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.

Human mesenchymal stem cells alter macrophage phenotype and promote regeneration via homing to the kidney following ischemia-reperfusion injury

“…Furthermore, MSC-induced M2 polarization was evident in both direct and indirect coculture systems, indicating that the alteration of macrophage phenotype was mediated through paracrine mechanisms. Screening of the coculture supernatants detected the presence of MSC-derived EGF, GM-CSF, CXCL1, IL-6, IL-8, MCP-1/CCL2, PDGF-AA, and RANTES/ CCL5, all of which, except for EGF, GM-CSF, CXCL1, and PDGF-AA, have previously been shown to promote M2 polarization (1,6,39,48,55). Interestingly, CXCL1 was only detected in the direct coculture system, indicating that its production required direct cell-to-cell contact.…”

M2-polarised macrophages in infantile haemangiomas: correlation with promoted angiogenesis

“…Moreover, given that expression of CSF-1 and CD163 distributed in the perivascular endothelium, which appeared only in proliferating IHs, it is possible that M-CSF-induced M2-polarised macrophage activation was mediated by proliferative endothelial cells. On the other hand, mounting evidence reveals17 33 34 that TAMs can release a number of potent proangiogenic factors, such as VEGF, TNF-a, IL-8 and bFGF, thereby promoting tumour angiogenesis. In our study, M2-polarised macrophages were found to express VEGF, which distributed in the perivascular sites of IHs.…”

The progress in understanding and treatment of diabetic retinopathy

“…In OIR, oxygen deprivation of the retinal glia and neurons drives expression of pro-angiogenic growth factors (such as VEGF, erythropoietin, TNF-alpha, and angiopoietin-2) and the neovascular membranes that ensue are similar to those occurring in PDR (Connor et al, 2009). The model has been extensively used for assessment of anti-angiogenic agents (Gardiner et al, 2003a;Gebarowska et al, 2002;Hammes et al, 1996;McVicar et al, 2011) and cell therapies Medina et al, 2011). In addition, a degree of BRB breakdown, glial and neuronal damage have been observed in the OIR model (Vessey et al, 2011).…”