Mechanisms of dental pulp stem cell differentiation into functional endothelium

Summary

Principal Investigator: JACQUES EDUARDO NOR
Abstract: DESCRIPTION (provided by applicant): The Problem: The dental pulp contains pluripotent stem cells that play a critical role in tooth development and tissue regeneration. We have recently demonstrated that human dental pulp stem cels diferentiate into vascular endothelial cells that organize themselves into functional blood vessels in vivo. This exciting observation suggest that dental pulp stem cells can give rise to blood vessels that support the high metabolic demands of "tissue-making", in addition to differentiate into the actual cells that generate the new tissue (e.g. odontoblasts, osteoblasts). However, the mechanisms that control the vasculogenic fate of dental pulp stem cells are not understood. Such knowledge is required to maximize the use of the diferentiation potential of dental pulp stem cells in clinical applications. Hypothesis: In preliminary studies, we demonstrated that vascular endothelial growth factor (VEGF) enhances the vasculogenic potential of dental pulp stem cells. However, the signaling events required for VEGF-induced differentiation of dental pulp stem cells into endothelial cells are unknown. It is known that the Wingless (Wnt) signaling pathway plays a critical role in the determination of cell fate during development. Notably, Wnt inhibits the differentiation of dental pulp stem cells into odontoblasts. But the role of Wnt signaling in directing dental pulp stem cells towards a vasculogenic fate is not understood. Interestingly, a tight correlation between vasculogenesis and bone formation is observed during development. However, the impact of stem cel- mediated vasculogenesis on dentin formation is not known. Here, we will use the tooth as an experimental model for the evaluation of mechanisms that regulate the commitment of stem cells towards the vasculogenic phenotype and determine the role of stem cell-derived blood vessels in mineralized tissue formation. The mechanistic hypothesis of this proposal is: "VEGF and Wnt signaling regulate the vasculogenic fate of dental pulp stem cells". To test this hypothesis, we propose the following specific aims: -Specific Aim #1: To study mechanisms involved in VEGF-induced differentiation of dental pulp stem cells into endothelial cells. -Specific Aim #2: To evaluate the function of Wnt signaling on the determination of dental pulp stem cell fate. -Specific Aim #3: To understand the functional relation between vascular differentiation of dental pulp stem cells and dentinogenesis. Significance: The clinical translation of stem cell-based therapies requires the understanding of mechanisms that control the differentiation fate of these cels. This project aims at the development of mechanism-based approaches that exploit the vasculogenic potential of stem cells to provide the blood vessels required for the generation of new tissues and organs. Our ultimate goal is to employ a deeper understanding of the biology of mesenchymal stem cells of dental origin to benefit patients that require tissue regeneration.
Funding Period: 2011-07-01 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Comparative analysis of two colorimetric assays in dental pulp cell density
    F Nedel
    School of Dentistry Center of Biotechnology, Federal University of Pelotas, Pelotas, RS, Brazil
    Int Endod J 44:59-64. 2011
  2. ncbi Transcriptional factor ATF6 is involved in odontoblastic differentiation
    J W Kim
    Department of Conservative Dentistry, School of Dentistry, Dental Science Research Institute, Chonnam National University, Gwangju, Korea
    J Dent Res 93:483-9. 2014
  3. pmc Dental pulp tissue engineering in full-length human root canals
    V Rosa
    Oral Sciences, Faculty of Dentistry, National University of Singapore, Singapore
    J Dent Res 92:970-5. 2013
  4. pmc Combined effects of simvastatin and enamel matrix derivative on odontoblastic differentiation of human dental pulp cells
    Lorena Karanxha
    Department of Conservative Dentistry, Wonkwang University School of Dentistry, Iksan, Korea
    J Endod 39:76-82. 2013
  5. pmc Tumor angiogenesis and lymphangiogenesis: tumor/endothelial crosstalk and cellular/microenvironmental signaling mechanisms
    Fausto Gueths Gomes
    Nucleus of Cellular and Tecidual Biology NCTBio, Department of Oral Pathology, School of Dentistry, Federal University of Pelotas, Brazil
    Life Sci 92:101-7. 2013
  6. pmc Endothelial differentiation of SHED requires MEK1/ERK signaling
    L W Bento
    Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109 1078, USA
    J Dent Res 92:51-7. 2013
  7. ncbi Telomeres and tissue engineering: the potential roles of TERT in VEGF-mediated angiogenesis
    Fernando P Hartwig
    Biotechnology Unit, Technology Development Center, Federal University of Pelotas, Rio Grande do Sul, Brazil
    Stem Cell Rev 8:1275-81. 2012
  8. pmc A hydrogel scaffold that maintains viability and supports differentiation of dental pulp stem cells
    Bruno N Cavalcanti
    Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109 1078, USA
    Dent Mater 29:97-102. 2013
  9. ncbi Nano-/microfiber scaffold for tissue engineering: physical and biological properties
    Bianca Palma Santana
    Department of Operative Dentistry School of Dentistry, Federal University of Pelotas, Pelotas, RS, Brazil
    J Biomed Mater Res A 100:3051-8. 2012
  10. pmc In vitro differentiation and mineralization of dental pulp stem cells on enamel-like fluorapatite surfaces
    Xiaodong Wang
    Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, Shaanxi, P R China
    Tissue Eng Part C Methods 18:821-30. 2012

