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RN1-00572-1: Oral and Craniofacial Reconstruction Using Mesenchymal Stem Cells
Recommendation: Recommended for funding
Scientific Score: 69
First Year Funds Requested: $623,064
Total Funds Requested: $3,253,464
Public Abstract (provided by applicant)
The overall goal of this proposal is to explore a new stem cell-based treatment for major defects in the orofacial regions resulted from burns, physical injuries, genetic diseases, cancers, infectious diseases, and recently, bisphosphonate-associated osteonecrosis of the jaw (BONJ), using the patient’s own stem cells obtained from the oral cavity known as orofacial mesenchymal stem cells (OMSCs).
The standard surgical reconstruction of orofacial defects relies on different sources of bone grafts harvested from distant anatomical site of the same patient or other donors. However, those approaches are associated with higher morbidity and unpredictable clinical outcomes. Evidences have shown that bone marrow mesenchymal stem cells (BMMSCs) could be a promising alternative for bone reconstruction but not in the orofacial region. These clinical results may be due, in part, to the fact that orofacial and long bones are derived from different cell origins, termed as neural crest cells and mesoderm, respectively. In addition, OMSCs are readily accessible from the oral cavity and can be easily expanded for cell-based therapies due to their inherently high proliferative capability. These evidences suggest that neural crest cell-associated OMSCs might be a superior cell source for orofacial bone regeneration as compared to BMMSCs.
In this study we will compare human OMSCs and BMMSCs in terms of stem cell characteristics and will test their tissue regeneration capacities in the restoration of orofacial defects including the recently drug-induced bone necrosis defects caused by the commonly used drug, bisphosphonate in our established animal models. Our laboratories have recently demonstrated feasibility of using BMMSCs to partially repair craniofacial defects in mouse models. In this proposed study, we will use OMSCs as a model system to determine whether and how individual OMSCs can be utilized as a novel cell therapy for orofacial tissue regeneration. We anticipate that the patient’s own OMSCs will be capable of forming orofacial tissues and will highlight future clinical treatments for orofacial defects.
Statement of Benefit to California (provided by applicant)
There is a great clinical demand for developing more optimized approaches to repair facial defects caused by burns, trauma, genetic anomalies, cancers, and recently, the devastating drug-induced osteonecrosis of the jaw associated with the commonly used drug, bisphosphonate (BONJ). Current therapeutic approaches are deficient in supplying appropriate tissues for major facial reconstruction. By generating an optimal supply of human orofacial mesenchymal stem cells (OMSCs) for stem cell-based therapy, we hope to circumvent the limited tissue resource and provide a more superior cell source for future facial tissue regeneration. More importantly, Californians who are head and neck cancer survivors, or suffer esthetic and functionally debilitating orofacial defects will benefit from the advances in stem cell biology and its clinical applications, specifically in the field of orofacial reconstruction. In this proposal, we will expand current knowledge of stem cell biology of OMSC and test the feasibility of utilizing these autologous stem cells in the treatment of diseases such as BONJ. The novel approach in the reconstruction of the orofacial defects using OMSC-based therapy will replace standard paradigm of treatment which involves multiple surgeries, lengthy operating time, cost, and morbidity to the patients. The success of this proposal will not only benefit the people of California, but will have high impact on the state economy by reducing the medical cost and overall financial burden on the State of California Health Insurance.
Review
SYNOPSIS: This study proposes to characterize stem cell (SC) properties of newly identified orofacial mesenchymal stem cells (OMSCs), and their use to repair orofacial bone defects. The use of bone marrow mesenchymal stem cells (BMMSCs) for orofacial skeletal repair is suboptimal, due to the distinct properties and embryonic origins of each progenitor SC population. Easily accessible OMSCs are highly proliferative, and provide a more robust stem cell source.
The proposal aims to determine whether human OMSCs are multipotent postnatal stem cells, to define the roles of two specific growth factors in human OMSC differentiation, and to test the feasibility of reconstructing orofacial defects including bisphosphonate-associated osteonecrosis of the jaw (BONJ), using OMSCs in an animal model.
STRENGTHS AND WEAKNESSES OF THE RESEARCH PLAN: This proposal is built on the premise that orofacial derived bone marrow mesenchymal stem cells (OMSCs) are different than BMMSCs derived from axial or appendial (long) bones and are better suited for repair of craniofacial bones. The proposed studies are significant and innovative, in that they will explore a new stem cell based treatment for repairing major defects in the orofacial region, using an autologous cell based therapy. This is a highly significant clinical problem. The development of the proposed large animal model is original, and clinically relevant to humans, based on similar size, shape, and morphology. The properties and regenerative capacity of human OMSCs and BMMSCs will be compared. The proposed studies have the potential to significantly move the field forward, and to improve craniofacial repair therapies, by using neural crest cell (NCC)-derived progenitor cell populations.
