Advances in Regenerative Dentistry: A Systematic Review of Harnessing Wnt/β-Catenin in Dentin-Pulp Regeneration

Abstract

Dentin pulp has a complex function as a major unit in maintaining the vitality of teeth. In this sense, the Wnt/β-Catenin pathway has a vital part in tooth development, maintenance, repair, and regeneration by controlling physiological activities such as growth, differentiation, and migration. This pathway consists of a network of proteins, such as Wnt signaling molecules, which interact with receptors of targeted cells and play a role in development and adult tissue homeostasis. The Wnt signals are specific spatiotemporally, suggesting its intricate mechanism in development, regulation, repair, and regeneration by the formation of tertiary dentin. This review provides an overview of the recent advances in the Wnt/β-Catenin signaling pathway in dentin and pulp regeneration, how different proteins, molecules, and ligands influence this pathway, either upregulating or silencing it, and how it may be used in the future for clinical dentistry, in vital pulp therapy as an effective treatment for dental caries, as an alternative approach for root canal therapy, and to provide a path for therapeutic and regenerative dentistry.

Keywords: Wnt/β-catenin; dentin; pulp; regeneration; signaling pathway.

Figure 1

Active Canonical Wnt/β-Catenin Signaling Pathway. Wnt signal triggers Frizzled protein and activates LRP 5/6, Dishevelled (Dvl), Glycogen Synthase Kinase 3β (GSK), Casein kinase 1 (CK1), adenomatous polyposis coli (APC).

Figure 2

Inactive Canonical Wnt/β-Catenin Signaling Pathway. Cadherin activates AXIN mediated with the help of α and β-catenin and triggers gene expression.

Figure 3

Different types of proteins, molecules, and ligands in Wnt signaling. The molecules activate Wnt signaling by modulating ligands (Wnt) and signaling proteins.

Figure 4

Prisma flowchart of recent advances in Wnt/β-Catenin pathway in dentin and pulp regeneration. Identification of articles through 4 platforms, followed by screening (duplicate and other reasons such as non-English articles) and then finalized 100 articles after screening for assessment.

Figure 5

Growth delay and anomalies in the root of OC-Cre, Ctnnb1 fl/f mice (A) 1 month-old OC-Cre, Ctnnb1 fl/f mice are smaller than (Ctnnb1 fl/fl) the wild type mice. (B) Incisors at P30 show hypoplastic teeth with semi-transparent dentin (Gross appearance) (C–F). Maxillary 1 molars at P15, P30, P45, and P60 with lengths of crown and root are shown by green and red brackets, respectively [39]. Reproduced with permission from Zhang R et al. [39], published by International Journal of Biological Sciences, 2013.

Figure 6

(A). Graph showing the decreased expression of miR-140-5p by qRT-PCR in differentiation groups on day 1, day 3, day 7, and day 14 vs the control group, p < 0.05. n = 6 whereby * represents significance of result [47]. Reproduced with permission from Lu Xiaohui et al. [47]., published by Stem Cell Research and Therapy (2019). (B). Tertiary dentin formation is promoted by Wnt3a in vivo in Wistar rats; molar injury as shown by white arrows in molars treated with distilled water (DI: (a,b)), phosphate-buffered saline (PBS: (c,d)), Lithium chloride (LiCl: (e,f)), and recombinant human Wnt3a (Wnt3a: (g,h)), (i) After 4 weeks analysis of specimens was performed. The dentin/bone volume to total volume was calculated as shown in the graph, with bars showing a significant difference [60]. Reproduced with permission from Sukarawan W et al. [60]., Published by International Endodontic Journal 2023.

Figure 7

(A) The Wnt/β-catenin pathway regulates reparative dentinogenesis, which is modulated by the autocrine release of Wnt by Axin2. The rapid proliferation of pulp cells is perceived after tooth damage, with a peak at day 3 and a return to baseline on day 14, with dentin bridge formation. (B) The Wnt/β-Catenin signaling pathway is inhibited by Baicailin. (A,B) β-Catenin Protein expression of Baicailin treated iDPSC at each time point (C), The expression of NLK, CaMK2, β-catenin, and GSK3β of baicailin treated iDPSCs by western blot whereby the * and ** represent the significance of the result [61]. Reproduced with permission from Mengyuan Li et al. [61], published by Springer Nature 2023.