Research Grants

Detail Information

Publications16

  1. pmc Comparative analysis of two colorimetric assays in dental pulp cell density
    F Nedel
    School of Dentistry Center of Biotechnology, Federal University of Pelotas, Pelotas, RS, Brazil
    Int Endod J 44:59-64. 2011
    ..To compare and contrast two colorimetric assays used for the measurement of proliferation using two dental pulp cell types: dental pulp stem cells (DPSC) and human dental pulp fibroblasts (HDPF)...
  2. ncbi Transcriptional factor ATF6 is involved in odontoblastic differentiation
    J W Kim
    Department of Conservative Dentistry, School of Dentistry, Dental Science Research Institute, Chonnam National University, Gwangju, Korea
    J Dent Res 93:483-9. 2014
    ..Inhibition of ATF6 decreased ALP activity and mineralization. These results suggest that ER membrane-bound transcriptional factor ATF6 may be involved in odontoblastic differentiation. ..
  3. pmc Dental pulp tissue engineering in full-length human root canals
    V Rosa
    Oral Sciences, Faculty of Dentistry, National University of Singapore, Singapore
    J Dent Res 92:970-5. 2013
    ....
  4. pmc Combined effects of simvastatin and enamel matrix derivative on odontoblastic differentiation of human dental pulp cells
    Lorena Karanxha
    Department of Conservative Dentistry, Wonkwang University School of Dentistry, Iksan, Korea
    J Endod 39:76-82. 2013
    ..This study further explored the role of extracellular signal-regulated kinase (ERK) as a target and mediator of the differentiation induced by simvastatin in hDPCs...
  5. pmc Tumor angiogenesis and lymphangiogenesis: tumor/endothelial crosstalk and cellular/microenvironmental signaling mechanisms
    Fausto Gueths Gomes
    Nucleus of Cellular and Tecidual Biology NCTBio, Department of Oral Pathology, School of Dentistry, Federal University of Pelotas, Brazil
    Life Sci 92:101-7. 2013
    ..Such multifactor studies are critical for the development of future therapeutic approaches for cancer because they take into account the complexities of cellular interactions within the tumor microenvironment...
  6. pmc Endothelial differentiation of SHED requires MEK1/ERK signaling
    L W Bento
    Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109 1078, USA
    J Dent Res 92:51-7. 2013
    ..Collectively, analysis of these data unveiled the VEGF/MEK1/ERK signaling pathway as a key regulator of the endothelial differentiation of dental pulp stem cells...
  7. ncbi Telomeres and tissue engineering: the potential roles of TERT in VEGF-mediated angiogenesis
    Fernando P Hartwig
    Biotechnology Unit, Technology Development Center, Federal University of Pelotas, Rio Grande do Sul, Brazil
    Stem Cell Rev 8:1275-81. 2012
    ....
  8. pmc A hydrogel scaffold that maintains viability and supports differentiation of dental pulp stem cells
    Bruno N Cavalcanti
    Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109 1078, USA
    Dent Mater 29:97-102. 2013
    ..Here, we assessed the compatibility of Puramatrix™ with dental pulp stem cell (DPSC) growth and differentiation...
  9. ncbi Nano-/microfiber scaffold for tissue engineering: physical and biological properties
    Bianca Palma Santana
    Department of Operative Dentistry School of Dentistry, Federal University of Pelotas, Pelotas, RS, Brazil
    J Biomed Mater Res A 100:3051-8. 2012
    ..Therefore, this is a feasible method to produce a scaffold with improved physical characteristics, while at the same time generating an enhanced environment for cell adhesion and proliferation...
  10. pmc In vitro differentiation and mineralization of dental pulp stem cells on enamel-like fluorapatite surfaces
    Xiaodong Wang
    Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, Shaanxi, P R China
    Tissue Eng Part C Methods 18:821-30. 2012
    ..This resulted in the differentiation of human DPSCs and mineralized tissue formation, and, thus, demonstrated that it may be a promising biomimetic model for dentin-pulp tissue engineering...
  11. pmc The stimulation of adipose-derived stem cell differentiation and mineralization by ordered rod-like fluorapatite coatings
    Jun Liu
    Department of Cariology, Restorative Sciences and Endodontics, Dental School, University of Michigan, Ann Arbor, MI 48109, USA
    Biomaterials 33:5036-46. 2012
    ..Both the intrinsic properties of the FA crystals and the topography of the FA coating appeared to dominate the cell differentiation and mineralization process...
  12. pmc Tissue engineering: from research to dental clinics
    Vinicius Rosa
    Post Graduate Program in Dentistry, Dental School, University of Passo Fundo, Passo Fundo, RS, Brazil
    Dent Mater 28:341-8. 2012
    ..The objective of this paper is to present the principles underlying tissue engineering and the current scenario, the challenges and the perspectives of this area in Dentistry...
  13. pmc Regenerative endodontics in light of the stem cell paradigm
    Vinicius Rosa
    Department of Cariology, Restorative Sciences and Endodontics, University of Michigan, USA
    Int Dent J 61:23-8. 2011
    ..Collectively, these findings suggest new treatment paradigms in the field of endodontics. The goal of this review is to discuss the potential impact of dental pulp stem cells to regenerative endodontics...
  14. ncbi Tooth slice/scaffold model of dental pulp tissue engineering
    V T Sakai
    Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, 48109 1078, USA
    Adv Dent Res 23:325-32. 2011
    ..In addition, we discuss the multipotency of dental pulp stem cells, focusing on the differentiation of these cells into functional odontoblasts and into vascular endothelial cells...
  15. pmc Dental pulp tissue engineering
    Flavio Fernando Demarco
    Graduate Program in Dentistry, Federal University of Pelotas, RS, Brazil
    Braz Dent J 22:3-13. 2011
    ....
  16. pmc Functionalized scaffolds to control dental pulp stem cell fate
    Evandro Piva
    Department of Operative Dentistry, School of Dentistry, Federal University of Pelotas, Pelotas, RS, Brazil Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan
    J Endod 40:S33-40. 2014
    ..The long-term goal of this work is to develop stem cell-based therapies that enable the engineering of functional dental pulps capable of generating new tubular dentin in humans. ..

