Homing and engraftment of CD34+ cells in the NOD/SCID model
The reduced engraftment potential of haemopoietic stem/progenitor cells after exposure to cytokines may be related to the impaired homing ability of actively cycling cells. I tested this hypothesis by quantifying the short-term homing of human adult CD34+ cells in NOD/SCID animals. I have demonstrated in adult CD34+ cells that cytokine exposure ex-vivo leads to a loss of engraftment ability in vivo which occurs rapidly and which is associated with a striking alteration in the tissue distribution of homed cells. Loss of homing to the BM and to a lesser extent, the spleen, coincides with increased accumulation of cells in the lungs. The loss of BM homing and engraftment is not related to cell cycle phase, and was not restored by blocking Fas ligation in vivo. The co-transplantation of adult MPB CD34+ cells with non-haemopoietic stem cells (e.g. MSCs and MAPCs) and heterologous T cells (e.g. CD4+ and CD8+) was also unable to improve the homing to the BM in the NOD/SCID mice. The work from this thesis suggest that these changes in homing, and as a consequence engraftment, induced by cytokine exposure are due to increased migratory capacity of infused activated cells, leading to loss of selectivity of the homing process.