Endothelial progenitor cells: identity defined?

Abstract

In the past decade, researchers have gained important insights on the role of bone marrow (BM)-derived cells in adult neovascularization. A subset of BM-derived cells, called endothelial progenitor cells (EPCs), has been of particular interest, as these cells were suggested to home to sites of neovascularization and neoendothelialization and differentiate into endothelial cells (ECs) in situ, a process referred to as postnatal vasculogenesis. Therefore, EPCs were proposed as a potential regenerative tool for treating human vascular disease and a possible target to restrict vessel growth in tumour pathology. However, conflicting results have been reported in the field, and the identification, characterization, and exact role of EPCs in vascular biology is still a subject of much discussion. The focus of this review is on the controversial issues in the field of EPCs which are related to the lack of a unique EPC marker, identification challenges related to the paucity of EPCs in the circulation, and the important phenotypical and functional overlap between EPCs, haematopoietic cells and mature ECs. We also discuss our recent findings on the origin of endothelial outgrowth cells (EOCs), showing that this in vitro defined EC population does not originate from circulating CD133(+) cells or CD45(+) haematopoietic cells.

1

Conditional EPC knockout mouse model based on a unique CEPC marker. A modified estrogen receptor (mER; in red) is co-expressed on CEPCs that expresses a unique marker (indicated in grey). This unique marker may be either a membrane (as shown) or a cytoplasmatic marker. Upon challenge with a receptor specific agent, the mER activates the Cre enzyme (indicated by scissors) in CEPCs. The Cre-enzyme recognizes the specific LoxP sequences (white) that flank a survival gene (black) resulting in its deletion and eventually CEPC death.

2

Haemato-endothelial developmental pathways and their relation to the expression of CD45. In the embryo, CD45 ⁻mesodermal precursors give rise to CD45⁻ endothelial precursors (EPCs), haemangioblasts and/or haemogenic endothelial cells (HECs). The CD45⁻ EPCs differentiate into functional and mature ECs. Embryonic haemangioblasts are CD45⁻ and differentiate to both CD45⁻ endothelial lineage cells and CD45⁺ HSCs/HPCs in vitro. Alternatively, or in addition to haemangioblasts, CD45⁻ HECs give rise to CD45⁺ haematopoietic stem/progenitor cells. HSCs/HPCs can give rise to EC-like cells in vitro and retain expression of CD45, whereas expression of the CD133 antigen is downregulated.