Histatin-1 promotes the expression of markers associated with odontoblastic differentiation in the dental pulp and apical papilla

Complex tooth injuries, including dental caries, require the reestablishment of tissue architecture and functionality through the regeneration of cellular populations that enable tertiary dentin formation and the reestablishment of vascular and neural components. Among these cellular populations, the odontoblasts play a critical role, as they are responsible for dentin formation and maintenance, and can differentiate from stem cells of the dental pulp and apical papilla. We previously demonstrated that Histatin-1, a salivary peptide with wound-healing properties, enhances the mineralizing activity of primary mesenchymal cells from immature permanent teeth. Here, we demonstrate that Histatin-1 upregulates odontoblastic differentiation markers, including dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP1), together with odontoblast-like cellular features. Immunohistochemistry and tissue immunofluorescence revealed increased DSPP and DMP1 expression in Histatin-1-treated apical papilla explants, and to a lesser extent, dental pulp explants. These findings were corroborated in primary cultures of these tissues, which also showed upregulation of DSPP and β-catenin. Histatin-1 further promoted primary ciliogenesis and Golgi-polarization. Moreover, Histatin-1 stimulated in vitro mineralization and cell migration in a VEGFR2-dependent manner, as confirmed by pharmacological inhibition and a VEGFR2-binding-deficient mutant of Histatin-1. Collectively, these results suggest that Histatin-1 drives odontoblastic differentiation, opening new avenues for dental regenerative medicine.