canonical Wnt signaling pathway.

Highlights

Dentin is a highly mineralized tissue which constitutes the bulk of the tooth in humans and many other mammalian species[1]
In the postnatal days from P5 to P25 (Fig. 1D–T), as the dental papilla cells began to differentiate into odontoblasts, Ape[1] expression was rapidly decreased and gathered towards the Hertwig’s epithelial root sheath until the end of root formation
For the first time we described the inhibition of Ape[1] redox activity promoted the osteo/ odontogenic differentiation capacity of Dental papilla cells (DPCs) via canonical Wnt signaling pathway

Summary

Introduction

Dentin is a highly mineralized tissue which constitutes the bulk of the tooth in humans and many other mammalian species[1]. Because of its functional pleiotropy, Ape[1] plays a central role in regulating the cellular response opposed to oxidative stress and maintaining the genome stability and transcriptional activity[5]. Little knowledge is available about its effect on the differentiation of DPCs. In this study, we hypothesized that Ape[1] regulates proliferation and osteo/odontogenic differentiation of DPCs through its redox functional domain. We hypothesized that Ape[1] regulates proliferation and osteo/odontogenic differentiation of DPCs through its redox functional domain For this purpose, DPCs were isolated from impacted human third molar tooth germ and treated with Ape1-shRNA or E3330 an inhibitor of Ape[1] redox regulation. Our experimental data showed that the osteo/odontogenic differentiation of DPCs was enhanced by E3330 and Ape1-shRNA, and canonical Wnt signaling was involved in this process

Methods

Results

Conclusion