The Journal of Experimental Medicine
3rd Skeletal Biology and Medicine Symposium
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Published 16 June 2003. doi:10.1084/jem.20021659
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© Rockefeller University Press, 0022-1007/2003/6/1755 $5.00
The Journal of Experimental Medicine, Volume 197, Number 12, 1755-1765

Multistep Nature of Microvascular Recruitment of Ex Vivo–expanded Embryonic Endothelial Progenitor Cells during Tumor Angiogenesis

Peter Vajkoczy2, Sabine Blum1, Mathias Lamparter1, Reinhard Mailhammer1, Ralph Erber2, Britta Engelhardt3, Dietmar Vestweber3,4 and Antonis K. Hatzopoulos1

1 GSF-Research Center for Environment and Health, Institute for Clinical Molecular Biology and Tumor Genetics, 81377 Munich, Germany
2 Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, 68167 Mannheim, Germany
3 Max-Planck Institute for Vascular Biology, 48149 Münster, Germany
4 Institute of Cell Biology, ZMBE, University of Münster, 48149 Münster, Germany

Address correspondence to Antonis K. Hatzopoulos, GSF-Research Center for Environment and Health, Institute for Clinical Molecular Biology and Tumor Genetics, Marchioninistrasse 25, 81377 Munich, Germany. Phone: 49-89-7099-214; Fax: 49-89-7099-225; E-mail: hatzopoulos{at}gsf.de

Tissue neovascularization involves recruitment of circulating endothelial progenitor cells that originate in the bone marrow. Here, we show that a class of embryonic endothelial progenitor cells (Tie-2+, c-Kit+, Sca-1+, and Flk-1-/low), which were isolated at E7.5 of mouse development at the onset of vasculogenesis, retain their ability to contribute to tumor angiogenesis in the adult. Using intravital fluorescence videomicroscopy, we further defined the multistep process of embryonic endothelial progenitor cell (eEPC) homing and incorporation. Circulating eEPCs are specifically arrested in "hot spots" within the tumor microvasculature, extravasate into the interstitium, form multicellular clusters, and incorporate into functional vascular networks. Expression analysis and in vivo blocking experiments provide evidence that the initial cell arrest of eEPC homing is mediated by E- and P-selectin and P-selectin glycoprotein ligand 1. This paper provides the first in vivo insights into the mechanisms of endothelial progenitor cell recruitment and, thus, indicates novel ways to interfere with pathological neovascularization.

Key Words: intravital fluorescence videomicroscopy • neovascularization • cell trafficking • PSGL-1 • selectins


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