Repair of Bone Defects with Human Autologous Pluripotent Very Small Embryonic lik


Principal Investigator: Russell S Taichman
Abstract: DESCRIPTION (provided by applicant): Bone loss due to fractures and disease is a serious medical condition in the US affecting millions of Americans. It is particularly a problem with oral craniofacial disorders were the costs of treating damage exceeds $60 billion annually. Furthermore, periodontitis is associated with systemic disorders such as diabetes mellitus, preterm low birth weight, and cardiovascular disease. While major efforts have been made to understand mechanisms of healing of large bones and to develop therapeutics to treat overall bone loss, very little information is available on bone remodeling in the human craniofacial skeleton, nor the mechanisms involved in osteonecrosis of the jaw and there are few effective treatments. The results of our phase 1 SBIR showed that a unique population of human, adult, pluripotent, Very Small Embryonic like (VSEL) stem cells, have important bone regenerative properties and could be useful in treating oral-craniofacial disorders. Human VSELs are pluripotent stem cells involved in the normal turnover and regeneration of tissues and their circulating levels greatly increase in response to injury. They are able to repair injured tissues such as the heart after myocardial infarct. Adult human VSELs, are SSEA-4+/Oct-4+/CD133+/CXCR4+/Lin-/CD45-, express pluripotency markers (Oct-4 and Nanog) and are capable of differentiation into cells from all three germ lineages. With our collaborator, Dr. Russell Taichman of the University of Michigan we showed that VSELs differentiate to osteoblastic lineage after intra-marrow transplant. Importantly, VSELs from adult humans repaired a calvarial defect in SCID mice. The human VSELs formed new bone when applied in the injured area as measured by u-CT scan, and histological analysis demonstrated osteogeneis, significant new bone formation, dense thickening of the trabeculae and bone marrow formation. Most importantly, new bone tissue was derived from the human VSELs. These studies show that VSELs can generate new bone and have the potential to repair bone injuries. In this phase 2 SBIR, we propose to further test the effectiveness of human VSELs to regenerate bone in human patients. Specifically, we will test the ability of VSELs to promote bone remodeling in the human craniofacial skeleton. For our studies, we will test the efficacy of human VSELs to generate bone in humans in a tooth extraction model in which individuals requiring tooth extraction due to caries or periodontal disease will be the subjects. In these individuals, the underlying jaw bone tissue is injured and depleted and while there is some healing overtime after tooth extraction, the process is slow. We will test whether VSELs isolated from the patient expedite bone growth in the oral cavity after tooth removal. The VSELs are autologous and will not cause rejection and do not form tumors or cause other health risks. This is not a clinical trial but a focused patient based study intended to move forward the development of VSELs as a therapeutic for bone repair. It successful, these studies will provide the basis for the rapid clinical development of VSELs for craniofacial osseous regeneration and treatment of a number of other skeletal based disorders.
Funding Period: 2012-09-11 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Human and murine very small embryonic-like cells represent multipotent tissue progenitors, in vitro and in vivo
    Aaron M Havens
    1 Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, Michigan
    Stem Cells Dev 23:689-701. 2014

Detail Information


  1. pmc Human and murine very small embryonic-like cells represent multipotent tissue progenitors, in vitro and in vivo
    Aaron M Havens
    1 Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, Michigan
    Stem Cells Dev 23:689-701. 2014
    ..These studies show that VSEL cells produce multiple cellular structures in vivo and in vitro and lay the foundation for future cell-based regenerative therapies for osseous, neural, and connective tissue disorders...

