Maintenance and Commitment of Hematopoietic Progenitors: Role of flt3, c-kit and c-mpl

Sammanfattning: The need for red blood cells to transport oxygen and CO2, blood platelets to stop bleedings, and neutrophils, macrophages, B- and T-cells for host defense, is a prerequisite for life. These mature blood cells have a limited life span and are thus constantly replenished by an enormous cell production (estimated to 1012 cells per day) which primarily takes place in the bone marrow (BM). Mature blood cells are produced by lineage-restricted progenitors, which themselves are generated from a small population of pluripotent hematopoietic stem cells (HSC) in a process called hematopoiesis. HSC and lineage-restricted progenitors in the BM have been the focus of this thesis. Hematopoiesis is regulated by soluble and membrane bound regulators called cytokines. We have demonstrated that a cytokine called Thrombopoietin (Tpo) promoted viability, when acting alone, and proliferation, if combined with other cytokines, of multipotent progenitors. Furthermore, we have investigated the cytokines FL, IL-7, IL-10 and KL for their role in promoting B-lymphoid differentiation. FL and IL-7 are essential to efficiently produce proB-cells in vitro from uncommitted progenitors. However, we demonstrated that both IL-10 and KL are recruiting FL+IL-7-non-responsive progenitors, thereby increasing the number of progenitors producing proB-cells. Additionally, we showed that KL enhanced proliferation of proB-cells, whereas IL-10 inhibited the same. Murine progenitors were subfractionated based upon expression of the FL-receptor (flt3) and their lineage potentials were characterized. Results suggest that the flt3(-)-population is enriched for HSC, whereas the flt3(+)-population contained a high fraction of macrophage-, B- and T-lymphoid-restricted progenitors. This last finding is in agreement with reports of a similar lineage-restricted progenitor during murine fetal development, but is in contrast to the current picture of hematopoietic development.