Teeth form by reciprocal interactions between epithelial and mesenchymal tissues derived from the ectodermal cell layer of the developing embryo. Tooth formation initiates when the epithelial lining of the oral cavity thickens to form primary epithelial bands (named placodes), which correspond in position to the future teeth in the upper and lower jaws. The epithelium then invaginates into the underlying mesenchyme, which responds to signals from this epithelium, to form the dental papilla. This process initiates a cascade of molecular signals. This cascade of signals between the dental epithelium and mesenchyme results in differentiation of the cells and tissues that make up a tooth organ, and the ultimate formation of a mature tooth.
Observations of teeth formed in teratomas, show us that teeth can form from germ cells. Teratomas are tumors derived from pluripotent germ cells, and when they form in the ovaries, these tumors often contain well-differentiated cells that make tissues and organs, including hair and teeth. This evidence shows us that with the right trigger, a cascade of cell differentiation and reciprocal signaling in germ cells, can result in the complete formation of a tooth organ. Studies of tooth formation from human embryonic stem cells will also help us to understand fate decisions of tooth-specific lineage in early odontogenesis, as well and epithelial/mesenchymal interactions required in the development of tooth and other organs.
We hypothesize that given suitable conditions, human embryonic stem cells (hESC) can commit to dental specific lineage cells. The odontogenic potential of these cells could progress once a reciprocal communication with mesenchyme is established, ultimately deposit dentin and enamel matrix proteins.
Our specific aims are as follows: 1) to direct hESCs differentiation to dental epithelial lineage cells. In this first stage of tooth formation, we will determine the factors required for the formation of dental epithelial lineage cells, which can then direct dental mesenchymal differentiation as the cascade of events that result in tooth formation begins. 2) To determine the factors in the dental mesenchyme responsible for inducing the differentiation of dental epithelial lineage cells into ameloblasts. This second stage of differentiation is important for continued tooth formation. These experiments will help us to understand the signals required for maturation of the dental epithelium into ameloblasts, which are the cells responsible for tooth enamel formation.
Our ultimate goal in these experiments is determine how teeth can differentiate from stem cells, and to use this knowledge to replace missing teeth in humans. In this seed grant we will take the first step toward this goal, to discover what directs the differentiation of dental lineage cells. The tooth organ model will help us to better understand epithelial-mesenchymal interactions in organ development.
Statement of Benefit to California:
There is currently much interest in bioengineering teeth, because dental decay and tooth loss constitutes an important health issue. In today’s market, the cost of each tooth replacement for Californians is around $2500. Currently, replacement of teeth requires prosthetic strategies including dental bridges, dentures and metal post implants covered by crowns. These prosthetic replacements must be replaced periodically, and there is no doubt that natural teeth are in all ways superior to these man-made materials. An ultimate goal in the use of stem cell research would be to promote the formation of new teeth to replace missing teeth, in the same way that permanent teeth replace the primary teeth of formed in early childhood.
Of additional importance in this study is to understand cell fate decisions that direct the formation of organ-specific epithelial and mesenchymal tissues toward tooth formation. In other words, what factors direct germ cells to differentiate into the epithelial and mesenchymal cells of a tooth organ? The tooth is a particularly interesting model of organ development, forming a simple organ system from ectodermally derived epithelial and neurocrest cells. These cells continue to interact and influence each other’s differentiation as they progress down separate developmental pathways. If teeth can form following an initial ”triggering” event that starts the cascade of cell differentiation and interaction that results in tooth formation, then similar mechanisms may be sought in development of other organ systems.
In summary, funding of this seed grant will allow us to pursue this unique research on tooth formation, helping us to understand the mechanisms of tooth formation, as well enhancing our basic knowledge of cell fate decisions in organ development. These studies could help Californian’s enjoy a life with functional teeth at all ages.