Endothelial Progenitor Cells—Potential New Avenues to Improve Neoangiogenesis and Reendothelialization - International Review of Cell and Molecular Biology - page 56

CXCR4 ( Bernhagen et al., 2007 ), a major receptor regulating progenitor
cell migration that is also expressed on EPC, it has been shown that MIF
contributes to ischemia-dependent recruitment of EPC ( Simons et al.,
2011 ). In this study, MIF was rapidly secreted from ECs upon hypoxia with
a bulk of MIF release after 1 h. The observation that anti-CXCR4 mono-
clonal antibodies completely inhibited the effect of hypoxia-conditioned
endothelial cell media collected after 1 h of hypoxia, indicated that MIF
might be an important EPC chemoattractant during the early posthypoxia
phase and that it acts through CXCR4.
This finding was intriguing, because previously CXCL12 was considered
the main protagonist in driving EPC recruitment following hypoxic/ische-
mic triggers. In line with this notion, it has been observed that the exposure
of MIFs noncognate receptors CXCR4 and CXCR2 is substantially
enhanced under hypoxic conditions. These findings thus are in accordance
with observations that angiogenesis occurs more rapidly in hypoxic tissues
and were also in line with the work of Grieb et al., who have shown that
MIF plays an important role in the mobilization of EPC, which is dependent
on the degree of ischemia. An in vitro and in vivo study proved that
MIF enhances the chemotactic migration of EPCs in clinical settings
( Grieb et al., 2012 ). Based on these results, another study also aimed to
clarify the functional role of proangiogenic chemokines, such as MIF,
CXCL12, and VEGF, after hypoxia-dependent induction in EPCs with
MIF and VEGF exhibiting the strongest effects under hypoxia ( Kanzler
et al., 2013 ).
2.5. Cytokines expressed by EPC
One of the explanations for the positive effects of EPC is their ability to
secrete large amounts of cytokines. Urbich et al. (2005) compared the levels
of secreted cytokines of CAC to the levels secreted by HUVECs and human
microvascular endothelial cells (HMVECs). They found that VEGF A and
VEGF B were highly expressed in CACs as compared with HUVECs and
HMVECs. The chemokines SDF-1, IGF-1, HGF, and, to a minor extent,
G-CSF were increased in CAC as compared with HUVECs. A similar result
was found in BM-EPCs. These BM-EPCs showed in vitro a release of
GM-CSF and VEGF ( Wang et al., 2011 ).
In another in vitro study, the secretome of human embryonic stem cell
(hESC)-derived EPC and CB-derived EPC (CB-EPC) was evaluated.
hESC-EPC secreted distinctively different cytokines and chemokines from