Regenerating Human Oral Mucosa by Bone Marrow-derived Mesenchymal Stem Cells

Summary

Principal Investigator: RUBIE ANN RAKIAN
Abstract: DESCRIPTION (provided by applicant): Oral mucosal defects are secondary to oncologic resection, traumatic events or congenital craniofacial malformations such as cleft palate. Current repair treatments such as autologous grafts are restricted by donor site morbidity, tissue shortage, and retention of the original characteristics of the donor tissue. AlloDerm, a native acellular dermal matrix, with an intact basement membrane, is currently used as a dermal oral soft tissue graft, however, a second procedure for epithelial grafting is required. Keratinocyte populated acellular dermal substrates in ex vivo produced oral mucosal equivalents have been proposed, however, the low cell number obtained from harvested tissue results in graft failure. The proposed research studies will address the capacity of bone marrow-derived mesenchymal stem cells (MSC) to regenerate the oral mucosa epithelium by mimicking an environment in vitro similar to that seen in the human body. Bone marrow- derived mesenchymal stem cells (MSC) are capable of self-renewal, differentiation into cell phenotypes of mesodermal lineage, and transdifferentiation into other cell lineages including epithelial cells. Their local microenvironment composed of growth factors and extracellular matrix (ECM) is known to play a critical role in controlling the proliferation and differentiation fate of stem cells. Our hypothess is that tissue-specific extracellular matrix provides a native microenvironment that governs the ability of multipotent stem cells seeded on Alloderm to both self-renew and differentiate into functional full-thickness oral mucosa epithelium. The following specific aims will be proposed to test this hypothesis: 1) Determine the capacity of MSCs maintained on tissue-specific microenvironment to differentiate into an epithelial cell lineage and form oral mucosa epithelium in vitro;2) Demonstrate the capacity of predifferentiated MSCs maintained on AlloDerm for oral mucosa epithelium regeneration in vivo using an athymic nude mouse model. These studies will provide training in stem cell maintenance and differentiation, quantitative gene expression, immunochemistry, flow cytometry, FACS sorting, animal modeling, and cell culture. This study is innovative because human bone marrow-derived MSC capability to transdifferentiate into epithelial cells for engineering oral mucosa epithelium has not been explored. The proposed research is significant because it will facilitate the optimization of in vitro oral mucosa equivalnt models for studies of oral mucosa biology and pathology as well as a model alternative to animals for testing of consumer products. These findings will have an impact by initiating human bone marrow-derived MSC research exploration of the field of craniofacial regenerative medicine and lay the foundation to further study the molecular complexity and dynamics of native and tissue-specific ECM in the regulation of MSC proliferation, survival, and differentiation. A better understanding of these mechanisms will move the field closer to bone marrow-derived MSC based therapeutic application by utilizing bone marrow- derived MSCs as an unlimited source of stem cells and treatment of craniofacial defects. Through these studies, I will acquire state-of-the-art knowledge and skills toward my goal to become an established dentist- scientist.
Funding Period: 2013-05-15 - 2017-05-14
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. Muscular Dystrophy Center Core Laboratories
    James M Ervasti; Fiscal Year: 2013
    ..4) To increase institutional, regional and national awareness of UMN-MDCenter and CCMBM to enhance provision of institutional resources commensurate with the potential of this program. ..
  3. Identification and Characterization of Adult Salivary Gland Stem Cells
    Soosan Ghazizadeh; Fiscal Year: 2013
    ..The knowledge gained in this study will be a first step in a long-range plan to restore salivary secretory function using adult progenitor cells. ..
  4. Skin Regeneration with Stem Cells and Scaffolds
    SUSAN RENEE OPALENIK; Fiscal Year: 2013
    ..abstract_text> ..
  5. GENE THERAPY USING HEMATOPOIETIC STEM CELLS
    Donald B Kohn; Fiscal Year: 2013
    ..The Project and Core leaders have complementary expertise in the relevant areas of experimental hematology, gene therapy, immunology, and signal transduction and have a long-standing record of interactive collaborations. ..
  6. Establishment of Marmoset iPS-derived Cranial Neural Crest Cells
    Steven Farnsworth; Fiscal Year: 2013
    ..This research proposal fits the applicant's career goal to become a dentist-scientist studying translational research in regenerative dentistry. ..
  7. Core Center for Musculoskeletal Disorders
    Louis J Soslowsky; Fiscal Year: 2013
    ..abstract_text> ..
  8. Role of Intestinal Cell Kinase in the Intestinal Epithelium
    Zheng Fu; Fiscal Year: 2013
    ....
  9. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
    ..abstract_text> ..
  10. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  11. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  12. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  13. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  14. Stem Cells for Corneal Engineering
    James L Funderburgh; Fiscal Year: 2013
    ..These stem cells can be produced in large numbers, are safe, and do cause tissue rejection. Successful development of these therapies may open new opportunity to restore vision to large numbers of people. ..
  15. Development of Adult Pluripotent Very Small Embryonic Like (VSEL) Stem Cells to T
    DENIS OVEREND RODGERSON; Fiscal Year: 2013
    ....
  16. Olfactory Epithelial Stem Cell Regulation by the Transcription Factor p63
    Nikolai Schnittke; Fiscal Year: 2013
    ..abstract_text> ..
  17. Skin Stem Cells: Purification and Characterization
    Elaine Fuchs; Fiscal Year: 2013
    ..This study is a fundamental prerequisite to ascertaining the potential of skin stem cells for regenerative therapies that go beyond burn treatments. ..
  18. GINGIVA DERIVED MSCS: ROLE IN IMMUNOMODULATION AND TISSUE REGENERATION
    Yufang Shi; Fiscal Year: 2013
    ..abstract_text> ..
  19. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..