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Role of membrane-type 1 matrix metalloproteinase in hematopoietic stem/progenitor cell trafficking

  • Author / Creator
    Shirvaikar, Neeta Chandan
  • Hematopoietic stem/progenitor cells (HSPC) are routinely used for transplantation to restore hematopoietic function; however, the molecular mechanisms governing their trafficking are not completely understood. Soluble matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to mediate HSPC mobilization from the bone marrow (BM) to peripheral blood (PB) and their homing back from PB to the BM niches. However, the role of membrane type (MT)-1 MMP (localized on the leading edge of migrating cells and activates proMMP-2), in these processes is unknown. In this thesis I test the hypothesis that MT1-MMP is involved in HSPC trafficking. In the first part, I investigated the role of MT1-MMP in granulocyte-colony stimulating factor (G-CSF)-induced mobilization and found that G-CSF incorporates MT1-MMP into membrane lipid rafts of hematopoietic cells in a phosphatidylinositol 3-kinase (PI3K)-dependent manner and enhances chemoinvasion of HSPC. Moreover, MT1-MMP expressed by HSPC activates proMMP-2 secreted by fibroblasts under conditions simulating the BM microenvironment. Thus, MT1-MMP contributes to a highly proteolytic BM microenvironment that facilitates egress of HSPC into the circulation. In the second part, I investigated the role of MT1-MMP in the homing-related responses of cord blood (CB) HSPC. Previously, we demonstrated that supernatants (isolated from leukapheresis products of G-CSF-mobilized patients) or their components [complement C3a, fibrinogen, fibronectin, hyaluronic acid (HA) and thrombin] had a priming effect on HSPC homing by enhancing their chemotaxis to stromal cell-derived factor-1 (SDF-1) and stimulating their secretion of proMMP-2 and proMMP-9. Here, I focused on the effect of HA and thrombin on the modulation of MT1-MMP expression in CB HSPC. HA and thrombin, in a PI3K- and Rac-1 GTPase-dependent manner, increase MT1-MMP expression in CB HSPC which activates proMMP-2 secreted by endothelial cells. Moreover, crosstalk between PI3K and Rac-1 signaling pathways leads to signal amplification and enhanced chemoinvasion of CB HSPC towards a low SDF-1 gradient in a MT1-MMP-dependent manner. Thus, MT1-MMP contributes to the priming of homing-related responses of HSPC. In conclusion, findings from this thesis suggest that modulation of MT1-MMP expression has potential as a target for development of new therapies for faster mobilization, homing and engraftment of HSPC, leading to improved transplantation outcomes.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Medicine
  • Supervisor / co-supervisor and their department(s)
    • Janowska-Wieczorek, Anna (Medicine)
  • Examining committee members and their departments
    • Duszyk, Marek (Physiology)
    • Hogge, Donna (Medicine, University of British Columbia)
    • Turner, Joan (Oncology)
    • Shaw, Andrew (Oncology)