Regulation of Hematopoietic Stem Cell Self-Renewal

Summary

Principal Investigator: Tannishtha Reya
Abstract: Hematopoietic stem cells (HSCs) have the capacity to generate all the cells of the blood. A defining feature of HSCs is their ability to perpetuate themselves through self-renewal. While the phenotypic and functional properties of HSCs have been extensively characterized a fundamental question that remains unanswered is how self-renewal is regulated. Our work has revealed that I_-catenin,a key mediator of Wnt signaling, can promote self-renewal of HSC in vitro. Moreover, Axin, which enhances _-catenin degradation, causes inhibition of growth and reconstitution by HSC. These studies reveal an important role for 13-cateninin the regulation of HSC growth and self-renewal. To further elucidate the role of Wnt and {3-cateninsignaling in HSC, we propose to 1) Determine whether Wnt signaling regulates HSC function in vivo, 2) Examine whether the effects of I_-catenin and Axin on HSC reflect the activity of Wnt proteins and 3) Identify the molecular mechanisms by which I_-catenin exerts its effects on HSC self-renewal. These studies will not only advance our understanding of self-renewal, a key characteristic of all stem cells, but will also help develop strategies for in vitro expansion of stem cells, and thereby contribute to improving transplantation therapies for hematopoietic and degenerative disorders.
Funding Period: ----------------2009 - ---------------2010-
more information: NIH RePORT

Top Publications

  1. ncbi Identification of adiponectin as a novel hemopoietic stem cell growth factor
    Leah DiMascio
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 178:3511-20. 2007
  2. ncbi Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia
    Bryan Zimdahl
    1 Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California, USA 2 Sanford Consortium for Regenerative Medicine, La Jolla, California, USA 3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA 4
    Nat Genet 46:245-52. 2014
  3. pmc β-Arrestin2 mediates the initiation and progression of myeloid leukemia
    Mark Fereshteh
    Department of Pharmacology, University of California, San Diego School of Medicine and Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093
    Proc Natl Acad Sci U S A 109:12532-7. 2012
  4. pmc Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration
    William Lento
    Department of Pharmacology, University of California at San Diego School of Medicine, La Jolla, California 92093, USA
    Genes Dev 28:995-1004. 2014
  5. pmc Divide and conquer: how asymmetric division shapes cell fate in the hematopoietic system
    Kendra L Congdon
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
    Curr Opin Immunol 20:302-7. 2008
  6. pmc Imaging hematopoietic precursor division in real time
    Mingfu Wu
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
    Cell Stem Cell 1:541-54. 2007
  7. ncbi Activation of Wnt signaling in hematopoietic regeneration
    Kendra L Congdon
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
    Stem Cells 26:1202-10. 2008
  8. pmc Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo
    Chen Zhao
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
    Cancer Cell 12:528-41. 2007
  9. pmc Regulation of myeloid leukaemia by the cell-fate determinant Musashi
    Takahiro Ito
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Nature 466:765-8. 2010
  10. pmc Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia
    Chen Zhao
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Nature 458:776-9. 2009

Scientific Experts

  • Tannishtha Reya
  • Chen Zhao
  • Hyog Young Kwon
  • Takahiro Ito
  • Kendra L Congdon
  • Jordan Blum
  • Bryan Zimdahl
  • Mark Fereshteh
  • William Lento
  • Takaaki Konuma
  • Charles Chuah
  • Vivian G Oehler
  • David Rizzieri
  • Anand Lagoo
  • Alan Chen
  • Carlijn Voermans
  • Mweia Uqoezwa
  • Mingfu Wu
  • Leah DiMascio
  • Nelson Chao
  • Jeevisha Bajaj
  • Kouros Owzar
  • Gary Hardiman
  • Omead Arami
  • Roman Sasik
  • Sadhna Piryani
  • Chen Jiang
  • H Elizabeth Broome
  • Joi Weeks
  • Wei Huang
  • Luigi Racioppi
  • Allen Blevins
  • Jeffrey R Harris
  • Claire S Koechlein
  • Robert J Lefkowitz
  • Jeffrey J Kovacs
  • Minyong Chen
  • Valerie Tornini
  • Gareth Gerrard
  • Harriet Goh
  • William E Lento
  • John Goldman
  • Craig T Jordan
  • Dong Wook Kim
  • Soo Hyun Kim
  • Letizia Foroni
  • Jerald P Radich
  • Annelie Abrahamsson
  • Jynho Kim
  • Todd Vanarsdale
  • John P Chute
  • Philip A Beachy
  • Michael Munchhof
  • Catriona H Jamieson
  • Emily C Ferguson
  • Leah N DiMascio
  • Tim Oliver
  • Rina Ashkenazi
  • Nicholas Gaiano
  • Seung Hye Jung
  • Danhong Lu
  • Uma Sankar
  • Judy Wu
  • Frederique Rattis
  • Trachette L Jackson
  • J Michael Cook
  • Andrew Duncan

Detail Information

Publications10

  1. ncbi Identification of adiponectin as a novel hemopoietic stem cell growth factor
    Leah DiMascio
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 178:3511-20. 2007
    ..These studies collectively identify adiponectin as a novel regulator of HSC function and suggest that it acts through a p38 dependent pathway...
  2. ncbi Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia
    Bryan Zimdahl
    1 Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California, USA 2 Sanford Consortium for Regenerative Medicine, La Jolla, California, USA 3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA 4
    Nat Genet 46:245-52. 2014
    ..These data identify a key role for Lis1 in hematopoietic stem cells and mark its directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development. ..
  3. pmc β-Arrestin2 mediates the initiation and progression of myeloid leukemia
    Mark Fereshteh
    Department of Pharmacology, University of California, San Diego School of Medicine and Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093
    Proc Natl Acad Sci U S A 109:12532-7. 2012
    ..These data cumulatively show that β-arrestin2 is essential for CML disease propagation and indicate that β-arrestins and the Wnt/β-catenin pathway lie in a signaling hierarchy in the context of CML cancer stem cell maintenance...
  4. pmc Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration
    William Lento
    Department of Pharmacology, University of California at San Diego School of Medicine, La Jolla, California 92093, USA
    Genes Dev 28:995-1004. 2014
    ....
  5. pmc Divide and conquer: how asymmetric division shapes cell fate in the hematopoietic system
    Kendra L Congdon
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
    Curr Opin Immunol 20:302-7. 2008
    ..These discoveries have opened new doors to understanding how regulation of division pattern contributes to the normal development and function of the immune system as well as how its dysregulation can lead to cancer...
  6. pmc Imaging hematopoietic precursor division in real time
    Mingfu Wu
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
    Cell Stem Cell 1:541-54. 2007
    ..These studies establish a system for tracking division of hematopoietic precursors and show that the balance of symmetric and asymmetric division can be influenced by the microenvironment and subverted by oncogenes...
  7. ncbi Activation of Wnt signaling in hematopoietic regeneration
    Kendra L Congdon
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
    Stem Cells 26:1202-10. 2008
    ..Cumulatively, our data reveal that growth signals in the hematopoietic system are re-activated during injury, and provide novel insight into the influence of the microenvironment during regeneration...
  8. pmc Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo
    Chen Zhao
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
    Cancer Cell 12:528-41. 2007
    ..These studies demonstrate that Wnt signaling is required for the self-renewal of normal and neoplastic stem cells in the hematopoietic system...
  9. pmc Regulation of myeloid leukaemia by the cell-fate determinant Musashi
    Takahiro Ito
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Nature 466:765-8. 2010
    ..These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias...
  10. pmc Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia
    Chen Zhao
    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Nature 458:776-9. 2009
    ....