title: Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8.
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 immunophenotypic 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.
authors.affiliation: Centre for Vision and Vascular Science, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors.forename: Reinhold J
authors.initials: RJ
authors.lastname: Medina
authors.forename: Christina L
authors.initials: CL
authors.lastname: O'Neill
authors.forename: T Michelle
authors.initials: TM
authors.lastname: O'Doherty
authors.forename: Henry
authors.initials: H
authors.lastname: Knott
authors.forename: Jasenka
authors.initials: J
authors.lastname: Guduric-Fuchs
authors.forename: Tom A
authors.initials: TA
authors.lastname: Gardiner
authors.forename: Alan W
authors.initials: AW
authors.lastname: Stitt
mesh_terms: D000328:Adult; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics / Q000379:methods; D012171:Retinal Vessels / Q000378:metabolism / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2