Damage and regeneration in the hematopoietic system

Summary

Principal Investigator: Tannishtha Reya
Abstract: During aging, hematopoietic stem cells (HSCs) are able to function normally under homeostatic conditions but are unable to mount effective regenerative responses under conditions of acute damage. Thus, in response to bleeding, infection or chemotherapy, elderly people often fail to replenish their blood effectively,and have an increased risk of hematopoietic disorders such as anemia and neutropenia that can often be fatal. To understand why this hematopoietic dysfunction occurs during aging, it is important to identify the molecular mechanisms that allow young HSCs to respond to acute damage and determine how these mechanisms fail in the aging hematopoietic system. To understand the molecular signals that normally allow the effective regeneration of the blood, we have studied animals treated with the chemotherapeutic drug Cyclophosphamide (Cy) and the growth factor G-CSF which causes an acute loss of proliferating progenitors in the bone marrow followed by expansion of HSCs to regenerate the progenitor pool. Using this as a damage model, we have found that that the Wnt signaling is sharply upregulated in a large fraction of HSCs responding to Cy/G-CSF suggesting that Wnt signaling may be a critical mediator of HSC regeneration after damage. In order to test this hypothesis, we now propose to define the significance of Wnt activation in regenerating HSCs and determine if this activity changes as HSCs age. Identifying the mechanisms that underlie the regenerative response to Cyclophosphamide/ G-CSF treatment will enhance our ability to harvest and expand stem cells for transplantation therapy. Furthermore, understanding the basis of impaired regeneration in the aging hematopoietic system may allow us to design novel means to improve the health and quality of life of aging patients.
Funding Period: 2006-05-15 - 2010-04-30
more information: NIH RePORT

Top Publications

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  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. 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
  8. 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
  • Kendra L Congdon
  • Jordan Blum
  • Mark Fereshteh
  • Takahiro Ito
  • Anand Lagoo
  • Alan Chen
  • Mweia Uqoezwa
  • Carlijn Voermans
  • Leah DiMascio
  • Mingfu Wu
  • Valerie Tornini
  • Jeffrey J Kovacs
  • Minyong Chen
  • Robert J Lefkowitz
  • Takaaki Konuma
  • Gareth Gerrard
  • Bryan Zimdahl
  • Soo Hyun Kim
  • Vivian G Oehler
  • Jerald P Radich
  • William E Lento
  • John Goldman
  • Craig T Jordan
  • Dong Wook Kim
  • Harriet Goh
  • Letizia Foroni
  • Charles Chuah
  • Philip A Beachy
  • Jynho Kim
  • Catriona H Jamieson
  • John P Chute
  • David Rizzieri
  • Michael Munchhof
  • Todd Vanarsdale
  • Annelie Abrahamsson
  • Leah N DiMascio
  • Emily C Ferguson
  • Seung Hye Jung
  • Uma Sankar
  • Andrew Duncan
  • Nicholas Gaiano
  • Danhong Lu
  • Judy Wu
  • Trachette L Jackson
  • Tim Oliver
  • Frederique Rattis
  • Rina Ashkenazi
  • J Michael Cook

Detail Information

Publications8

  1. 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...
  2. 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...
  3. 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...
  4. 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...
  5. 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...
  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. 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...
  8. 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
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