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Endogenous cytokines and adhesive molecules involved in hematopoietic stem cell mobilization Volume 9, issue 3, Mai 2003

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Unité de thérapie cellulaire et Inserm U 553, hôpital Saint‐Louis, 1, avenue Claude‐Vellefaux, 75475 Paris cedex 10, France.

The molecular mechanisms that govern the trafficking of hematopoietic cells from the bone marrow into the blood are poorly understood. However mobilizing treatments are routinely used to collect hematopoietic cells for transplantation. Among the variety of hematopoietic growth factors inducing hematopoietic cell mobilization in animals and humans, G‐CSF is by far the most commonly used agent in patients and normal donors. More and more experimental arguments are in favor of a main role of endogenous cytokine production induced by the mobilizing treatments. These cytokines have a central role, interacting with adhesive molecules, particularly integrins, and inducing the production of a variety of proteases which have a major role for the migration of hematopoietic stem cells (HSC) from the bone marrow into the blood. HSC adhesion to the bone marrow stroma and to the sinusoidal endothe‐lium is mediated by adhesion molecules, mainly integrins VLA‐4, VLA‐5 (β 1) and LFA‐1 (β 2) and their ligands VCAM‐1 and ICAM‐1\2, but also selectins‐E, P, L and their ligands. Stem cell factor (SCF), binding to its receptor c‐kit on HSC membrane modulates integrin functions. SCF and stromal cell‐derived factor‐1 (SDF‐1) induce the production of matrix metalloproteinases, MMP‐2 and MMP‐9 by HSC and stromal cells. These cytokines are also chemotactic for HSC which are particularly able to migrate in the direction of the higher SDF‐1 concentrations. IL‐8 could play a major role by inducing, inside the bone marrow, polymorphonuclear degranulation and release of serine proteases, particularly neutrophil elastase which is able to cleave VCAM‐1. Angiogenic factors, particularly VEGF, are able to mobilize HSC and could participate to the recruitment of HSC together with endothelial progenitors, in situations of tissue repair or tumoral angiogenesis.