Expression of growth factor receptors by haematopoietic stem and progenitor cells

Mooney, Ciarán James (2017). Expression of growth factor receptors by haematopoietic stem and progenitor cells. University of Birmingham. Ph.D.

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Abstract

The mechanisms that govern the lineage commitment of haematopoietic stem and progenitor cells (HSPCs) have been a topic of debate since the 1960s. Two models of lineage commitment have been described; a permissive model, in which haematopoietic growth factors (HGFs) stimulate proliferation and survival of distinct HSPC subpopulations to permit stochastic lineage-specification, and a deterministic model, which proposes that HGFs instruct HSPCs to differentiate towards a specific cell lineage. To provide further insight into whether HGFs provide instructive cues or act in a selective manner, this study has investigated the expression of fms-like tyrosine kinase 3 (Flt3), and the receptors for erythropoietin (EpoR) and macrophage-colony stimulating factor (M-CSFR) by single HSPCs within the bone marrow. Using single-cell qRT-PCR and flow cytometry, a large number of novel HSPC subpopulations have been identified based on receptor expression. Importantly, multiplex analysis of protein and mRNA expression revealed that the above receptors are rarely co-expressed during the early stages of haematopoiesis. Furthermore, Flt3 expression was identified within the haematopoietic stem cell compartment and in vitro analysis demonstrated that Flt3 ligand primarily acts on a subpopulation of downstream progenitors. These findings suggest that Flt3, EpoR and M-CSFR differentially regulate distinct early HSPC subpopulations.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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