Mechanisms underlying cytokine-induced changes in homing and engraftment of human haemopoietic stem and progenitor cells

The reduced engraftment potential of cytokine cultured haemopoietic stem/progenitor cells from adult mobilised peripheral blood has been associated with their defective homing to bone marrow niches. In this work, using established in vivo systems and a novel ex vivo model, an additional cytokine-induced attachment defect is described that reduces the retention of these cells in the bone marrow, post-transplantation. This defect was found to be related to specific niche ligands and was not caused by downregulation of their respective receptors on the expanded cells. CD26 is a protease that cleaves SDF-1 abrogating its chemotactic effect. CD26 inhibition on the transplanted cells was not sufficient to reverse the engraftment defect, although infusion of the inhibitor in immunodeficient animals, together with ex vivo treated cells, significantly increased engraftment. Finally, mobilised peripheral blood stem/progenitor cells were found to express neuroreceptors and their expression was altered after exposure to cytokines. Epinephrine pre-treatment of these cells rescued their adhesion to specific niche ligands, increased their short-term homing and improved their long-term engraftment in immunodeficient animals.