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Hématologie

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Modulation of haematopoietic stem cell homing by cell cycle-associated mechanisms Volume 8, issue 6, Novembre - Décembre 2002

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In steady state, the majority of haematopoietic stem cells (HSC) reside in the G0 phase of the cell cycle. Cell cycle progression may be induced in vitro by stimulatory cytokines in order to multiply HSC or as a preparative step in retroviral gene transfer procedures. As compared to quiescent HSC, activated HSC have a reduced capacity to support haematopoietic regeneration after transplantation into conditioned hosts. This is not caused by irreversible differenciation but is rather modulated by cell cycle progression. Indeed, transplantability of activated HSC returns to normal levels after cell cycle completion or withdrawal of mitogenic stimuli. We present experimental evidence suggesting that mitotic activation of HSC and progenitor cells induces defective homing into host bone marrow. First, adhesion of progenitor cells to the bone marrow stroma increases during cell cycle progression. Specifically, fibronectin (Fn) binding of ex vivo activated progenitors is stimulated in S/G2+M phases. This stimulation is reversible after termination of the cycle. Cell-Fn interactions are mediated by two main receptors, VLA (very late antigen) -4 and VLA-5 integrins. Mitogenic stimuli induce a functional inactivation of VLA-4 and increase the affinity of VLA-5 for Fn. Stimulated Fn binding is associated with a reduction in progenitor cell motility. Contrarily to Fn, adhesion to VCAM (vascular cell adhesion molecule) -1, another important ligand within the bone marrow stroma, is reversibly reduced during cell cycle progression. Finally, it is observed that activated progenitor cells lose their ability to respond to inhibitory signals triggered by engagement of adhesion receptors VLA-4 and PSGL (P-selectin glycoprotein ligand) -1. Further studies will be necessary to assess the role of such modifications in the ineffective homing of activated HSC and to define means to overcome what may be a major drawback to clinical transplantation of ex vivo generated HSC.