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

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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Neutrophil proteases NE and CG cleave and inactivate CXCL12α. Aliquots o...
Neutrophil proteases NE and CG cleave and inactivate CXCL12α. Aliquots of synthetic human CXCL12α were incubated overnight at 37°C in the presence of medium conditioned by either human BM CD34– cells, PB neutrophils, or nonconditioned medium. In parallel, CXCL12α was also incubated with purified human NE, CG, or proteinase-3. In the top panel, the remaining chemotactic activity of exogenous human CXCL12α was measured on purified BM CD34+ cells in transmigration assays as described in Figure 4a. A representative experiment from three performed in triplicate is shown. The bottom panel shows Western blot analysis of the same samples with a goat anti-human CXCL12 antibody. BM, BM CD34– cells; Neut, PB neutrophils; NC, nonconditioned medium; P3, proteinase-3.