Preconditioned Endothelial Progenitor Cells as Biomarker of Vascular Reparation?

Endothelial progenitor cells (EPCs) have determined primitive cells originated from precursors found in the bone marrow and peripheral blood [1]. The ability of EPCs for self-renewal and differentiation into mature endothelial cells has recently been under intense investigation [2] and remains of high interest for regenerative medicine [3]. The recent pre-clinical and clinical studies have shown a key role of bone marrow EPCs in the endothelial repair, angiogenesis, neovascularization and attenuation of vascular function, whereas EPCs derived from peripheral blood cells including circulating mononuclears are under tight epigenetic control, and several paracrine and metabolic mechanisms and they are considered a central mechanism of immediate reparative response of injury [4-6]. There is a large body of evidence regarding that the both subpopulations of EPCs are mobilized or released into systemic circulation in response to specific stimuli [7-9].


Introduction
Endothelial progenitor cells (EPCs) have determined primitive cells originated from precursors found in the bone marrow and peripheral blood [1]. The ability of EPCs for self-renewal and differentiation into mature endothelial cells has recently been under intense investigation [2] and remains of high interest for regenerative medicine [3]. The recent pre-clinical and clinical studies have shown a key role of bone marrow EPCs in the endothelial repair, angiogenesis, neovascularization and attenuation of vascular function, whereas EPCs derived from peripheral blood cells including circulating mononuclears are under tight epigenetic control, and several paracrine and metabolic mechanisms and they are considered a central mechanism of immediate reparative response of injury [4][5][6]. There is a large body of evidence regarding that the both subpopulations of EPCs are mobilized or released into systemic circulation in response to specific stimuli [7-9].
Formerly EPCs were defined as cells positively labeled with both hematopoietic stem cells (CD34) and endothelial cell markers predominantly VEGF receptor-2 (VEGFR2) cumulatively [1]. Later an expression of other hematopoietic stem cells markers (CD133, AC133) and some endothelial markers (platelet-endothelial cell adhesion molecule known as CD31, VE-cadherin also known as CD 144, caveolin-1, von Willebrand factor, and endothelial NO synthase) on the surface of EPCs was found [10-13]. Therefore, some subsets of EPCs may express mononuclear antigens, i.e., CD14, CD11b, CD11c, together with CD34 or VEGFR2, CD45, Tei2 and Flt-1 [14] and shape so called "non-classical" phenotypes. All these EPCs remain vascular protective capacity and may differentiate into mature endothelial cells under effect of microenvironment, paracrine regulators and appropriate growth factors (e.g., VEGF, fibroblast growth factor).

Abstract
The endothelial progenitor cells (EPCs) have defined as cells positively labeled with both hematopoietic stem cells (CD34) and endothelial cell markers predominantly VEGF receptor-2 (VEGFR2) cumulatively. Therefore, there are at least two types of EPCs labelled as early outgrowth EPCs and late outgrowth EPCs probably distinguished their vascular protective ability. Recent animal and clinical studies have shown that reduced number and weak function of EPCs may not only indicate to higher CV risk, but contribute to the impaired heart and vessels reparation. Interestingly, there are some subpopulations of EPCs especially recruited from peripheral blood cells, which may exhibit very variable pro-angiogenic effect and endothelial repair capacity and they are called "preconditioned" EPCs. The aim of the short commentary is depicted the possibilities to use of measurement of traditionally labeled EPCs as biomarker of cardiovascular risk.  [34]. On the one hand, all these mediate inadequate response of endothelial repair system toward vascular injury. On the other hand, preconditioned by CV risk factors EPC are discussed a main modulator of vascular reparation and restoring endothelial functions [35].

Discussion
In this context, measurement of circulating preconditioned EPCs' level might be much more pretty accurate biomarker of CV risk and CV outcomes in various diseases. Consequently, a simple measurement of circulating EPC number showing potential for improved endothelial function based on labeling of specific antigens might be wrong step to determine the regenerative ability of EPCs. Probably, we have precious many investigations with controversial results regarding predictive role of EPC count in peripheral blood in CV disease and diabetes [36][37][38][39][40][41]. However, lack of accessible and affordable approved methods regarding an assay of ability to survive, moving, differentiation, and colony forming of preconditioned EPCs is challenge for use of this approach in routine clinical practice, although there are data that the even simple measurement of EPCs in circulation might be useful for CV risk predicting in patients with acute coronary syndrome, atherosclerosis, heart failure and diabetes [42,43].

Conclusion
Large clinical studies are required to re-assay the role of circulation EPC number measurement in CV risk prediction. Probably, novel methods regarding exam of functionality preconditioned EPCs are needed in future. 24