Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide.
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.
Lévesque
Jean-Pierre
JP
Stem Cell Biology Laboratory, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia. jp.levesque@pmci.unimelb.edu.au
Hendy
Jean
J
Takamatsu
Yasushi
Y
Simmons
Paul J
PJ
Bendall
Linda J
LJ
D000818:Animals; D056649:Cathepsin G; D002403:Cathepsins / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000032:analysis / Q000378:metabolism*; D003520:Cyclophosphamide / Q000494:pharmacology*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000502:physiology; D019718:Receptors, CXCR4 / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D012697:Serine Endopeptidases
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534096:Ctsg protein, mouse; D019272:Leukocyte Elastase