Central Archives of Stem Cell Research Cite this article: Tsikandelova R, Isaeva A, Mitev V, Ishkitiev N (2015) WNT Signaling and Implications for Dental Regenerative Medicine. Arch Stem Cell Res 2(1): 1007. *Corresponding author Ishkitie v N, De p a rtme nt o f Pe d ia tric De ntistry, Me d ic a l University – Sofa, 1431 G. Sofyski Street, Sofa, Bulgaria, Tel: 35-988-510-8620; Email: Submitte d: 27 February 2015 Accepted: 10 April 2015 Publishe d: 20 April 2015 Copyright © 2014 Ishkitiev et al. OPEN ACCESS Ke ywo rds • Stem cell biology • WNT signaling • Mesenchymal pulp stem cells • Dental regenerative medicine Review Article WNT Signaling and Implications for Dental Regenerative Medicine Rozaliya Tsikandelova 1 , Antonia Isaeva 1 , Vanyo Mitev 1 and Nikolay Ishkitiev 2 * 1 Department of Medical Chemistry and Biochemistry, Medical University- Sofa, Bulgaria 2 Department of Pediatric Dentistry, Medical University – Sofa, Bulgaria Abstract WNT signaling pathway functions throughout the lifetime of the organism by ensuring the normal patterning of tissues during development and by regulating self- renewal and cell fate commitment in multiple adult stem cell types. Currently, not enough is known about the role of WNT signaling in the maintenance of adult dental tissues. In this review we briefy outline current developments in the feld of WNT signaling with regard to the regulation of mesenchymal dental pulp cells and pose outstanding questions to be addressed in the future. ABBREVIATIONS ESC: Embryonic Stem Cells; FZD: Frizzled Receptors; APC: Adenomatous Polyposis Coli; CKIα: Casein Kinase I Alpha; GSK3: Glycogen Synthase Kinase 3; DSPP: Dentin Sialophosphoprotein; SNP: Single Nucleotide Polymorphism; DPSCS: Dental Pulp Stem Cells INTRODUCTION A new paradigm has emerged, suggesting that in cycling tissues, adult stem cells achieve a fine balance between self- renewal and differentiation as a result of stochastic cell fate decisions involving either a cell-autonomous or cell-extrinsic mode of action [1,2]. Central to understanding the mechanisms of stem cell behavior is the need to further investigate the ability of different niche growth factors to communicate context- dependent developmental cues to stem cells in the niche. A highly conserved pathway that has been implicated in the self- renewal and differentiation of embryonic (ESC) and adult stem cells is the WNT/ β-catenin signaling pathway. WNT ligands are glycoprotein molecules that have a short-range mode of action due to lipid modifications, which render them hydrophobic [3] and tether them to their cognate Frizzled (FZD) receptors and LRP5/6 family co-receptors on cell membranes [1]. Thus, by being highly insoluble, WNT ligands can only exert an effect on neighboring cells within the limited range of the niche [1]. In the light of recent advances in the field and consistent with studies implicating WNT pathway components in the functioning of the mitotic spindle during division, mitosis and cell fate determination appear to converge at the level of WNT signaling [4,5]. Following the purification of an active WNT3a ligand, a well-known canonical WNT ligand, which has previously been shown to maintain mouse ESCs in a self-renewing state [6] and to drive mesodermal and endodermal differentiation in human ESC [7], it has been eloquently demonstrated that a targeted delivery of WNT3a can induce asymmetric inheritance of cell fate determinants in mouse ESCs [8]. The case for WNT signaling in the maintenance of the adult stem cell pool during homeostasis is further reinforced as aberrant WNT signaling often underlies chromosome instability and tumor progression in tissues that exhibit high rates of cellular turnover [9]. WNT signaling can be classified into canonical and non- canonical signaling. Non-canonical signaling pathways, which have been known to regulate cell polarity and cell movement, act independently of β-catenin [10], which is a key component of the canonical WNT pathway. In the absence of a WNT signal, β-catenin binds to a multimeric destruction complex composed of APC (adenomatous polyposis coli), AXIN (1/2), casein kinase I alpha (CKIα) and glycogen synthase kinase 3 (GSK3), where it is phosphorylated by CKIα and GSK3 and targeted for proteasome degradation [1] (Figure 1). When present, WNT ligands engage with Frizzled receptors and LRP5/6 co-receptors, ultimately leading to clustering of these receptors in complexes. The conformational changes ensuing this coupling enable the LRP cytoplasmic tail to be phosphorylated by GSK3 and CKIα, resulting in the sequestration of the scaffold protein AXIN to the membrane and the inhibition of GSK3 [1,11]. Stabilized β-catenin then translocates to the nucleus and initiates Lef/Tcf - dependent transcription of global and tissue- specific WNT target genes. Lineage tracing experiments using broadly activated WNT target genes such as AXIN2 and LGR5,