Circulating endothelial progenitors have been defined as highly proliferative cells that are derived from the bone marrow with the capacity to adopt endothelial characteristics in vitro and incorporate into neovasculature and differentiate into mature endothelial cells in vivo. Asahara, Isner, and colleagues published the first description of circulating endothelial progenitor cells in an adult in 1997. In this initial description, human peripheral blood mononuclear cells enriched for expression of the markers Flk-1 (VEGFR2) and CD34 were found to have the capacity to develop traits of mature endothelial cells when cultured. The conditions used to produce this phenotype attempted to recapitulate an angiogenic environment by including bovine brain extract in the culture medium. The cells expressed endothelial characteristics such as the markers CD31, Tie-2, Flk-1, von Willebrand Factor (vWF), and endothelial nitric oxide synthetase (ecNOS). The cells also took up DiI-labeled acetylated low-density lipoprotein (Dil acLDL) and lost the hematopoietic cell surface marker CD45. This initial work was a prelude to several studies in the area that have used a variety of culture conditions to induce the expression of endothelial traits in bone marrow-derived cells. The starting populations of cells that have been used in these experiments can be roughly divided into two categories: hematopoietic stem cells and monocytes. (See Table I for a summary of these experiments.)
Several groups have reported that cells with one or more of a constellation of markers CD133, CD34, and the vascular endothelial growth factor receptor flkl (VEGFR2) identifies a subpopulation of circulating cells with endothelial potential. These cells have been isolated both from the bone marrow and peripheral blood and been found to adopt endothelial characteristics in culture. Upon culture with angiogenic cytokines such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and others, the precursor endothelial cells lose the expression of hematopoietic stem cell markers CD133 and CD34 and begin expressing the endothelial markers VE-Cadherin, von Willebrand factor, and Ulex europaeus agglutinin-1 (UEA-1) binding. Additionally, these cells are able to show some functional endothelial characteristics in vitro, including uptake of acLDL and tube formation in matrigel.
Another hematopoietic cell population that has been shown to adopt endothelial characteristics in vitro and participate in neovasculature formation in vivo are peripheral blood monocytes. The ability of a monocyte fraction of cells to assume endothelial characteristics in vitro was first demonstrated in 2001 by Haaraz and colleagues and has been subsequently repeated in other studies. As with the CD34+/CD133+/FLK1+ cells, monocytes require culture under angiogenic conditions to express endothelial traits. These cells were found to express the EC markers von Willebrand factor, VE-Cadherin (CD 144), endoglin (CD105), thrombospondin receptor (CD36), VEGFR1, and VEGFR2. However, unlike the CD34+/CD133+/FLK1+ derived cells, the monocyte-derived cells continue to express myeloid markers such as CD45 and CD14, even as they begin showing endothelial characteristics.
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