Dental stem cells as a promising source for cell therapy

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Growing interest in the field of stem cell applications arises from the potential to control their fate and consequently their functions during tissue repair and/or regeneration (Mitsiadis and Graf 2009). For any therapeutic implication surrounding cell-based therapies, selecting a suitable cell source and knowledge on their microenvironment/niche is a pre-requisite. Thus, any cells that can provide the systematic framework for new cellular differentiation and tissue growth might be considered as an ideal cell choice as long as they are guided by appropriate signals and growth factors from their microenvironment (Srijaya et al. 2012). Further maneuver for facilitating tissue regeneration and growth can be made through formation of new vasculature and scaffolds made of biomaterials or matrix proteins to model and create three-dimensional structures (Srijaya et al. 2012). Herein we describe some potential properties of dental MSCs and their biological characteristics that may be essential for core elements of cell-based therapeutics.

Easy accessibility

Originating from the lineage of NC, dental stem cells can be considered as one of the most suitable cell source in terms of easy accessibility. These cells can be obtained in non-invasive or minimally invasive ways from teeth that are extracted in clinical practices and typically discarded as medical waste (Lensch et al. 2006; Jo et al. 2007). Considering that approximately 20 deciduous teeth are exfoliated in average human life and in some instances, unerupted third molars are extracted for clinical or orthodontic purposes, virtually everyone possesses a rich source of stem cells.  

Immature cell source

Compared to other MSC sources, dental-derived stem cells, particularly dental pulp stem cells (DPSCs) hold the status of more immature, youthful form of MSCs next to umbilical cord- and Wharton's Jelly-derived stem cells (Kashyap 2015). In general, immature MSCs exhibit higher proliferation, differentiation and regenerative functions than more mature ones. Thus, dental stem cells may offer a unique stem cell source for diverse clinical applications.

Quick isolation procedure

The techniques for isolation, culturing and differentiation of various MSCs have prominently advanced over the last decade. Growing evidence demonstrates that though found in various niches, certain tissues contain more stem cells than others (De Miguel et al. 2012). Among all the stem cells identified so far from different tissues, dental pulps are considered as a rich source of MSCs (DPSCs) in regard to the number of potential stem cells extracted from human tissue samples (Huang et al. 2009). Besides the cell number, enzymatic digestion for isolating stem cells from dental tissues is less time consuming compared to other MSC sources (Guilak et al. 2004). These factors allow dental stem cells to be less susceptible to potential enzymatic stress and expand faster than other cell sources. Therefore, although they are isolated from a tiny amount of dental tissue, potentially sufficient number of cells can be generated in time for many clinical applications. 

Multipotency

Apart from having higher proliferative capacity when compared to other well-known MSCs, such as bone marrow-derived stem cells, DPSCs in particular are an outstanding cell source considering their multi-potent differentiation potential (Liu et al. 2015). Apart from their differentiation potential into odontogenic cell types under in vitro culture conditions, DPSCs have been reported to have the ability to differentiate into adipocytes, neurons, osteoblasts, chondrocytes, myocytes, cardiomyocytes, melanocytes, and hepatocyte-like cells (Jiang et al. 2012; Liu et al. 2015).

 

Immunomodulatory properties

Immunomodulatory properties of dental stem cells have been reported both in vivo and in vitro. It was demonstrated that when DPSCs are co-cultured with peripheral blood mononuclear cells (PBMCs), DPSCs inhibited the proliferation of PBMCs via soluble factors (Liu et al. 2015). Key molecules identified were associated with innate and adaptive immune responses; Toll-like receptors (TLRs) were found to be responsible for immunosuppressive activities of DPSCs through activation of transforming growth factor-b (TGF-b) and interleukin-6 (IL-6) (Liu et al. 2015). In addition, expression of mediator proteins, such as HGF, immunosuppressive minor H antigen, major histocompatibility complex (MHC) classes, nitric oxide (NO), prostaglandin, interferon-γ and TGF-β is involved in their pro/anti-inflammatory properties in dental stem cells (Karamzadeh and Eslaminejad 2013). Further studies have demonstrated the immunosuppression properties of DPSCs by close association of the Fas ligand leading to apoptosis of T-cells in vitro (Liu et al. 2015). In addition, similar to other MSC types it is thought that dental stem cells are immunoprivileged or more precisely, ‘immune evasive,’ due to low expression of MHC class II and co-stimulatory molecules. This means that these cells do not elicit significant immune reactions even when cells from immune-mismatched donors are transplanted into heterologous recipients (Leprince et al. 2012). Thus, dental stem cells hold one of the most desirable features for the treatment of immune related disorders and for allogeneic and potentially heterologous cell transplantation.

 

Efficient reprogramming of dental stem cells into induced pluripotent stem cells

Previous studies have reported the generation of induced pluripotent stem cell (iPSCs) from various cell sources, typically by introducing reprogramming factors consisting of Oct3/4, Sox2, Klf4 and Myc. While the first cell type to be reprogrammed into iPSCs was dermal fibroblasts, many other sources were used such as amniotic fluid-derived cells, skin keratinocytes, adipose-derived cells, embryonic stem cell-derived fibroblasts, CD34 blood cells, MSCs and DPSCs (Ong et al. 2013; Srijaya et al. 2012).

Remarkably, the attainment of pluripotent status from somatic cells requires alteration of many biological processes including genes, genetic regulations, epigenetics, metabolism, signaling pathways, and mesenchymal-to-epithelial transitions which are the prime properties for reprogramming dynamics. It was reported that DPSCs could be effectively reprogrammed into iPSCs compared to various other cell sources, possibly because of their mesectodermal origin and inherent expression of pluripotent factors including Oct-4, Nanog, c-Myc, Sox2, stage specific embryonic antigens (SSEA-3, SSEA-4), and tumor recognition antigens (TRA-1–60 and TRA-1–81) (Yildirim 2013; Karamzadeh and Eslaminejad 2013). On the other hand, signaling molecules such as Wnt, Notch, and BMP were shown to control the fate of stem cells by molecular cross-talk among cells and regulate their microenvironment  interactions (Mitsiadis and Graf 2009). Notably, one of the most studied pathways, TGF-β/Activin pathway has been reported to play an important role in the maintenance of the pluripotent state (Yildirim 2013). Furthermore it was reported that p53 pathways act as a barrier for cell reprogramming (Yildirim 2013). Intriguingly, the positive responses of DPSCs for reprogramming process can be partly explained by its abundant expression of all the members of TGF-b family and lower levels of p53 molecule. Therefore, the balance of such inherent signaling pathways and genetic switches found in DPSCs may be valuable for their iPSC generation, which can be useful for their use as a disease modeling platform to evaluate molecular basis of human genetic disorders and as a drug screening platform and personalized cell therapy by differentiating them into required cell types.