Development of tooth regenerative medicine strategies by controlling the number of teeth using targeted molecular therapy

Abstract

Analysis of various genetically modified mice, with supernumerary teeth, has revealed the following two intrinsic molecular mechanisms that increase the number of teeth. One plausible explanation for supernumerary tooth formation is the rescue of tooth rudiments. Topical application of candidate molecules could lead to whole tooth formation under suitable conditions. Congenital tooth agenesis is caused by the cessation of tooth development due to the deletion of the causative gene and suppression of its function. The arrest of tooth development in Runx2 knockout mice, a mouse model of congenital tooth agenesis, is rescued in double knockout mice of Runx2 and Usag-1. The Usag-1 knockout mouse is a supernumerary model mouse. Targeted molecular therapy could be used to generate teeth in patients with congenital tooth agenesis by stimulating arrested tooth germs. The third dentition begins to develop when the second successional lamina is formed from the developing permanent tooth in humans and usually regresses apoptotically. Targeted molecular therapy, therefore, seems to be a suitable approach in whole-tooth regeneration by the stimulation of the third dentition. A second mechanism of supernumerary teeth formation involves the contribution of odontogenic epithelial stem cells in adults. Cebpb has been shown to be involved in maintaining the stemness of odontogenic epithelial stem cells and suppressing epithelial-mesenchymal transition. Odontogenic epithelial stem cells are differentiated from one of the tissue stem cells, enamel epithelial stem cells, and odontogenic mesenchymal cells are formed from odontogenic epithelial cells by epithelial-mesenchymal transition. Both odontogenic epithelial cells and odontogenic mesenchymal cells required to form teeth from enamel epithelial stem cells were directly induced to form excess teeth in adults. An approach for the development of targeted therapeutics has been the local application of monoclonal neutralizing antibody/siRNA with cationic gelatin for USAG-1 or small molecule for Cebpb.

Keywords: Cebpb; Molecular targeted therapy; Odontogenic epithelial stem cells; SOX2; Supernumerary teeth; Third dentition; Tooth regeneration; Usag-1.

Fig. 1

Treatment plan for congenital tooth agenesis. RUNX2, EDA, MSX1, PAX9, AXIN2, and WNT10A have been identified as causative genes for congenital tooth agenesis. The mutation of the causative gene is used as a biomarker, and a neutralizing antibody of USAG-1 or USAG-1 siRNA is administered as a molecularly targeted drug

Fig. 2

Expanding the target from congenital tooth agenesis to general missing teeth (the third dentition). Both the human third dentition and mouse rudimentary incisor usually regressed

Fig. 3

Tooth regeneration by stimulation of the third dentition. a This treatment involves regenerating the third dentition following permanent teeth eruption by locally administering a neutralizing antibody or siRNA with DDS like cationic gelatin hydrogel for USAG-1. b Frontal section of a computerized tomography (CT) scan of the tooth germ of the third dentition located in the lingual side of the lower right premolar that is preceding the permanent molar in an 11-year-old individual. The yellow arrow indicates the tooth germ of the third dentition. c Occlusal view and frontal section of a CT scan of the erupted third dentition in an 18-year-old individual. The white arrows indicate the erupted third dentition

Fig. 4

Development of tooth regenerative medicine targeting odontogenic epithelial stem cells. a Cebpb is involved in maintaining the stemness of enamel epithelial stem cells and suppressing epithelial-mesenchymal transition (EMT). Odontogenic epithelial stem cells (OESCs) are differentiated from one of the tissue stem cells; enamel epithelial stem cells and odontogenic mesenchymal cells are formed from odontogenic epithelial cells by EMT. It was demonstrated that both odontogenic epithelial cells and odontogenic mesenchymal cells, required to form teeth from enamel epithelial stem cells, were directly induced to form excess teeth. b Occlusal view of erupted multiple supernumerary teeth derived from odontogenic epithelial stem cells. The yellow arrows indicate the erupted multiple supernumerary teeth