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    Identification of the homing molecules that escort pluripotent stem cells-derived hematopoietic stem cells to their niches and human activated T-cells to inflammatory sites.

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    Name:
    Amal Ali Dissertation.pdf
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    132.6Mb
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    PDF
    Description:
    Amal Ali Dissertation
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    Type
    Dissertation
    Authors
    Ali, Amal J. cc
    Advisors
    Merzaban, Jasmeen cc
    Committee members
    Di Fabrizio, Enzo M. cc
    Li, Mo cc
    Ley, Klaus
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Science and Engineering (BESE) Division
    Date
    2017-12
    Embargo End Date
    2018-12-05
    Permanent link to this record
    http://hdl.handle.net/10754/626311
    
    Metadata
    Show full item record
    Access Restrictions
    At the time of archiving, the student author of this dissertation opted to temporarily restrict access to it. The full text of this dissertation became available to the public after the expiration of the embargo on 2018-12-05.
    Abstract
    Hematopoietic cells exploit the multistep paradigm of cell migration to ultimately enable them to perform their function. This process is dictated by the ability of adhesion molecules on the circulating hematopoietic cells to find their counter-receptors on endothelial cells. Of those molecules, the selectin family and their respective ligands induce the initial transient interactions between circulating cells and the opposing endothelium. In this thesis, I focused on studying E-selectin mediated cellular migration in two hematopoietic cell types, namely human hematopoietic stem and progenitor cells (HSPCs) and human T-lymphocytes. HSPCs derived from pluripotent sources theoretically offers a novel, unlimited source for hematopoietic stem cell transplantation therapy. In vitro pluripotent stem cell derived- hematopoietic stem/progenitor cells (ES/iPS-HSPCs) behave much like somatic HSPCs in that they exhibit clonal expansion and multilineage hematopoietic capacity. However, unlike somatic sources, ES/iPS-HSPCs do not give rise to effective hematopoietic repopulation, which may be due to insufficient HSPCs homing to the bone marrow. HSPCs exploit E- and P-selectin to home and engraft into bone marrow niches. Thus, one of my objectives in this thesis was to study the expression of E-selectin ligands associated with ES/iPS-HSPCs. I showed that ES/iPS-HSPCs lack functional E-selectin ligand(s). In an effort to enhance the interaction between Eselectin and ES/iPS-HSPCs, we decorated the cell surface with sialyl-Lewis x (sLex) using the ex-vivo glycan engineering technology. However, this decoration did not improve the engraftment capacity of ES/iPS-HSPCs, in vivo. Induction of E-selectin expression during inflammation is key to recruitment of immune cells and therefore I also focused on analyzing the expression of E-selectin ligands on activated human T-cells. I identified several novel glycoproteins that may function as E-selectin ligands. Specifically, I compared the role of the known E-selectin ligands, namely PSGL-1 and CD43, to CD44. I showed that CD44 purified from in vitro human activated T-cells or from psoriasis patients acts as a functional E-selectin ligand. Furthermore, our knock-down studies demonstrated that CD44, and not CD43, cooperates with P-selectin glycoprotein ligand-1 (PSGL-1) as a major E-selectin ligand.
    Citation
    Ali, A. J. (2017). Identification of the homing molecules that escort pluripotent stem cells-derived hematopoietic stem cells to their niches and human activated T-cells to inflammatory sites. KAUST Research Repository. https://doi.org/10.25781/KAUST-26098
    DOI
    10.25781/KAUST-26098
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-26098
    Scopus Count
    Collections
    Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; PhD Dissertations

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