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

Abstract

Regulation of the availability of chemokine SDF-1 (CXCL12) in bone marrow is still not fully understood. Here we describe a unique function for the chemokine receptor CXCR4 expressed on bone marrow endothelial cells, which efficiently internalize circulating SDF-1, resulting in its translocation into the bone marrow. Translocated SDF-1 increased the homing of transplanted human CD34+ hematopoietic progenitors to the bone marrow. The chemokine transporter function of CXCR4 was a characteristic of endothelial and stromal cells but not of hematopoietic cells. Thus, chemokine translocation across the blood–bone marrow barrier allows effective transfer of functional SDF-1 from the periphery to the stem cell niche in the bone marrow during both homeostasis and 'alarm' situations.

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Figure 1: SDF-1 and CXCR4 expression and presentation by bone marrow sinusoids.
Figure 2: CXCR4-dependent translocation of circulating bSDF-1 into the bone marrow.
Figure 3: SDF-1 internalization by human and mouse bone marrow endothelium is CXCR4 dependent.
Figure 4: Transcytosis of SDF-1 by endothelial cells via clathrin-coated pits.
Figure 5: Resecretion of functional bSDF-1 by BMECs.
Figure 6: SDF-1 internalization is exclusive to stromal cells, not to hematopoietic cells.

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Acknowledgements

We thank B. Frisch and B. Lifschitz–Mercer (Sourasky Medical Center, Tel-Aviv, Israel) for providing human bone marrow specimens; and A. Globerson, D. Zipori, R. Alon and S. Berrih-Aknin for critical remarks and discussions. Supported by The Israel Science Foundation (794/04) and Ares-Serono Group and by the Edith Stein Professional Chair of Immunology (T.L.).

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Correspondence to Tsvee Lapidot.

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Dar, A., Goichberg, P., Shinder, V. et al. Chemokine receptor CXCR4–dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells. Nat Immunol 6, 1038–1046 (2005). https://doi.org/10.1038/ni1251

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