Cell therapy holds significant potential for the reconstruction and regeneration of craniofacial defects and deformities. One of the most important aspects of cell therapy is the identification of the most appropriate cell source for isolation of cells. Historically, mesenchymal stem cells (MSCs) derived from bone marrow have demonstrated regenerative potential in many preclinical studies. However, traditional techniques for isolating MSCs typically involve a bone marrow harvest from the iliac crest. Due to the invasive nature of the iliac crest bone marrow harvest procedure and the developmental (endochondral) origin of this tissue, it would be far more desirable to have a more readily accessible and developmentally similar (intramembranous) source of MSCs for craniofacial therapeutic indications. To this end, we have preliminary evidence which suggests that MSCs can be predictably isolated from alveolar bone marrow, using a simple, standardized, reproducible technique. Our hypothesis is that using current Good Manufacturing Practices (cGMP) guidelines, alveolar bone marrow derived MSCs (aBMSCs) can be safely expanded ex vivo, to numbers sufficient for autogenous clinical transplantation in human craniofacial bone defects. Additionally, we hypothesize that in vitro and preclinical surrogate markers exist which can be predictive of clinical regenerative outcomes. To test these hypotheses, the project proposed has three Specific Aims (SAs). In SA1, we will isolate, expand, and phenotypically characterize populations of alveolar bone marrow derived stem cells from 30 different human subjects. SA2 will evaluate the preclinical bone regenerative potential of aBMSCs in vivo using ectopic and clinically relevant orthotopic model systems. Finally, in SA3, following autologous transplantation of aBMSCs into human craniofacial bone defects, we will determine how the phenotypic characteristics of different aBMSC populations correlate to their respective capacities to regenerate bone in vivo and clinically. Key outcome measures include: phenotypic characterization of aBMSCs;in vivo potential of aBMSCs to regenerate bone and vascular tissue;safety of aBMSC cell isolation and expansion methodologies for human application;clinical potential of aBMSCs to regenerate bone and vascular tissue;and examination of correlations between in vitro phenotype, in vivo bone regeneration, and clinical bone regeneration. Findings of the proposed study could significantly advance clinical cell therapy approaches for craniofacial regeneration. Additionally, the isolation of aBMSCs with the technique employed would have broad scientific impact in providing an alternative source of MSCs to be used in fundamental investigations of stem cell and bone biology.

Public Health Relevance

Cell therapy holds significant potential for the rehabilitation of head and neck deformities. One of the most important aspects of cell therapy is the identification of the best cell source to be used in treatment. Historically, stem cells derived frm bone marrow of the hip have demonstrated the potential to regenerate tissues in many animal studies. However, techniques for obtaining these cells from the hip are complex and invasive. It would be far more desirable to have a better, more readily available source of these cells for clinical therapies. To this end, we have conducted preliminary studies which show that similar types of stem cells can be obtained more easily from bone marrow of the jaw using a routine dental procedure. Our hypothesis is that these stem cells can be safely collected from the jaw, grown outside of the body in a specialized system used to grow cells, and then re-transplanted back into the same individual for treating bone defects of the jaw. To test this hypothesis, the project proposed has three Specific Aims (SAs). In SA1, we will determine if our method for obtaining the cells and growing them is reproducible and predictable. SA2 will involve animal studies to evaluate the ability of these cells to grow bone. Finally, in SA3, the stem cells will b used to treat human bone defects of the jaw and the safety and effectiveness of this treatment will be evaluated. Findings of the proposed study could significantly advance clinical cell therapy approaches for head and neck regeneration. Additionally, these studies would provide much needed insights toward the biology of stem cells and how they behave and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56DE023095-01A1
Application #
8733350
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Lumelsky, Nadya L
Project Start
2013-09-25
Project End
2014-08-31
Budget Start
2013-09-25
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$311,000
Indirect Cost
$111,000
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109