A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb.

Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy. Editor's summary: Peripheral vascular disease can cause chronic limb-threatening ischemia (CLTI), which decreases quality of life and can lead to amputation. Patel et al. found that a specific population of proangiogenic/arteriogenic monocytes (PAMs) are increased in circulation in response to CLTI. PAMs from patients with CLTI secreted growth factors that led to increased vascular cell proliferation in vitro. Markers of angiogenesis and arteriogenesis were increased in mice with hindlimb ischemia treated with PAMs from patients. PAMs adhered to ischemic human muscle more than other monocytes. In a clinical study, PAMs injected into human ischemic limb muscle were partially retained around the injection site for up to 72 hours. These results suggest that using patient-derived PAMs could be a therapeutic approach for treating CLTI. —Brandon Berry [ABSTRACT FROM AUTHOR]