In 1963, in an attempt to define the source of endothelium on vascular grafts, Stump and colleagues suspended a Dacron patch within the lumen of a prosthetic vascular graft in the aorta of a juvenile pig (1). As early as 14 days following placement, islands of endothelial cells (ECs) were identified on the patch surface. Because the patch had been isolated from contact with both the prosthesis and native vascular tissue, these findings implicated circulating blood as the source of ECs. These observations were not actively pursued from an experimental or clinical context until recently.

This original observation of a vascular source of endothelium has been corroborated in chimeric transplantation models that have enabled the discrimination of host- and donor derived cells by genetic markers. These studies have revealed bone marrow–derived circulating progenitors to contribute to both endothelial and intimal smooth muscle cell formation in multiple models of vascular injury as reviewed by Sata (2). Moreover, treatment with 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) appears to accelerate the incorporation of bone marrow–derived ECs following arterial denudation in rodent models (3,4). These studies confirm the presence of cells with either an endothelial phenotype or endothelial potential within human blood. Furthermore, strategies have been developed to utilize these cells for the prevention and treatment of vascular disease. In this chapter, identification, classification, and potential translational uses of these cells will be discussed.

CIRCULATING ENDOTHELIAL CELLS

Definition and Phenotype

The blood of normal individuals contains circulating ECs (CECs) as well as monocytic cells with the potential to develop endothelial features in culture (culture-modified mononuclear cells – CMMCs) and progenitors capable of differentiation into ECs (so-called true endothelial progenitor cells [EPCs]).