Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use

Abstract

Diverse subsets of endothelial progenitor cells (EPCs) are used for the treatment of ischemic diseases in clinical trials, and circulating EPCs levels are considered as biomarkers for coronary and peripheral artery disease. However, despite significant steps forward in defining their potential for both therapeutic and diagnostic purposes, further progress has been mired by unresolved questions around the definition and the mechanism of action of EPCs. Diverse culturing methods and detection of various combinations of different surface antigens were used to enrich and identify EPCs. These attempts were particularly challenged by the close relationship and overlapping markers of the endothelial and hematopoietic lineages. This article will critically review the most commonly used protocols to define EPCs by culture assays or by fluorescence-activated cell sorter in the context of their therapeutic or diagnostic use. We also delineate new research avenues to move forward our knowledge on EPC biology.

Figure 1

An overview of the most common methods used to isolate EPCs.

Figure 2

A pooled analysis of crude data from 4 longitudinal studies of circulating progenitor cells for cardiovascular risk stratification.^–, In the left panel, characteristics of the study are presented: thickness of the arrows are proportional to the number of patients (y-axis), while length of the arrow is proportional to duration of follow-up (x-axis). The right panel shows Kaplan-Meier curves of occurrence of 1^st or recurring major adverse cardiovascular event (MACE) in patients categorized as belonging to the higher, intermediate or lower tertile of circulating progenitor cell levels.

Figure 3

EPC mirror the natural history of atherosclerosis. The level of EPC (set at maximal in patients with normal arterial anatomy and function) starts to decline when cardiovascular risk factors appear in high risk patients. Further, EPC progressively decline with initial vascular remodeling (IMT), plaque development and progression. Lower EPCs are markers of high risk for future cardiovascular events. Finally, when complications occur (such as AMI or stroke) EPCs should be increased by bone marrow mobilization. When this mechanism is perturbed, a worse outcome can be predicted.