A homing mechanism for bone marrow–derived progenitor cell recruitment to the neovasculature
Hui Jin, Aparna Aiyer, Jingmei Su, Per Borgstrom, Dwayne Stupack, Martin Friedlander, Judy Varner
Hui Jin, Aparna Aiyer, Jingmei Su, Per Borgstrom, Dwayne Stupack, Martin Friedlander, Judy Varner
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Research Article

A homing mechanism for bone marrow–derived progenitor cell recruitment to the neovasculature

Abstract

CD34+ bone marrow–derived progenitor cells contribute to tissue repair by differentiating into endothelial cells, vascular smooth muscle cells, hematopoietic cells, and possibly other cell types. However, the mechanisms by which circulating progenitor cells home to remodeling tissues remain unclear. Here we show that integrin α4β1 (VLA-4) promotes the homing of circulating progenitor cells to the α4β1 ligands VCAM and cellular fibronectin, which are expressed on actively remodeling neovasculature. Progenitor cells, which express integrin α4β1, homed to sites of active tumor neovascularization but not to normal nonimmune tissues. Antagonists of integrin α4β1, but not other integrins, blocked the adhesion of these cells to endothelia in vitro and in vivo as well as their homing to neovasculature and outgrowth into differentiated cell types. These studies describe an adhesion event that facilitates the homing of progenitor cells to the neovasculature.

Authors

Hui Jin, Aparna Aiyer, Jingmei Su, Per Borgstrom, Dwayne Stupack, Martin Friedlander, Judy Varner

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Figure 1

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Human CD34+ progenitor cells home to peripheral tumor vasculature. (A) N...
Human CD34+ progenitor cells home to peripheral tumor vasculature. (A) Nude mice with GFP-N202 breast carcinomas under dorsal skinfold transparent chambers are injected with labeled progenitor cells. (B) Real-time video microscopy: GFP tumors in transparent chambers. Magnification, ×10. (C) Tumor vasculature is visible in the transparent chambers. Magnification, ×100. (D) Two images each of peripheral and central tumor vascular beds at 15 minutes after injection in animals injected with CMTMR-labeled CD34+ cells (arrowheads). Magnification, ×200. Blood vessels are observed as dark channels (arrows). (E) Average number of CMTMR CD34+ cells in the tumor center, tumor periphery, and fat-pad per ×200 field ± SEM. *P < 0.0019. (F) Five micron cryosections of the same tumors from animals injected with CD34+ cells were fixed in acetone, then incubated with rat anti-mouse CD31 and goat anti-rat FITC antibodies and photographed. Magnification, ×200. Arrowheads indicate CD34+ cells. Arrows indicate CD31+ blood vessels. Scale bar: 50 μm. (G) Average number of CD34+ cells per ×200 microscopic field in 5 μm cryosections. **P < 0.015. (H) Cryosections from F observed at ×630 magnification indicate CD34+ cells (arrows) are found adhering to the blood vessel wall or within tissues near blood vessels (arrowheads).