Current clinical practice in hematopoietic stem cell transplantation has been to shift from bone marrow to """"""""mobilized peripheral blood"""""""" (MPB) as a source of stem cells. Mobilization can be accomplished inefficiently by infection, endotoxin, and treatment with cytoreductive agents, and efficiently with a combination of cytoreductive agents, plus hematopoietic cytokines. Mobilization is conserved in all species tested from mouse to man. Although the word mobilization implies a net transfer of stem cells from bone marrow to blood, no direct experiment has been carried out to prove the mobilization phenomenon. In preliminary studies we have demonstrated that the efficient mobilization regimen of cytoxan plus G-CSF results first in massive expansion of stem cell numbers in the bone marrow (mostly in the mitotic cell cycle), mid- term appearance of Go-G1 stem cells in the blood, and late appearance of massively expanding stem cells in the spleen. There are two hypotheses to explain the """"""""mobilization"""""""" phenomenon: 1) Stem cells expand in response to the inductive signals, emigrate from bone marrow to blood, and from blood to spleen. 2) Stem cells in bone marrow, blood and spleen expand independently in response to the inductive stimuli, the kinetics and frequency dependent on their endogenous stem cell content, and the presence or absence of factors that control cell cycle status. The experiments described in this application are designed first to distinguish between these hypotheses and second to identify cell surface adhesion receptors that may play a role in de-adhesion events, blood homing events, and interactions among stem cells and microenvironments in bone marrow and spleen that promote their expansion. Because the phenomenon of mobilization is conserved in vertebrate species at least, understanding the biology of mobilization should permit us to understand some fundamental new principals in the homeostasis of hematopoietic cells. Because MPB stem cells are currently used for autologous and allogeneic transplants in man, the results of these experiments could impact on clinical protocols.
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