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Title: The origin and regulation of haematopoietic stem cells during mammalian embryogenesis
Author: Marshall, Caroline Jean
ISNI:       0000 0001 3619 5805
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2004
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Mammalian haematopoiesis is sustained by multipotent haematopoietic stem cells (HSCs) that have the capacity to self-renew and to effect long-term haematopoietic repopulation. These HSCs first appear during embryogenesis as intravascular clusters of cells associated with the floor of the dorsal aorta within a region of embryonic mesoderm termed the aorta-gonad-mesonephros (AGM) region. Their appearance within the AGM region is tightly regulated and precedes the onset of foetal liver haematopoiesis. Lineage tracing analysis in lower vertebrates and in vitro studies using murine embryonic stem cell lines suggest that HSCs are derived from haemangioblast cells that can also differentiate into cells of the endothelial lineage. However, the extracellular factors and downstream processes that regulate HSC emergence and development during mammalian embryogenesis are largely unknown. This thesis examines the cellular origin of AGM-derived HSCs in human and murine embryos, the mode of HSC emergence in vivo and the role of the growth factor bone morphogenetic protein 4 (BMP4) in embryonic haematopoietic development. Gene expression and ultrastructural analysis within the AGM suggested a close relationship between the two lineages, hi the human embryonic AGM, BMP4 and the extracellular matrix (ECM) molecule tenascin C were expressed in a distinctive pattern within a stroma-like region underlying the aortic floor and coincident with the appearance of HSCs. BMP4 increased the haematopoietic potential of cultured murine embryonic cells isolated from AGM tissue and appeared to extend the multipotency of AGM-derived cells in subsequent colony forming unit (CFU)-assay. These results implicate BMP4 in haematopoietic specification and/or maintenance within the earliest stages of adult HSC development in mammals.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available