The tooth represents an attractive target organ for multiple reasons. Tooth development, or odontogenesis, is potentially the best understood of the three systems. Its early signaling pathways have been defined. Through an elegant series of experiments in which mutant and wild-type epithelium and mesenchyme were juxtaposed and allowed to develop, discrete developmental stages have been demonstrated. These stages are defined by the stepwise action of key developmental regulators, such as BMP4 and MSX1.
Significantly, the tooth is also the most accessible system for eventual human translation. For example, replacement of teeth that are damaged or prematurely lost can be accomplished during an office visit, and does not typically require hospitalization. Furthermore, owing to their accessibility, teeth can be replaced more than once – in contrast to vital organs. Finally, the risk associated with restoring tooth function, compared with heart or pancreas, is clearly lower, which makes this system well suited for initial clinical studies.
Our work on tooth germ engineering currently involves three strategies. First, we are establishing parameters that facilitate the induction of tooth germs in situ. Principal among the manipulations being explored are those involving the canonical WNT signaling pathway, which when activated has the capacity to generate supernumerary teeth in rodent models. Second, we are using endogenous tooth development as a source of detailed gene expression information by laser capture microdissection (LCM) of dental epithelial and mesenchymal tissues over time. These data sets and child monitoring software free are being compiled by the SysCODE Computational and Genome Science Team along with annotations of genes that are either necessary or sufficient for tooth induction in vivo to build an odontogenic gene regulatory network. To this are being added protein and extracellular matrix expression information obtained. Lastly, we are establishing a pipeline for introduction of pro-odontogenic genes and factors into stem cells, with cell fate being assayed by immunostaining and RT-PCR. The additional data sets obtained from the in vitro ES cell-odontogenic system should help bootstrap the gene regulatory network and molecular blueprint.
Tooth Loss Statistics
- Major health disparity; 35% adults over 65 edentulous
- Prostheses and implants highly imperfect
- Powerful model; near term translational opportunities