Epiregulin enhances odontoblastic differentiation of dental pulp stem cells via activating MAPK signalling pathway

Abstract

Objectives The odontoblastic differentiation of dental pulp stem cells (DPSCs) contributes to tertiary dentin formation. Our previous study indicated that epiregulin (EREG) enhanced odontogenesis potential of dental pulp. Here, we explored the effects of EREG during DPSC odontoblastic differentiation. Methods The changes in EREG were detected during tertiary dentin formation. DPSCs were treated with recombinant human EREG (rhEREG), EREG receptor inhibitor gefitinib and short hairpin RNAs. The odontoblastic differentiation was assessed with ALP staining, ALP activity assay, alizarin red S staining and real‐time RT‐PCR of DSPP, OCN, RUNX2 and OSX. Western blot was conducted to examine the levels of p38 mitogen‐activated protein kinase (p38 MAPK), c‐Jun N‐terminal kinase (JNK) and extracellular signal‐regulated kinase 1/2 (Erk1/2). The expression of EREG and odontoblastic differentiation‐related markers was investigated in human dental pulp from teeth with deep caries and healthy teeth. Results Epiregulin was upregulated during tertiary dentin formation. rhEREG enhanced the odontoblastic differentiation of DPSCs following upregulated p38 MAPK and Erk1/2 phosphorylation, but not JNK, whereas depletion of EREG suppressed DPSC differentiation. Gefitinib decreased odontoblastic differentiation with decreased phosphorylation of p38 MAPK and Erk1/2. And suppression of p38 MAPK and Erk1/2 pathways attenuated DPSC differentiation. In human dental pulp tissue, EREG upregulation in deep caries correlates with odontoblastic differentiation enhancement. Conclusion Epiregulin is released during tertiary dentin formation. And EREG enhanced DPSC odontoblastic differentiation via MAPK pathways.

Glioblastoma mutations impair ligand discrimination by EGFR

“…Rather than simply activating EGFR to promote tumor development as in lung cancer (Sharma et al, 2007), our data suggest that EGFR aberrations in GBM may instead alter the qualitative nature of EGFR signaling – as has also been suggested for EGFR vIII (Fan et al, 2013) – possibly by signaling to the microenvironment in a way that promotes tumor growth (An et al, 2018b). EREG is known to promote differentiation by activating EGFR in a plethora of cell types (Cao et al, 2020; Cui et al, 2019; Du et al, 2013; Freed et al, 2017; Jeong et al, 2020; Rizzi et al, 2013; Takahashi et al, 2003), and different EGFR ligands can promote preferential differentiation (Mukhopadhyay et al, 2013). One possibility suggested by our findings is that GBM mutations in EGFR ‘redirect’ responses of the receptor to activation by EREG so that they more closely resemble those seen with EGF.…”

Depletion of EREG Enhances the Osteo/Dentinogenic Differentiation Ability of Dental Pulp Stem Cells via P38 MAPK and Erk Pathway in Inflammatory Microenvironment

“…The plates were then detained for 30 minutes at room temperature with 10% cetylpyridinium chloride. (28)The absorbance of the cell cultures was measured at 562 nm on a multi-plate reader, and the final calcium level was normalized according to the total protein concentration in duplicate plates.…”

Human Dental Pulp Stem Cells: recent findings and current research

“…When the inflammation is controlled, factors promoting the function of stem cells need to be considered. As for the expression of foetal dental papilla genes being more explicit comparing with dental pulp genes, experimental evidences has shown that epiregulin (EREG) holds the ability to enhance the non-dental epithelial cells differentiation into fully developed epithelium [14]. Broader specificity of EREG to be exploited in other biological processes includes stimulation of DPSCs via activating the MAPK signalling pathway and c-Jun N -terminal kinase, or alternatively mitogen activated protein kinase.…”