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.
The promise of stem cell biology for regenerative medicine lies in the ability of these remarkable cells to give rise to more differentiated cell types that, individually or as part of a bioengineered organ, can replace structures that have been damaged by disease or aging. We propose to help lay the groundwork for organ regeneration by focusing on the tooth as a prototype organ. In addition to addressing the health issues posed by dental decay and tooth loss, which require prosthetic replacements that are functionally inferior to natural teeth, our project will help to pave the way for safe clinical applications of human embryonic stem cells in regeneration of larger organs, such as hearts or lungs. We anticipate that our research will be a significant step towards making the promise of regenerative medicine from adult stem cells and human embryonic stem cells a reality. Our studies will provide a much-needed model system that will allow us to study the basic mechanisms underlying guided development of organs from stem cells, which will be central to fulfilling the therapeutic potential of stem cell-based organ regeneration. Eventually, stem cell-based therapies will reduce health care costs for Californians by improving treatment for diseases for which we currently do not have effective therapies. Our work could provide economic benefits to the state by helping to lay the groundwork for commercial efforts to regenerate teeth as well as other solid organs, such as the heart and pancreas. Such developments would be of great benefit to California by making the state a leader in a field that is poised to become economically important in the future. The State of California will also stand to benefit from the intellectual property generated by this research, as generalizable principles regarding the use of stem cells, in vitro differentiation of cells, scaffolding materials, and organ bioengineering may be patentable.
The applicant focuses on teeth as a model for understanding regenerative processes of complex organs. Despite their accessibility and recent published work demonstrating the clinical feasibility of tooth regeneration, little is known about the genetic regulation and biology of the cells that participate in tooth regeneration. This application is directed at filling in some of the gaps in this knowledge. The applicant uses mouse incisors as a source of continually growing epithelial progenitor cells and proposes to establish the incisor as a model for dental stem cell biology. The applicant also proposed studies to isolate tooth epithelial stem cells from human embryonic stem cells (hESC). The applicant proposes a plan for identification of the epithelial stem cells and their mechanisms of self-renewal. Then the applicant will establish the optimal conditions for growing epithelial (progenitor) cells from incisors and for maintaining their undifferentiated state. The applicant will examine the potential of these epithelial cells and mesenchymal stem cells (or the two in combination) in tooth regeneration.
This area of stem cell biology was considered an important area for CIRM to emphasize as it is currently underdeveloped and inadequately supported. Reviewers felt that the novelty of the proposed work was high, and that the proposal was quite high risk, but also had great potential to be high gain. The reviewers noted that though published work supporting Aim 1 was extant, the applicant is significantly extending the work by examination of cell adhesion molecules and assessing the role of particular growth factors in the biology of this stem cell population. Overall, the proposed studies would not have been thought feasible in the hands of most young investigators, but because of the particular strengths of this new investigator and the enormous institutional support, reviewers were very confident that both basic science insights into epithelial stem cell biology and practical, clinically relevant information would emerge from these studies.
Reviewers expressed some concern that the over-arching hypothesis was not presented clearly. Another cited weakness of the application was the lack of adequate characterization of the cells, but extant literature should help guide the characterization of these epithelial stem cells in vitro. Reviewers felt that, in the regeneration studies, the applicant did not sufficiently account for the niche or microenvironmental effects, and the culture system was simplistically discussed. The microenvironment may have to be considered in greater detail in order for the generation of epithelium from hESC to be successful. These considerations led reviewers to conclude that the tooth regeneration studies were risky in terms of feasibility. Much of the proposed work for Aim 1 appears to have been published, likely a problem with the timing of submission of this application and the paper. Some criticisms that the application was too large in scope and speculative were raised, but again, these concerns were balanced by a highly favorable impression that the applicant has already tackled difficult problems successfully.
The greatest strength of the grant is the Principal Investigator. Although she/he has been an assistant professor of orofacial science and pediatrics at a prestigious medical center only since 2007, she/he is already a widely recognized scientist with highly significant publications, including some as senior author. The applicant communicated great motivation and clear determination to accomplish the research. Though there were some problems with the proposed science in the grant, the applicant is likely to overcome these given the applicant’s and institutional strengths. Reviewers felt that the potential for this applicant to be a leader in the field was high. The institutional support for this applicant could not have been more positive. The extraordinary level of institutional support was clear in a letter signed by the dean, chair, division director and the director of the institutional stem cell center. Importantly, the applicant will have a 90% protected research time allotment, another indication of the institution’s commitment to the applicant’s project.