Abstract
Dental pulp stem cell (DPSC) transplantation has shown new prospects in dental pulp regeneration, and is of great significance in the treatment of pulpitis and pulp necrosis. The fate and regenerative potential of stem cells are dependent, to a great extent, on their microenvironment, which is composed of various tissue components, cell populations, and soluble factors. N-cadherin-mediated cell–cell interaction has been implicated as an important factor in controlling the cell-fate commitment of mesenchymal stem cells. In this study, the effect of N-cadherin on odontogenic differentiation of DPSCs and the potential underlying mechanisms, both in vitro and in vivo, was investigated using a cell culture model and a subcutaneous transplantation mouse model. It was found that the expression of N-cadherin was reversely related to the expression of odontogenic markers (dentin sialophosphoprotein, DSPP, and runt-related transcription factor 2, Runx2) during the differentiation process of DPSCs. Specific shRNA-mediated knockdown of N-cadherin expression in DPSCs significantly increased the expression of DSPP and Runx2, alkaline phosphatase (ALP) activity, and the formation of mineralized nodules. Notably, N-cadherin silencing promoted nucleus translocation and accumulation of β-catenin. Inhibition of β-catenin by a specific inhibitor XAV939, reversed the facilitating effects of N-cadherin downregulation on odontogenic differentiation of DPSCs. In addition, knockdown of N-cadherin promoted the formation of odontoblast-like cells and collagenous matrix in β-tricalcium phosphate/DPSCs composites transplanted into mice. In conclusion, N-cadherin acted as a negative regulator via regulating β-catenin activity during odontogenic differentiation of DPSCs. These data may help to guide DPSC behavior by tuning the N-cadherin-mediated cell–cell interactions, with implications for pulp regeneration.
Highlights
Dental caries is one of the most common bacterial infectious diseases worldwide, leading to destruction of the tooth structure and irreversible pulpitis or pulp necrosis
These results indicate that a functional decrease in N-cadherin was required during odontogenic differentiation of dental pulp stem cell (DPSC)
Given that there is a negative correlation between N-cadherin and the odontogenic markers, it was investigated whether inhibition of N-cadherin could promote DPSC differentiation by knockingdown N-cadherin via lentiviral transfection (Figure 2A). quantitative real-time polymerase chain reaction (qPCR) and western blot analysis showed that N-cadherin was significantly downregulated both at the mRNA and protein level after N-cadherin short hairpin RNA (shRNA) lentivirus transfection in DPSCs (Figures 2B,C)
Summary
Dental caries is one of the most common bacterial infectious diseases worldwide, leading to destruction of the tooth structure and irreversible pulpitis or pulp necrosis. Root canal therapy is the common endodontic treatment for pulp diseases that involves the extirpation of diseased pulp and the subsequent obturation of root canal systems with bioinert synthetic materials, N-Cadherin Regulates the Odontogenic Differentiation of DPSCs resulting in a permanently inactivated tooth that is more prone to fractures and re-infection (Gong et al, 2016). Dental pulp stem cell (DPSC)-mediated approaches for regeneration have demonstrated promising results in terms of generating dental pulp-like tissues with morphologic characteristics that resemble those of normal dental pulp in vivo and in situ (Gronthos et al, 2000, 2002; Huang et al, 2010; Nakashima et al, 2017; Xuan and Li, 2018). The improvement of regenerative endodontic procedures requires a better understanding of how the microenvironment controls DPSC behavior
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