THE PHENOMENON OF BLOOD STEM-CELL MOBILIZATION

The use of mobilised blood to effect haematological rescue now exceeds that of bone marrow. Despite the now broad application of blood stem cells (BSC) in a variety of clinical settings little is known of the p recise mechanisms responsible for their release into the peripheral ci rculation. Under steady state conditions, primitive haemopoietic proge nitor cells (HPC) are restricted to the bone marrow and circulate at l ow to undetectable levels. Although the basis for this specific retent ion of HPC within the BM remains to be defined, adhesive interactions between HPC and their surrounding stromal cell and ECM environment are hypothesised to play a major role. Mobilisation occurs in response to a variety of perturbations including physical exercise, following mye losupressive chemotherapy and following administration of a number of different cytokines. The kinetics of release may vary from as little a s a few minutes to several weeks. Such observations suggest that a sin gle unifying mechanism is therefore unlikely to be responsible for mob ilisation in all cases and in all likelihood the predominant mechanism (s) will vary according to the mobilising agent employed. Nevertheless , mobilising agents are proposed to act to a greater or lesser extent by perturbing the function of the various cell adhesion molecules (CAM ) or ligands which restrict KPC to the BM, In accord with this notion, studies by other have shown that antibody induced perturbation of VLA -4 function results in mobilisation of HPC in primates. How therefore do cytokines, the most commonly mobilising agents, result in HPC relea se? The most frequently employed agent to induce HPC release is granul ocyte colony-stimulating factor (G-CSF). We have previously demonstrat ed that in vitro exposure of human CD34+ cells (HPC) to G-CSF, in comm on with several cytokines including IL-3, GM-CSF and SCF, results in t ransient increases in the affinity of the beta(1) integrins VLA-4 and VLA-5 for their ligands fibronectin (FN) and VCAM-1. Thus in addition to the well documented mitogenic effects of cytokines these molecules also regulate the adhesive properties of HPC. Data will therefore be p resented which examine the regulation of integrin function on human HP C and its relevance to the phenomenon of mobilisation, In addition we will also review recent observations in man and in a murine model whic h suggest an unanticipated link between bone turnover and BSC release. Collectively these studies provide some novel insights into the pheno menon of mobilisation but also suggest that the actual mechanisms invo lved are more complex than is currently appreciated.