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Michelle O'Doherty, Reinhold Medina, Christina O'Neill, Henry Knott, Jasenka Guduric-Fuchs, Tom Gardiner, Alan Stitt; Circulating Angiogenic Cells (CACs) Promote Retinal Angiogenesis, A Response Mediated By Paracrine Release Of Interleukin-8 (IL-8). Invest. Ophthalmol. Vis. Sci. 2011;52(14):3184.
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Endothelial Progenitor Cells (EPCs) can promote revascularisation of ischaemic tissues and hold therapeutic promise for promoting tissue repair and reperfusion. A diverse range of EPC types are being utilised for therapeutic applications, although results are variable. We recently characterised two distinct EPC cell populations; CACs and Outgrowth endothelial cells (OECs). OECs were identified as the only EPC type with true progenitor and endothelial characteristics. Despite being widely described as "EPCs", CACs were shown to be monocytic cells without endothelial characteristics. Since they are now widely used clinically, this study investigates the CAC phenotype and potential role in retinal angiogenesis.
CACs were isolated from human peripheral blood and characterised using a broad range of markers assessed by immunofluoresecence and flow cytometry. Retinal microvascular endothelial cells (RMECs) were co-cultured with CACs and tubulogenic potential assessed. Cytokines released from CACs were assessed by protein array. CACs were also intra-vitreally delivered to a murine model of ischaemic retinopathy. In both in vitro and in vivo experiments, IL-8 activity was blocked using the CXCR2 inhibitor SB225002.
Transcriptomic and immunophenotypic analysis indicated that CACs represent alternative activated M2 macrophages. CACs had no intrinsic tubulogenic potential in RMECs, although they significantly induced tube formation in co-cultures (p<0.05) without directly incorporating into a microvascular network. This was suggestive of a paracrine effect and IL8 was identified in CAC-conditioned media as a key paracrine factor. CACs significantly reduced avascular areas when compared to controls (p<0.01), although they never incorporated into the resident vasculature. Blockade of IL8 but not VEGF prevented CAC-induced angiogenic function in vitro and in vivo.
CACs act as alternative M2 macrophages with pro-angiogenic, anti-inflammatory and pro-tissue repair properties in the ischaemic retina. This mechanism of action is linked to paracrine release of cytokines such as IL-8.
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