Key result
Late outgrowth endothelial cells form tubules directly, while early EPCs boost angiogenesis ~115% via paracrine effects.
Why the study?
The nature and angiogenic roles of different endothelial progenitor cell subpopulations remain debated.
Answers are grounded in this paper and cite their sources.
Early EPCs and late OECs have distinct mechanisms of promoting angiogenesis, with early EPCs acting via paracrine effects and late OECs directly participating in tubulogenesis, which has implications for optimizing cell therapies for neovascularization.
OBJECTIVES: An endothelial cell (EC)-specific angiogenesis assay was developed to functionally characterize angiogenic properties of 2 distinct putative endothelial progenitor cells (EPCs): early EPCs and late outgrowth endothelial cells (OECs). BACKGROUND: Endothelial progenitor cells promote revascularization of ischemic tissue. However, the nature of different EPCs and their role in angiogenesis remains debated. METHODS: Tubulogenesis was assessed by immunohistochemistry in co-cultures of differentiated ECs (including human umbilical vein, coronary artery, and microvascular ECs) or non-ECs with monolayers of human fibroblasts (MRC5). Using adaptations of the co-culture assay, early EPCs and OECs, isolated from peripheral blood mononuclear cells, were assessed by 3-dimensional immunofluorescence microscopy for their capacity for: 1) independent tubulogenesis; 2) incorporation into pre-existing vascular networks; and 3) paracrine angiogenic effects using transwell cultures. RESULTS: Branched interconnecting EC-specific tubules formed with all differentiated ECs after 72 h. Proangiogenic and antiangiogenic agents modulated tubulogenesis appropriately (vascular endothelial growth factor 10 ng: +142 +/- 13%, 1 microM anti-vascular endothelial growth factor: -44 +/- 7% vs. control, p < 0.001). In contrast, early EPCs, along with nonendothelial cell types, failed to independently form tubules or incorporate into differentiated EC tubules. Nevertheless, early EPCs indirectly augmented tubulogenesis by differentiated ECs even when physically separated by transwells (+115 +/- 4% vs. control; p < 0.001). By contrast, OECs independently formed tubules and incorporated into differentiated EC tubules but exerted no significant paracrine angiogenic effects. CONCLUSIONS: A novel EC-specific tubulogenesis assay highlights strikingly different angiogenic properties of different EPCs: late OECs directly participate in tubulogenesis, whereas early EPCs augment angiogenesis in a paracrine fashion, with implications for optimizing cell therapies for neovascularization.
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Sieveking et al. (2008) studied Angiogenesis. Early endothelial progenitor cells (EPCs) and late outgrowth endothelial cells (OECs) vs. Control was evaluated on Tubulogenesis capacity (independent, incorporation, and paracrine effects) (p=<0.001). Late outgrowth endothelial cells directly participate in tubulogenesis, whereas early endothelial progenitor cells augment angiogenesis in a paracrine fashion (+115% vs. control; P<0.001).
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