Research Grants30

  1. 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. ..
  2. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  3. The Role of ARNT in Endothelial Cells
    Diana L Ramirez-Bergeron; Fiscal Year: 2013
    ..The studies proposed herein intend to expand our understanding of the mechanisms by which hypoxia regulates vessel generation and homeostasis in both normal and pathological settings. ..
  4. Non-Thermal Plasma in Biomedicine: A New Paradigm for Redox Cell Activation
    Gregory Fridman; Fiscal Year: 2013
    ..Results generated from the proposed studies will provide improved methods for tissue repair and regeneration with direct applicability to both clinical research and surgical procedures. ..
  5. Vasculogenesis and hyperoxia in the developing retina.
    GERARD ANTHONY LUTTY; Fiscal Year: 2013
    ....
  6. Multilineage regulation of mesenchymal stem cell differentiation by microRNAs
    Glyn Palmer; Fiscal Year: 2013
    ..This should improve our current understanding of mesenchymal stem cell differentiation and aid future cell-based therapies for musculoskeletal repair. ..
  7. Induction of Vascular Morphogenesis
    Luisa Iruela-Arispe; Fiscal Year: 2013
    ....
  8. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  9. 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. ..
  10. Molecular Regulation of Human Dental Stem Cell Properties
    Cun Yu Wang; Fiscal Year: 2013
    ..Moreover, because demethylases, being enzymes, can be readily targeted by small molecule inhibitors, our work may help to develop novel strategies for improving dental and craniofacial tissue regeneration and repair. ..
  11. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  12. Function and Integration of Stem Cell-derived Cardiac Tissue Patch
    Nenad Bursac; Fiscal Year: 2013
    ..The knowledge obtained in this project will allow us to pursue in the future engineering of a functional cardiac tissue patch made of human stem cells for potential clinical applications. ..
  13. A Novel Approach for Biomaterials Assisted Regeneration of Pulp-Dentin Complex
    Satish Alapati; Fiscal Year: 2013
    ....
  14. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..