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Title: Investigation of the dynamics of 'haematological synapse' formation
Author: Bullock, Tabitha Emily
ISNI:       0000 0004 2743 4079
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2007
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The transmembrane sialomucin, CD34, is a marker of primitive haemopoietic stem and progenitor cells. Studies have implicated a role for CD34 in both heterotypic and homotypic cell adhesion and signalling pathways, including cell cycle regulation and control of haemopoietic progenitor cell self-renewal, potentially by influencing the balance between asymmetrical and symmetrical cell division. Asymmetrical cell division depends on cell polarisation, which may be conferred by location and/or interaction with neighbouring cells. The haematological synapse is proposed to be an adhesive structure formed between homotypically aggregated CD34-positive cells, which is analogous to the immunological synapse formed between a T cell and antigen-presenting cell. We aimed to investigate the mechanisms by which this specialised junction is formed and how it may be involved in the control of haemopoietic stem/progenitor cell division kinetics. KG1 and primary AC133-positive cells were found to be polarised prior to aggregation. As during immunological formation, additional adhesion molecules are recruited to the contact point between homotypically aggregated cells and are involved at different stages of adhesion, while others are actively excluded. The aggregation was found to be dependent on divalent cations and can be influenced by cytokines. Surface molecules became redistributed by mechanisms that included transport by lipid rafts and the interacting cells were able to communicate via gap junctions, the disruption of which abolished the effect of aggregation on self-renewal. Interaction between AC133-positive cells influenced the plane of cell division in a way that suggests unequal sharing of polarised surface markers including Notch-1 between daughter cell progeny. Therefore, interaction between haemopoietic stem and progenitor cells results in the formation of a 'haematological synapse', comparable to the immunological synapse, which functions in the contact-mediated inhibition of haemopoietic progenitor cell self-renewal through modulation of the cell cycle and the plane of cell division.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available