The p75NTR/Mdm2 signaling axis promotes odontogenic differentiation and mineralization in ectomesenchymal stem cells

Tooth development and regeneration depend on precise regulation of odontogenic stem cell fate. With advances in stem cell tissue engineering and regenerative medicine, biological tooth regeneration has become a focus of regenerative medicine. As a positive marker of neural crest-derived ectomesenchymal stem cells, p75NTR actively participates in tooth development. Mdm2, a key negative regulator of p53, is functionally associated with p75NTR. However, the crosstalk between p75NTR and Mdm2 and their roles in tooth mineralization during development remain unclear. This study investigated the functions of p75NTR and Mdm2 in odontogenic differentiation and mineralization and their regulatory relationships. A p75NTR knockout mouse model was established to investigate the regulatory effect of p75NTR on Mdm2. Ectomesenchymal stem cells derived from mouse dental germs were used for in vitro experiments. The results revealed that Mdm2 expression was reduced in the dental tissues of p75NTR knockout mice and that p75NTR overexpression in EMSCs in vitro significantly upregulated Mdm2 expression. Moreover, Mdm2 enhanced the expression of Dspp, Dmp1, Runx2, and Opn in EMSCs. Luciferase reporter assays and coimmunoprecipitation experiments demonstrated that p75NTR increased the transcriptional activity of the Mdm2 gene while interacting with the Mdm2 protein in the nucleus. Furthermore, p75NTR overexpression reversed the inhibitory effects of Mdm2 knockdown on odontogenic differentiation and mineralization of EMSCs. These findings indicate that Mdm2 mediates p75NTR-induced odontogenic differentiation and mineralization of EMSCs and that p75NTR activates Mdm2 transcription while binding to the Mdm2 protein in the nucleus.