Laying the groundwork for building a tooth: analysis of dental epithelial stem cells

To fix a broken car, the mechanic either repairs or replaces the defective part. Similarly, one of the most promising approaches physicians foresee for treating human disease and ameliorating the aging process is regenerative medicine. A major aim of this field is to restore function by repairing or replacing damaged organs. Scientists envision a day when people with heart failure can be cured with hearts grown from their own cells, and a future in which dialysis machines are not needed because patients with damaged kidneys can be furnished with new ones. However, organ engineering is highly complex, and the field of regenerative biology is still in its early stages. Therefore, it is important to provide proof of principle and lay the foundation for creation of new organs by first using as simple a system as possible, and teeth provide an excellent model system for organ replacement. Their physiology is less complex than many other organs, but their development has much in common with that of other organs. This means that much of the information obtained from studying tooth regeneration will be generally applicable for building other organs. Teeth are a relatively safe prototype for organ regeneration, and there is a significant need for replacement teeth, as those born without teeth due to genetic defects, as well as elderly patients, patients with caries and periodontal disease, and victims of physical trauma all need new teeth. Our ultimate goal is to take advantage of basic biological principles in order to develop new therapeutic approaches. As such, we seek to help lay the groundwork for the formation of new teeth that can replace missing teeth, in the same way that permanent teeth replace the primary teeth formed in early childhood. This ambitious goal must be built on the proper foundation if it is to succeed. Therefore, we will first concentrate on a more readily achievable objective, which is to understand a naturally occurring version of regeneration by studying the continuous growth of the mouse incisor. This unusual tooth depends on the presence of adult stem cells to constantly produce all the cell types of the mature organ. Toward this end, we propose in this application to first analyze the biological processes that regulate the stem cells in this remarkable tooth. We will develop tools to grow the mouse stem cells outside of the animal in order to better understand them. Subsequently, we propose to translate what we have learned from the mouse model into human cells by learning how to induce human embryonic stem cells, fetal cells, or adult cells to become tooth progenitor cells. This last step will help lay the necessary groundwork for growing human teeth and blaze the trail for regeneration of larger organs.