Abstract 14755: Striking Differences of Distinct Endothelial Progenitor Cell Subtypes in Coronary Collateral Formation and Ischemia-mediated Neovascularization - Implications for Therapeutic Angiogenesis
Endothelial progenitor cells (EPCs) are strongly implicated in angiogenesis. However, results from EPC clinical trials have been underwhelming and contradictory, possibly due to the use of unselected cell populations. Two distinct EPC subtypes (early EPCs and late-outgrowth endothelial cells, OECs) have been found to exhibit different angiogenic properties in vitro but have rarely been compared in vivo. To investigate, we compare EPC properties in patients with CAD and murine models.
In patients with single-vessel CAD involving the left anterior descending artery (n=26, age=63±10, male=81%) a positive correlation was found between the extent of coronary collateralization (invasively assessed) and OEC numbers (r=0.405,p=0.045), migration (r=0.578,p=0.006) and tubulogenesis (r=0.65,p=0.005). Patients with adequate vs inadequate collateralization (CFI≥0.25 vs <0.25) had better OEC characteristics (p<0.02). No correlation was found with early EPCs. Consistent with this, xenotransplantation of human OECs enhanced blood flow recovery (0.30±0.02 vs 0.21±0.02, p<0.05) and capillary density over controls in a murine model of hindlimb ischemia (HLI) but early EPCs did not.
In vivo biokinetics of intravenously transplanted murine EPCs co-expressing firefly luciferase and enhanced green fluorescent protein in an HLI model showed comparable homing to ischemic sites and similar cell survival in ischemic tissue with some cell survival ≥6 weeks (Early EPC vs OEC bioluminescence, p≥0.42). Nevertheless, both intravenous (IV) and intramuscular (IM) delivery of murine OECs accelerated blood flow recovery (0.50±0.04 vs 0.39±0.06, p<0.01 and 0.65±0.05 vs 0.35±0.04, p<0.05 respectively) over early EPCs. Cell number studies showed IM cell transplantation required less cells for efficacy than IV.
Adequate coronary collateralization in CAD is associated with enhanced OEC but not early EPC characteristics. Despite similarities in cell homing and survival, OECs were markedly superior to early EPCs for enhancement of ischemia-mediated neovascularization. Intramuscular transplantation and selection for OECs may enhance cell therapies for augmentation of angiogenesis.
Author Disclosures: S.G. Yuen: None. K.H. Chan: None. P. Simpson: None. Z. Clayton: None. A. Dantanarayana: None. L. Lecce: None. L. Dunn: None. A. