The challenges for cardiac vascular precursor cell therapy: lessons from a very elusive precursor

There is compelling evidence that cardiovascular disorders arise and/or progress due mainly to endothelial dysfunction. Novel therapeutic strategies aim to generate new myocardial tissue using cells with regenerative potential, either alone or in combination with biomaterials, cytokines and advanced monitoring devices. Among the human adult progenitor cells used in such methods, those historically termed 'endothelial progenitor cells' show promise for vascular growth and repair. Asahara et al. [Science 1997;275:964-967] initially described putative endothelial cell precursors in 1997. Subsequently, distinct cell populations termed endothelial colony-forming units-Hill, circulating angiogenic cells and endothelial colony-forming cells were identified that varied in terms of phenotype, vascular homeostasis contribution and purity. Notably, most of these cells are not genuine vascular precursor cells belonging to the endothelial lineage. This review provides a broad overview of the main properties of the endothelium, focusing on the basis governing its growth and repair. We discuss efforts to identify true vascular precursors, a matter of debate for the past 15 years, as well as recent methodological advances in identifying new hierarchies of more homogeneous, clonogenic and proliferative vascular endothelial-lineage precursors. Consideration of these issues provides insights that may help develop more effective therapies against human diseases that involve vascular deficits.