PROJECT SUMMARY
Effective utilization of organ-specific somatic stem cells to repair injured tissues or to bioengineer organs will
revolutionize disease treatment and relieve numerous problems caused by aging and trauma. However, it
remains significantly challenging to derive somatic stem cells with precision and expand them with high efficiency
for clinical applications. The technical hurdles are in large part due to our incomplete understanding of the genetic
regulation that controls fate specification of progenitors during development, as well as cell plasticity in adults.
Teeth provide an excellent test case to further understand these aspects and apply clinically, as adult human
teeth do not maintain dental epithelial stem cells and lack the capability to regenerate. The mouse tooth is a
powerful model system to study both organogenesis and adult stem cell-based regeneration, and amenable for
both in vivo genetic studies and ex vivo manipulations to investigate progenitor cell functions. Leveraging this
remarkable experimental system and combining it with cutting-edge single cell transcriptomic analysis, this
proposal will deliver an in depth understanding of the genetic program and transcriptional changes during the
formation of dental epithelial progenitors. This knowledge will allow us to identify a genetic network and critical
regulators required to specify the dental fate and provide a blueprint to derive dental progenitors by differentiating
pluripotent stem cells along a genetic path. In parallel, this project will test the function and utilization of IRX1/2
and YAP in inducing the formation of dental progenitors through differentiation of oral epithelium and
dedifferentiation of ameloblasts respectively. We will compare single cell transcriptomes between induced,
embryonic, and adult progenitors to determine whether IRX1/2 and YAP can activate a dental genetic program.
Based on these data, we will also be able to address an important question in stem cell biology, which is how
different progenitor types in embryos and adults resemble each other transcriptionally. The main innovation of
the project arises from the integration of genomic techniques and mouse genetic models to understand the
genetic regulation of dental progenitor and stem cell formation, which is understudied. Such knowledge will form
the basis of future research and grant applications, and enable developmental principle-driven approaches to
tooth bioengineering.
