Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lymphohematopoietic progenitors

Abstract

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine produced by stromal cells that acts as a chemoattractant for human CD34 + progenitor cells. We investigated the expression of CXCR4, the receptor for SDF-1, on CD34 + cells from different hematopoietic sites and developmental stages. CXCR4 was detected by flow cytometry on 37 % of fetal bone marrow (BM) [gestation weeks (gw) 14-23] and 40 % of adult BM CD34 + cells. Interestingly, in fetal liver CD34 + cells, CXCR4 was expressed at lower levels at later stages (9 %, gw 20-23) compared to early stages of development (39 %, gw 7.5-18), suggesting a development-related change in the migratory capacity of progenitors. CXCR4 was detected at similar levels on both phenotypically primitive and committed progenitors from fetal and adult sites. However, B cell lineage progenitor and precursor cells expressed CXCR4 at the highest density (80 % of BM CD34 + /CD10 + pro-B cells are CXCR4 +). CXCR4 was also expressed in the fetal thymus in early T cell precursors and found to be down-regulated during T cell matura-tion. Finally, we found that stem cell factor, alone or in combination with other cytokines, can up-modulate CXCR4 expression on CD34 + cells by three-to fourfold. In conclusion, our results suggest that CXCR4 may play an important role in the local and systemic trafficking of human CD34 + cells as well as in human B lymphopoiesis and that its expression can be modulated by cytokines.

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

“…The chemokine receptor, CXCR4, and its endogenous ligand SDF-1 have been shown to be key components in both chemokineinduced leucocyte trafficking (Aiuti et al, 1997(Aiuti et al, , 1999Hamada et al, 1998) and the migration of malignant epithelial cells to the BMS (Koshiba et al, 2000;Muller et al, 2001;Robledo et al, 2001;Murakami et al, 2002;Schrader et al, 2002;Taichman et al, 2002; Sun et al, 2003). This has led to the hypothesis that CXCR4 is the key component of metastatic implantation in bone marrow and that it represents an important therapeutic target for metastatic bone disease.…”

“…The key molecular axis for this homing has been shown to involve the CXC chemokine stromal-derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 (CD186). This model is supported by the facts that both bone marrow endothelial cells and osteoblasts express SDF-1 (Aiuti et al, 1997;Hamada et al, 1998;Ponomaryov et al, 2000), CXCR4 knockouts do not show haematopoietic engraftment of the bone marrow (Aiuti et al, 1999) and that the level of CXCR4 expression by HSC determines their ability to engraft the bone marrow (Peled et al, 1999). It has been shown recently that the CXCR4/CXCL12 axis also plays a crucial role in the targeting of several solid tumour metastases, including breast (Muller et al, 2001) kidney (Staller et al, 2003), lung (Burger et al, 2003), pancreas (Koshiba et al, 2000) and CaP (Taichman et al, 2002;Sun et al, 2003) to the bone marrow.…”

BCR/ABL-mediated downregulation of genes implicated in cell adhesion and motility leads to impaired migration toward CCR7 ligands CCL19 and CCL21 in primary BCR/ABL-positive cells

“…41 They are implicated in migration of leukocytes, inflammatory responses and regulation of tumor growth, as well as hematopoiesis. [42][43][44] SDF1a and its receptor CXCR4 play important roles in migration of HSC from the fetal liver to the fetal BM 45,46 as well as in postnatal life. 47,48 In CML, chemotaxis towards SDF1a is impaired, 49,50 which may contribute to the premature release of leukemic progenitors from the BM into the circulation.…”

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“…CXCR4 is broadly expressed by many cells within the body including cells of the immune and the central nervous system [4-7]. This receptor mediates the migration of resting leukocytes and hematopoietic progenitors in response to its specific ligand [8,9].…”