Research Grants30

  1. Targeted Stem Cell Therapy Coupling Angiogenesis and Osteogenesis for Bone Defect
    Selvarangan Ponnazhagan; Fiscal Year: 2013
    ..A positive outcome of these studies could lead to the development of new and effective treatment strategies for bone repair. ..
  2. Stem Cell Based Therapy for Regenerative Endodontics
    George T J Huang; Fiscal Year: 2013
    ..If successful, a subsequent human trial may be carried out in the future and its success will promise a reduced need of traditional aggressive root canal therapies. ..
  3. Differential Effects of BMPs on the Healing of Craniofacial Defects
    Russell R Reid; Fiscal Year: 2013
    ..abstract_text> ..
  4. Role of Angiogenesis in Distraction Osteogenesis
    ..The completion of Aims 1 and 2 will determine if ECs are a primary cell source of BMP2 in regulating skeletal healing after surgery or injury and if BMP2 has a functional role in vasculogenesis. ..
  5. Large Animal Model for Novel Autologous Treatments of Alveolar Clefts
    JOHN ANANDA VAN AALST; Fiscal Year: 2013
    ..The long-term goal is to be able to translate these findings to children using human cells. ..
  6. NIAMS: CORT Innovations to Assess and Forestall Post-Traumatic Osteoarthritis
    Joseph A Buckwalter; Fiscal Year: 2013
    ..The four projects will be supported by an administrative-biostatistics core, a biomechanics-imaging core, and a tissue and experimental modeling core. ..
  7. Therapeutic S1P Drug Targets for Cranial Bone Repair
    Edward A Botchwey; Fiscal Year: 2013
    ..AIM 3 tests the hypothesis that S1P1 and S1P3 modulation of inflammatory and mesenchymal progenitor cell recruitment will enhance bone healing outcomes. ..
  8. Role of osteogenic stem cells in bone regeneration and repair in vivo
    Dongsu Park; Fiscal Year: 2013
    ..3. Test the role of osteogenic stem cells in bone loss diseases. By studying three specific, clinically relevan questions, we will further define new biological and clinical insights of osteogenic stem cells in physiological conditions. ..
  9. Complex Nanocomposites for Bone Regeneration
    Antoni P Tomsia; Fiscal Year: 2013
    ..The present standard of care for such defects may be altered to eliminate bone grafts, decrease risks to patients, improve quality of life, and increase the armamentarium of the clinician. ..
  10. PTHrP/IHH Microenvironment Control for Growth Plate Tissue Engineering
    JUAN MANUEL TABOAS; Fiscal Year: 2013
    ..We will implant these constructs in dorsal subcutaneous pockets of immunodeficient mice and use histological and micro-CT assays to evaluate construct growth and GP-like structure maintenance. ..
  11. Biomimetic Scaffold Delivering Osteogenic Molecules for Alveolar Bone Engineering
    Min Lee; Fiscal Year: 2013
    ..The results from this proposal will be critical towards clinical translation of Nell-1 mediated therapeutics to augment alveolar bone regeneration while minimizing potential adverse effects of current osteoinductive therapeutics. ..
  12. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  13. Translational Optimization of Bone Regeneration in the Irradiated Mandible
    Steven R Buchman; Fiscal Year: 2013
    ..The current proposal entails developing those synergies and innovative solutions in order to translate our findings from the bench to the operative suite to improve the treatment for this severely compromised patient population. ..
  14. Mesenchymal Regulation of Osteogenesis
    Richard A Schneider; Fiscal Year: 2013
    ..The goal of this project is to identify genes and embryonic events that control bone formation. ..
  15. Development of Adult Pluripotent Very Small Embryonic Like (VSEL) Stem Cells to T
    DENIS OVEREND RODGERSON; Fiscal Year: 2013
  16. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  17. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
    Yufang Shi; Fiscal Year: 2013
    ..abstract_text> ..
  19. PTH Effects of Craniofacial Allografts
    Edward M Schwarz; Fiscal Year: 2013
    ..abstract_text> ..
  20. Injectable Anabolic Biomaterials for Bone Regeneration
    LAKSHMI SREEDHARAN NAIR; Fiscal Year: 2013
    ..If successful, the injectable lactoferrin based delivery vehicle could have a significant impact in the clinical translation of cell based therapeutic strategies by addressing some of its current limitations. ..
  21. Osteogenic Repair from Human Pluripotent Stem Cells
    Dan S Kaufman; Fiscal Year: 2013
  22. The Role of BMP2 in the Regenerative Effects of MSC in Fracture Repair
    TIMOTHY JOSEPH MYERS; Fiscal Year: 2013