Regeneration of enamel forming ameloblasts from human non-dental epithelial cells
Tooth defect and loss greatly diminishes the quality of individual's life, and bioengineering of teeth is an important goal in regenerative medicine. Tooth regeneration requires both ameloblasts to form enamel, and dental mesenchyme to form dentin/pulp complex. Human ameloblasts are not available in the erupted teeth.
We have observed that when human developing tooth mesenchyme is combined with epithelial cells, the tooth mesenchyme can instruct the epithelial cells to differentiate into ameloblasts. We propose to de-differentiate pulp cells from extracted human teeth toward an early developmental stage that is capable of instructing epithelial cells to form ameloblasts. In a parallel effort, we will use key gene transcriptional regulators that we have identified as important for ameloblast differentiation, to directly transdifferentiate accessible human non-dental epithelial cells into an ameloblast fate.
Reprogramming accessible human cells toward tooth lineage allows us to further develop cell based strategies for enamel or even whole tooth regeneration. The knowledge we gain from the epithelial-mesenchymal cells interation will benefit the goals for regeneration of other epithelial appendages, such as skin and mammary gland, which use the similar mechanism regulating organogenesis. Finally, the reprogrammed dental pulp cells can be used to regenerate or repair pulp in teeth with pulpal infection or those requiring pulp removal such as in root canal therapy.
A full and functional dentition and intact tooth structures are critical for the health and well being of all Californians. A survey conducted in 2004 by American Public Health Association shows the rate of tooth loss for population in California is 13.3%, indicating that tooth related diseases and trauma are of significant concern for Californians. The lack of readily available cell sources for ameloblast regeneration constrains the advance of tooth bioengineering. In this proposal, we will explore two strategies to bioengineer ameloblasts. First, we will reprogram pulp cells from either fully formed permanent or primary teeth, to an earlier developmental stage, which can then instruct differentiation of epithelial cells into ameloblasts. Second, we propose to directly reprogram epithelial cells to an ameloblast phenotype, to further enhance the potential for successful tooth regeneration. These studies will allow us to move our current material based dental therapies toward a more biological approach of regenerating tooth tissues. It is also possible that de-differentiated dental pulp cells could be used to regenerate missing or infected tooth pulp cells, and may also be used for regeneration of other neural crest derivatives that comprise the periodontal ligament, alveolar bone, Schwann cells and neurons, further benefiting the health and well being of Californians.