Jones, Hilary Mark; (1994) Regulation of fetal and adult human haemopoiesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis has examined the response of human fetal erythroid progenitors to erythropoietin and other haemopoietic growth factors (HGF's). This work has been performed in order to explain the different haemopoietic response seen during fetal life and to establish a system whereby large numbers of human progenitors cells can be obtained for the study of growth factor actions on primitive haemopoietic cells. Fetal erythroid progenitor cells are more sensitive in vitro to erythropoietin than their adult counterparts. A switch in sensitivity occurs just before term. Highly purified fetal erythroid progenitor cells do not have an absolute requirement for 'early' acting factors, such as granulocyte-macrophage colony stimulating factor (GM-CSF), nor does GM-CSF modulate the erythropoietin dose response curve. Adult cells on the other hand require such factors even in the presence of erythropoietin. If fetal cells are cultured without erythropoietin however, cell death occurs. This can be prevented by a range of HGF's including IL-1.IL-3, IL-9 and GM-CSF. It is presently unclear as to which of these growth factors act directly or indirectly. Using highly purified fetal haemopoietic cells it was shown that these cells respond to erythropoietin within twenty four hours of culture with increased tritiated thymidine uptake and maintainance of high levels of c-myc protein. Erythropoietin did not cause rapid elevation of intracellular calcium ion concentration [Ca2+]i, suggesting that there was no activation of phospholipase C. Fetal haemopoietic cells express the low affinity Fc receptor for IgG (FcγRII). Cross linking of this receptor with a monoclonal antibody causes a rise in [Ca2+]i indicating that these purified cells can respond to calcium mobilizing signals and that FcyRII is a functional signal transduction molecule on these cells. In view of the different growth factor requirements of fetal and adult progenitor cells, the serum concentration of HGFs has been measured in fetal blood obtained at fetoscopy, in neonates and in pregnant and non pregnant adults. Trace amounts of IL- 6 are present in the fetal circulation but this cytokine is not detected in adult samples. GM-CSF, IL-1 or IL-3 are not detectable in fetal samples.

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