The strengths of this application include the expertise of the Principal Investigator (PI) and the collaborators in MSCs and orofacial surgery, the seeming differences between OMSCs and BMMSCs including their neural crest origin, the focus on human MSCs, and the preliminary establishment of a large animal model for bone regeneration. There is preliminary data that addresses the role and expression of two specific growth factors in OMSCs and BMMSCs and that demonstrates the development of the proposed animal models for study.
These strengths are balanced by some concerns about the scientific plan and feasibility. The exact methods used to isolate OMSCs (from what orofacial structures?) is not provided, although experimental approaches used to manipulate these stem cells, anticipated results, and alternative strategies are discussed. One reviewer felt that there is no evidence that OMSCs are stem cells, and that they might well be progenitor cells. Other reviewers recognized difficulties in characterization of the desired cells. Some of the preliminary data are less convincing: the immunohistochemistry shows almost complete overlap of two cell surface molecules with the nuclear stain DAPI, so differences in the MSCs as well as the likely heterogeneity of the isolated clones is hard to determine. Heterogeneity of the cells within an isolation may not yield differences in bone restoration but are likely to confound understanding of the mechanisms.
Finally, concerns were raised over the choice of the large animal model for the reconstruction experiments. It is unclear whether the animal and human OMSCs are similar enough in their cell surface marker signatures to ensure that demonstrated repair methods in the model will be directly relevant to human repair approaches. Finally, if a model already exists in the mouse why use the new system? Advantages of a large animal model should be balanced with the ease of manipulation and availability of a tremendous amount of genetic background.
QUALIFICATIONS AND POTENTIAL OF THE PRINCIPAL INVESTIGATOR: The applicant is a talented investigator with many important contributions to the field, as shown by the list of publications. The applicant is already recognized as an established leader in the field of craniofacial stem cell characterizations, based on seminar publications and numerous invited presentations. One reviewer expressed no hesitation in affirming that the applicant and the team are perfectly qualified to perform all the specific aims of this grant.
The applicant trained as a dentist and received a PhD in craniofacial biology in the 1990s, with three years of postdoctoral training in skeletal biology. After a year in private practice, the applicant served as a clinical fellow in craniofacial and skeletal diseases, and in another position at a prominent research institution. The applicant was appointed Assistant Professor in 2006 at the current institution. The applicant has a number of papers in both specialty and high profile journals on mesenchymal stem cells. The PI has an NIH grant on stem cells, and a pending NIH grant.
The career development plan of the PI is to “further develop my career in stem cell research to incorporate translational medicine”. The applicant’s long-term goal is to “be an outstanding clinician-scientist engaged in exploring mechanisms of stem cell-associated diseases and translating stem cell technologies to clinical applications”. The applicant presents a reasonable career development plan with plans for training in clinical trials, translational issues and use of human ESCs (no mention of why this), organized by NIH and other organizations. The applicant also mentions a 2 month stay outside the US to work with a collaborator on a clinical trial. The applicant has initiated lab meetings with a clinician-scientist specializing in oral and maxillofacial surgery with expertise in transplantation of MSC in animal models, who will provide exposure to ongoing NCI/NIH supported clinical trials. Training in human bone diseases will be received in monthly consultations with an oral pathologist collaborator, and the applicant will visit a long-term collaborator, who is using human SCs to repair myocardial infarction patients. The applicant provides a list of metrics to judge his/her career development.
INSTITUTIONAL COMMITMENT TO PRINCIPAL INVESTIGATOR: The institution has committed over 1,200 sq ft of laboratory space, a competitive salary and start up package, and excellent fringe benefits. An internal advisory committee has been established, to review overall progress and provide advice on research and future directions. There is a strong letter from the Dean of the Dental School outlining how the applicant fits into the plans for more tissue regeneration in the school as well as at the institution. There is a commitment for space, salary and protected time as well as other efforts to promote the applicant as a leader in the field.
The institutional support appears to be excellent, and encompasses all of the necessary resources and centers to successfully execute the proposed specific aims. The institution has established an ES cell core laboratory, providing access and support to all core scientists. The applicant institution has reduced the applicant’s teaching load to 20-30 hours/year, and has provided excellent laboratory space, facilities, and infrastructure. The applicant is being promoted as a leader in translation of stem cell research into the clinic, and is provided with annual travel expenses to attend meetings. The institution has a strong record of promoting the development of new biomedical faculty, and has received significant capital for the establishment of a stem cell research center. Establishment of an institutional center to promote stem cell regeneration of lost or damaged tissues is anticipated.
DISCUSSION: The panel was generally enthusiastic about this proposal. There was discussion about whether sufficient evidence was presented that the proposed cells are stem cells (i.e., that they can self-renew). Another panelist commented that the RFA embraces stem cells and other progenitor cells, as long as the cells might be clinically relevant. The panel’s discussion also addressed the importance of the proposal as a translational effort for regeneration of orofacial bone, or for increased bone formation. This therapy could be important in many clinical situations including: nasopharyngeal cancer, injury, cleft palate, and craniosynostoses. Finally, the panel expressed strong support for the candidate; as a dentist with clinical and basic experience, this person is poised to become a leader in the field.
The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:
- None