Epigenetic regulation of dental pulp stem cells and its potential in regenerative endodontics

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.

The Role of Epigenetic in Dental and Oral Regenerative Medicine by Different Types of Dental Stem Cells: A Comprehensive Overview

“…Although these are not specific markers of DPSCs, they provide further evidence of DPSCs in vivo . Characteristics of CD34 and 117 as hematopoietic lineage markers and glia-2, a marker of neurovascular origin, are promoted in DPSCs for the DPSCs' regenerative potential [ 17 ]. The current studies of epigenetic regulation of DSCs are summarized in Table 1 in regenerative medicine.…”

“…Genetic control is mediated by signaling pathways and transcription factors, and epigenetic control is mediated by DNA methylation, histone modifications, and ncRNAs. The manipulation of DPSCs' fate toward pulp–dentin regeneration is possible with an epigenetic modulation understanding in DPSCs [ 17 ]. Among the most well-researched epigenetic modifications, DNA methylation is often associated with gene silencing and stem cell fate regulation.…”

“…In the same way, miR-675 inhibits the DNMT3b-mediated methylation of DLX3 in DPSCs for promoting human DPSC odontogenic differentiation. In addition, colon cancer-associated transcript 1/lncRNA increases cell differentiation and proliferation by suppressing the miR-218 signaling pathway [ 17 ]. H3K4 trimethylation activates remodeling acetylases of histone and enzymes along with the increment of transcription.…”

Characterization of a Stemness-Optimized Purification Method for Human Dental-Pulp Stem Cells: An Approach to Standardization

“…Functionally, the developmental complexity of the dental pulp explains why it harbors very different cell populations. The latter also indirectly reflect the multilineage differentiation potential of DPSCs [ 31 ], i.e., they can differentiate into odontoblasts, osteoblasts, cementoblasts, chondrocytes, neural cells, myoblasts, endothelial cells, and adipocytes in vitro and in vivo [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. The molecular mechanisms behind the respective lineage decisions are complex and yet incompletely understood.…”

Pluripotency of periodontal ligament and dental pulp cells is induced by intercellular communication via the CDX2/Oct-4/Sox2 pathway

“…Epigenetic regulation plays a crucial role in the renewal of tooth tissue, such as increased levels of acetylated histone H3 lysine 9 (H3K9ac) and H3K27ac involved in odontoblast differentiation ( 11 ). Caudal-type homeobox transcription factor 2 (CDX2) is a transcription factor that has been shown to modulate proliferation and differentiation in the intestine ( 12 ).…”