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Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide
Jean-Pierre Lévesque, … , Paul J. Simmons, Linda J. Bendall
Jean-Pierre Lévesque, … , Paul J. Simmons, Linda J. Bendall
Published January 15, 2003
Citation Information: J Clin Invest. 2003;111(2):187-196. https://doi.org/10.1172/JCI15994.
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Article Hematology

Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide

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Abstract

Hematopoietic progenitor cells (HPCs) normally reside in the bone marrow (BM) but can be mobilized into the peripheral blood (PB) after treatment with GCSF or chemotherapy. In previous studies, we showed that granulocyte precursors accumulate in the BM during mobilization induced by either GCSF or cyclophosphamide (CY), leading to the accumulation of active neutrophil proteases in this tissue. We now report that mobilization of HPCs by GCSF coincides in vivo with the cleavage of the N-terminus of the chemokine receptor CXCR4 on HPCs resident in the BM and mobilized into the PB. This cleavage of CXCR4 on mobilized HPCs results in the loss of chemotaxis in response to the CXCR4 ligand, the chemokine stromal cell–derived factor-1 (SDF-1/CXCL12). Furthermore, the concentration of SDF-1 decreased in vivo in the BM of mobilized mice, and this decrease coincided with the accumulation of serine proteases able to directly cleave and inactivate SDF-1. Since both SDF-1 and its receptor, CXCR4, are essential for the homing and retention of HPCs in the BM, the proteolytic degradation of SDF-1, together with that of CXCR4, could represent a critical step leading to the mobilization of HPCs into the PB in response to GCSF or CY.

Authors

Jean-Pierre Lévesque, Jean Hendy, Yasushi Takamatsu, Paul J. Simmons, Linda J. Bendall

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Figure 1

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Mobilized CD34+ PBPCs express a CXCR4 molecule truncated in the first ex...
Mobilized CD34+ PBPCs express a CXCR4 molecule truncated in the first extracellular domain. (a) Nalm-6 cells were incubated for 2 hours at 37°C in the presence of indicated concentrations of purified NE (circles) or CG (squares) and were stained with the mAbs 6H8 or 12G5. After analysis by flow cytometry, results are expressed as a percentage of 6H8/12G5 binding of nontreated cells. Data represent means ± SD of three independent experiments. (b) Binding of 6H8 and 12G5 mAbs to steady-state CD34+ BM cells, GCSF–mobilized CD34+ PBPCs, and GCSF–mobilized CD34+ PBPCs after overnight culture. The flow cytometry analysis was gated on CD34+ cells. Representative data from two experiments are shown. (c) CD34+ cells isolated from normal steady-state BM were treated with 100 μg/ml of NE or CG. Control cells were pretreated in an identical manner with PBS in the absence of protease. The chemotactic response of cells was assessed in the presence (black bars) or absence (white bars) of 200 ng/ml of CXCL12 in the lower chamber. Representative data from two experiments in triplicate are shown. P, PBS. (d) Freshly isolated GCSF–mobilized CD34+ PBPCs or CD34+ cells derived from steady-state BM were compared for their chemotactic response in the absence (white bars) and presence (black bars) of 200 ng/ml CXCL12. Representative data from two experiments are shown.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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