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World J Stem Cells. Nov 26, 2021; 13(11): 1647-1666
Published online Nov 26, 2021. doi: 10.4252/wjsc.v13.i11.1647
Epigenetic regulation of dental pulp stem cells and its potential in regenerative endodontics
Ying Liu, Lu Gan, Di-Xin Cui, Si-Han Yu, Yue Pan, Li-Wei Zheng, Mian Wan
Ying Liu, Lu Gan, Di-Xin Cui, Si-Han Yu, Yue Pan, Li-Wei Zheng, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
Mian Wan, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
Author contributions: Liu Y and Wan M conceived the idea and designed the work; Gan L, Cui DX, Yu SH and Pan Y integrated materials; Liu Y wrote the paper; Zheng LW, Wan M revised the manuscript critically; all authors have read and approve the final manuscript.
Supported by National Natural Science Foundation of China, No. 81800929 and No. 81771033; Sichuan Science and Technology Program, No. 2019JDRC0096; and Research and Develop Program, West China Hospital of Stomatology Sichuan University, No. LCYJ2019-24.
Conflict-of-interest statement: The authors declare that there is no conflict of interests regarding the publication of this paper.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mian Wan, DDS, PhD, Academic Fellow, Academic Research, Attending Doctor, Lecturer, Postdoctoral Fellow, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, No. 14 3rd Section of Renmin South Road, Chengdu 610041, Sichuan Province, China. mianwan@scu.edu.cn
Received: February 28, 2021
Peer-review started: February 28, 2021
First decision: May 5, 2021
Revised: June 7, 2021
Accepted: November 2, 2021
Article in press: November 2, 2021
Published online: November 26, 2021
Processing time: 269 Days and 19 Hours
Abstract

Regenerative endodontics (RE) therapy means physiologically replacing damaged pulp tissue and regaining functional dentin–pulp complex. Current clinical RE procedures recruit endogenous stem cells from the apical papilla, periodontal tissue, bone marrow and peripheral blood, with or without application of scaffolds and growth factors in the root canal space, resulting in cementum-like and bone-like tissue formation. Without the involvement of dental pulp stem cells (DPSCs), it is unlikely that functional pulp regeneration can be achieved, even though acceptable repair can be acquired. DPSCs, due to their specific odontogenic potential, high proliferation, neurovascular property, and easy accessibility, are considered as the most eligible cell source for dentin–pulp regeneration. The regenerative potential of DPSCs has been demonstrated by recent clinical progress. DPSC transplantation following pulpectomy has successfully reconstructed neurovascularized pulp that simulates the physiological structure of natural pulp. The self-renewal, proliferation, and odontogenic differentiation of DPSCs are under the control of a cascade of transcription factors. Over recent decades, epigenetic modulations implicating histone modifications, DNA methylation, and noncoding (nc)RNAs have manifested as a new layer of gene regulation. These modulations exhibit a profound effect on the cellular activities of DPSCs. In this review, we offer an overview about epigenetic regulation of the fate of DPSCs; in particular, on the proliferation, odontogenic differentiation, angiogenesis, and neurogenesis. We emphasize recent discoveries of epigenetic molecules that can alter DPSC status and promote pulp regeneration through manipulation over epigenetic profiles.

Keywords: Dental pulp stem cells; Regenerative endodontics; Epigenetic regulation; Noncoding RNAs; Histone deacetylase inhibitor; DNA methyltransferase inhibitor

Core Tip: We review the role of epigenetic modifications during fate determination of dental pulp stem cells, highlighting cellular processes implicating proliferation, odontogenesis, angiogenesis, and neurogenesis that are tightly correlated with regenerative endodontics (RE). We emphasize the potential of epigenetic manipulation through enzyme inhibitors in RE and provide insights for future development in regaining dental pulp function.