Chemokine receptor CXCR4–dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells

Dar, Ayelet; Goichberg, Polina; Shinder, Vera; Kalinkovich, Alexander; Kollet, Orit; Netzer, Neta; Margalit, Raanan; Zsak, Marion; Nagler, Arnon; Hardan, Izhar; Resnick, Igor B.; Rot, Antal; Lapidot, Tsvee

doi:10.1038/ni1251

Cited by 332 publications

(264 citation statements)

References 52 publications

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“…SDF-1 released within the intravascular compartment is translocated from the plasma to the BM compartment through a complex vesicular transport system, a process referred to as transcytosis [36]. When SDF-1 enters the BM microenvironment, it induces the activation of matrix metalloproteinase-9 (MMP-9) and the release of soluble kit-ligand (sKitL).…”

Section: How Does Activation Of the Sdf-1-cxcr4 Pathway Support Mobilmentioning

confidence: 99%

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Petit

Jin

Rafii

2007

Trends in Immunology

530

382

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Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4 + BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4 + VEGFR1 + hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.

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Section: How Does Activation Of the Sdf-1-cxcr4 Pathway Support Mobilmentioning

confidence: 99%

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Petit

Jin

Rafii

2007

Trends in Immunology

530

382

View full text Add to dashboard Cite

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“…Although the homing process is not fully understood, SDF-1, which is produced by BM stromal and endothelial cells, has been reported to play an important role. [31][32][33] As human and mouse SDF-1 are crossreactive, SDF-1 must be potentially involved in the LSC homing. However, MAS express a low level of CXCR4, a receptor of SDF-1, on the cell surface, and MAS cells did not migrate toward the SDF-1 axis using EZ-TAXIScan (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice

et al. 2006

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The cellular components of the hematopoietic stem cell niche have been gradually identified. However, the niche for malignant hematopoiesis remains to be elucidated. Here, using human leukemia cells, which could be transplanted to immunodeficient mice, we studied the in vivo homing, proliferation and survival sites by immunohistopathology, compared with the corresponding sites for cord blood CD34 þ (CBCD34 þ ) cells. The human leukemia cells initially localized on the surface of osteoblasts in the epiphysial region, and expanded to the inner vascular and diaphysial regions within 4 weeks. The percentage of CD34 þ leukemia cells in the bone marrow was transiently increased up to 50%. In vivo 5-bromo-2 0 -deoxyuridine labeling revealed that the epiphysis was the most active site for leukemia cell proliferation. CBCD34 þ cells showed the similar pattern of homing and proliferation to leukemia cells. After high-dose administration of cytosine-1-b-D-arabinofuranoside, residual leukemia cells were localized in the perivascular endothelium as well as in contact with the trabecular endosteum. These findings suggest that xenotransplantation into immunodeficient mice provides a useful model to study the leukemia niche.

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“…These cells, in fact, express CXCR4 31,32 and are capable of capturing SDF-1, which is stored within their cytoplasm and released in response to external stimuli 33 . The concentration of soluble SDF-1 in the blood, however, increases in association with many of the conditions that induce stem/progenitor cell mobilization.…”

Section: Introductionmentioning

confidence: 99%

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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Objective-To assess whether alterations in the SDF-1/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1 low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking.Materials and Methods-In the mouse, SDF-1 mRNA levels were assayed in liver, spleen and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients.Results-In Gata1 low mice, the plasma SDF-1 protein was 5-times higher than normal in younger animals. Furthermore, SDF-1 immuno-staining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, the plasma SDF-1 levels in PMF patients were significantly higher (by 2-fold) than normal (p<0.01) and SDF-1 immuno-staining of marrow biopsiy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similarly to what already has been reported for PMF patients, the marrow from Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Gata1 low mice contained fewer CXCR4 pos CD117 pos cells and these cells expressed low levels of CXCR4 mRNA and protein. NIH Public AccessConclusion-Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1 low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF.

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Chemokine receptor CXCR4–dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells

Cited by 332 publications

References 52 publications

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

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