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Molecular Medicine

, Volume 17, Issue 9–10, pp 1045–1055 | Cite as

Myeloid Angiogenic Cells Act as Alternative M2 Macrophages and Modulate Angiogenesis through Interleukin-8

  • Reinhold J. Medina
  • Christina L. O’Neill
  • T. Michelle O’Doherty
  • Henry Knott
  • Jasenka Guduric-Fuchs
  • Tom A. Gardiner
  • Alan W. Stitt
Research Article

Abstract

Endothelial progenitor cells (EPCs) promote angiogenesis, and clinical trials have shown such cell therapy to be feasible for treating ischemic disease. However, clinical outcomes have been contradictory owing to the diverse range of EPC types used. We recently characterized two EPC subtypes, and identified outgrowth endothelial cells as the only EPC type with true progenitor and endothelial characteristics. By contrast, myeloid angiogenic cells (MACs) were shown to be monocytic cells without endothelial characteristics despite being widely described as “EPCs.” In the current study we demonstrated that although MACs do not become endothelial cells or directly incorporate into a microvascular network, they can significantly induce endothelial tube formation in vitro and vascular repair in vivo. MAC-derived interleukin-8 (IL-8) was identified as a key paracrine factor, and blockade of IL-8 but not vascular endothelial growth factor (VEGF) prevented MAC-induced angiogenesis. Extracellular IL-8 transactivates VEGFR2 and induces phosphorylation of extracellular signal-regulated kinases. Further transcriptomic and immunopheno-typic analysis indicates that MACs represent alternative activated M2 macrophages. Our findings demonstrate an unequivocal role for MACs in angiogenesis, which is linked to paracrine release of cytokines such as IL-8. We also show, for the first time, the true identity of these cells as alternative M2 macrophages with proangiogenic, antiinflammatory and pro-tissue-repair properties.

Notes

Acknowledgments

This work was funded by grants from the Juvenile Diabetes Research Foundation, Fight for Sight UK, The Sir Jules Thorn Trust, the Department of Employment & Learnng (DEL) (Northern Ireland), and the Medical Research Council UK. AW Stitt holds a Royal Society Wolfson Merit Award. The authors thank Sharon Alexander for constant support and assistance in taking samples. We also thank Jessica Neisen and David Waugh for assistance with ELISA for IL-8.

Supplementary material

10020_2011_1791045_MOESM1_ESM.pdf (1.6 mb)
Myeloid Angiogenic Cells Act as Alternative M2 Macrophages and Modulate Angiogenesis through Interleukin-8

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Reinhold J. Medina
    • 1
  • Christina L. O’Neill
    • 1
  • T. Michelle O’Doherty
    • 1
  • Henry Knott
    • 1
  • Jasenka Guduric-Fuchs
    • 1
  • Tom A. Gardiner
    • 1
  • Alan W. Stitt
    • 1
  1. 1.Centre for Vision and Vascular Science, School of Medicine, Dentistry and Biomedical ScienceQueen’s University Belfast, Royal Victoria HospitalBelfastUK

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