The role of mTert-expressing stem cells in tooth formation and renewal

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DESCRIPTION (provided by applicant): Adult dental stem cells play a critical role in the continual renewal of the mouse incisor. Although recent loss and gain of function studies have begun to define key factors involved in maintaining normal tooth morphogenesis and renewal, which include Wnt/b-catenin signaling, the lack of markers for these cells has hampered our understanding of their genetic characteristics and location within the incisor. Therefore, establishing the tools to directly identify, isolate and study these cells will greatly advance our understanding of their role in tooth biology, which may ultimately lead to improved therapeutic treatment options for a wide range of diseases, including those affecting teeth. Telomerase (Tert) activity prevents cellular senescence and is required for maintenance of stem cells in regenerative tissues. Recent analysis of human teeth has identified telomerase activity within putative dental stem cells. We have generated and validated transgenic reporter mouse lines (mTert-GFP, mTert-CreER and mTert-rtTA) that allow for the identification, isolation and genetic manipulation of telomerase-expressing cells. Previously, we have shown that mTert-GFP expression marks telomerase-expressing ES cells, iPS cells and self-renewing tissue stem cells in blood and intestine. In addition, recent preliminary studies indicate that mTert expression marks a population of bone marrow-derived putative mesenchymal stem cells. Moreover, stabilization of Wnt/b-catenin signaling within this population results in dramatic changes in bone homeostasis consistent with a loss of this population. Interestingly, these mice also exhibit supernumerary tooth formation indicating that mTert expression marks a population of putative dental stem cells involved in tooth renewal. Given our striking preliminary results we hypothesize that mTert expression is a biomarker for dental stem cells within the incisor. Further study of mTert-expressing cells will allow us to identify the factors and pathways that underlie tooth renewal. Therefore, this proposal aims to 1) phenotypically and functionally characterize mTert-expressing dental cells and to 2) define the role of Wnt/b- catenin signaling in mTert-expressing dental cells.