Endothelial Progenitor Cells (EPCs) represent a novel therapeutic approach for the revascularisation of ischaemic tissues. However clinical outcomes have been contradictory due to the lack of a uniform cell definition, resulting in a diverse range of EPC types being utilised for therapeutic applications. This study investigates the phenotype and potential role in retinal angiogenesis of a specific subset known as early EPCs (eEPCs). eEPCs isolated from human peripheral blood were characterised using immunophenotyping and transcriptomics. Tubulogenic potential was determined using a co-culture system with Retinal microvascular endothelial cells (RMECs). Cytokine release was assessed by protein array. IL-8 activity was blocked using the CXCR2 inhibitor SB225002. In vivo angiogenic potential was tested using a murine model of ischaemic retinopathy. Our data indicates that eEPCs are not endothelial progenitors, but represent alternative activated M2 macrophages. These cells were therefore named myeloid angiogenic cells (MACs). MACs significantly induced tube formation in co-cultures (p<0.05) without directly incorporating into a microvascular network. IL-8 was identified in MAC-conditioned media as a key paracrine factor. Interestingly, blockade of IL-8, but not VEGF, prevented MAC-induced angiogenic function. In vivo, MACs significantly reduced avascular areas when compared to controls (p<0.01), despite never incorporating into the resident vasculature. In conclusion, MACs act as alternative M2 macrophages with pro-angiogenic, anti-inflammatory and pro-tissue repair properties in the ischaemic retina. This role in reparative retinal angiogenesis and reversal of ischaemia has been linked to paracrine release of cytokines such as IL-8.
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