gms | German Medical Science

Introduction: Endothelial progenitor cells (EPCs) promote vasculogenesis and play an important role in tissue revascularization and wound healing. Yet, the exact stimuli and mechanisms for their mobilization remain poorly understood. Our recent discovery demonstrated that the Macrophage migration inhibitory factor (MIF), a structurally unique pleiotropic cytokine, exhibits chemokine-like functions and promotes atherogenic T cell recruitment through a non-cognate interaction with the CXC chemokine receptor CXCR4 (Bernhagen et al., Nat. Med. 2007), a major receptor regulating progenitor cell migration that is also expressed on EPCs. Recently, we could show that MIF is rapidly released by endothelial cells upon hypoxia and is a potential inducer of ischemia-dependent EPC migration in vitro (Simons et al., JCMM 2010). The aim of this study was to verify this hypothesis in a clinical setting.

Material and methods: The study included 20 patients who underwent flap surgery. Patients were divided into three groups according to the pattern of flap applied. The number of circulating EPCs, MIF, and CXCL12 (SDF-1) serum levels were determined at different time points. An in vitro chemotaxis assay was carried out to test whether MIF promotes the chemotactic migration of EPCs. To functionally underscore the chemotactic potential of MIF towards EPCs in flap patients, the in vitro assays were also used to test the chemotactic effects of serum samples from all groups in the presence and absence of monoclonal MIF and CXCL12 antibodies on EPC recruitment.

Results: In flap patients, the number of circulating EPCs and MIF but not CXCL12 serum levels were markedly increased compared to pre-operative levels, especially in the group of free microvascular flaps. Analysis between EPCs and MIF revealed a remarkable and significant correlation, whereas no correlation was observed for CXCL12. MIF exerted a dose-dependent pro-chemotactic effect on isolated human EPCs and serum samples from all flap patients promoted EPC migration. Importantly, this effect was partially blocked by anti-MIF and to a weaker extent by anti-CXCL12 antibodies.

Conclusion: We conclude that MIF plays an important role in the mobilization of EPCs which is depending on the degree of ischemia. Enhancement by MIF of chemotactic EPC migration in vitro underpins its proposed in vivo function.