The chemokine (C-X-C motif) receptor 4 inhibitor AMD3100 accelerates blood flow restoration in diabetic mice.

Abstract

AIMS/HYPOTHESIS: Bone marrow cell mobilisation potently induces vascular growth in ischaemic tissue, possibly by mobilising endothelial cell progenitors. Thus, mobilising agents might not be therapeutic when endothelial cell progenitors are dysfunctional, as in diabetes mellitus. Local injection of autologous endothelial cell progenitors also stimulates vascular growth in ischaemic tissue, but endothelial cell progenitors from people with multiple cardiovascular risk factors and from obese diabetic mice are marginally therapeutic or inhibitory. We sought to identify possible strategies to improve vascularisation in patients with diabetes mellitus by determining if (1) mobilisation accelerates neovascularisation in diabetic animals, and (2) mobilised cells from a non-diabetic source accelerate vascularisation in diabetic animals. METHODS: We tested whether systemic administration of the chemokine (C-X-C motif) receptor 4 inhibitor AMD3100 or local injection of human CD34(+) circulating cells mobilised by AMD3100 could speed or enhance blood flow restoration in ischaemic limbs of diabetic mice. The small-molecule-mobilising drug AMD3100 was selected because mobilisation and apheresis can be done on the same day. RESULTS: Systemic administration of AMD3100 and local injection of cells mobilised by AMD3100 greatly accelerated the restoration of blood flow to ischaemic limbs of diabetic mice. CD34(+) cells mobilised by AMD3100 appeared to be more potent growth stimulators than their unmobilised counterparts. CONCLUSIONS/INTERPRETATION: Unlike other mobilising agents requiring multi-day mobilisation, AMD3100 enables mobilised donors to undergo mobilisation and apheresis on the same day. The combination of excellent therapeutic benefits as well as ease of use indicates that AMD3100 could be a powerful tool to ameliorate tissue ischaemia in the diabetic environment.