Emerging evidence to support the use of endothelial progenitor cells (EPCs) for angiogenic therapies or as biomarkers to assess cardiovascular disease risk and progression is compelling. However, there is no uniform definition of an EPC, which makes interpretation of these studies difficult. Although hallmarks of stem and progenitor cells are their ability to proliferate and to give rise to functional progeny, EPCs are primarily defined by the expression of cell-surface antigens. Here, using adult peripheral and umbilical cord blood, we describe an approach that identifies a novel hierarchy of EPCs based on their clonogenic and proliferative potential, analogous to the hematopoietic cell system. In fact, some EPCs form replatable colonies when deposited at the singlecell level. Using this approach, we also identify a previously unrecognized population of EPCs in cord blood that can achieve at least 100 population doublings, replate into at least secondary and tertiary colonies, and retain high levels of telomerase activity. Thus, these studies describe a clonogenic method to define a hierarchy of EPCs based on their proliferative potential, and they identify a unique population of high proliferative potentialendothelial colony-forming cells (HPPECFCs) in human umbilical cord blood.
The limited vessel-forming capacity of infused endothelial progenitor cells (EPCs) into patients with cardiovascular dysfunction may be related to a misunderstanding of the biologic potential of the cells. EPCs are generally identified by cell surface antigen expression or counting in a commercially available kit that identifies "endothelial cell colony-forming units" (CFU-ECs). However, the origin, proliferative potential, and differentiation capacity of CFU-ECs is controversial. In contrast, other EPCs with blood vesselforming ability, termed endothelial colonyforming cells (ECFCs), have been isolated from human peripheral blood. We compared the function of CFU-ECs and ECFCs and determined that CFU-ECs are derived from the hematopoietic system using progenitor assays, and analysis of donor cells from polycythemia vera patients harboring a Janus kinase 2 V617F mutation in hematopoietic stem cell clones. Further, CFU-ECs possess myeloid progenitor cell activity, differentiate into phagocytic macrophages, and fail to form perfused vessels in vivo. In contrast, ECFCs are clonally distinct from CFU-ECs, display robust proliferative potential, and form perfused vessels in vivo. Thus, these studies establish that CFUECs are not EPCs and the role of these cells in angiogenesis must be re-examined prior to further clinical trials, whereas ECFCs may serve as a potential therapy for vascular regeneration. IntroductionNew blood vessel formation occurs via angiogenesis, vasculogenesis, or arteriogenesis. 1,2 Since 1997, postnatal vasculogenesis has been purported to be an important mechanism for angiogenesis via marrow-derived circulating endothelial progenitor cells (EPCs). 3 Based on this paradigm, EPCs have been extensively studied as biomarkers of cardiovascular disease and as a cell-based therapy for repair of damaged blood vessels. [4][5][6] However, administration of EPCs or bone marrow-derived cell populations enriched for EPCs into subjects with cardiovascular disease has had limited efficacy, with regard to new vessel formation. Many investigators speculate that the paracrine effects of cultured EPCs are responsible for the modest effects in patients because there is no evidence of long-term engraftment of EPCs into newly formed vessels. 7-9 These clinical observations are surprising given animal studies where EPC administration partially rescued cardiovascular dysfunction following ischemic hind limb or myocardial injury with some evidence for EPC contribution to new vessel growth. 5,9 In most studies, EPCs are identified and enumerated via flow cytometric identification of cells expressing CD34, CD133, or the VEGF receptor 2 (KDR). 3,10,11 Because these molecules are also expressed on hematopoietic stem/progenitor populations, 12-15 the presence of hematopoietic contamination of EPCs should be expected. EPCs are also quantitated by counting in a commercially available kit that identifies "endothelial cell colony-forming units" (CFU-ECs). Identification of CFU-ECs from peripheral blood by use of colony-forming ...
Rationale: Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown.Objectives: To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA).Methods: Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH. Measurements and Main Results:A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P , 0.05).Conclusions: Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.Keywords: bronchopulmonary dysplasia; pulmonary vascular disease; pulmonary hypertension; echocardiography; prematurity At a Glance CommentaryScientific Knowledge on the Subject: Preterm infants remain at high risk for late respiratory morbidity and mortality caused by the development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Early injury to the developing lung can impair angiogenesis and alveolarization and result in simplification of distal lung airspace and the clinical manifestations of BPD and PH. However, whether early signs of pulmonary vascular disease are indicative of the subsequent development of BPD or PH at 36 weeks postmenstrual age (PMA) has not been well established.What This Study Adds to the Field: This paper presents a longitudinal study identifying echocardiogram-derived risk factors at 7 days of age for the subsequent development of both BPD and PH. We also describe the incidence of PH at 36 weeks PMA and its relationship to BPD severity.
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.
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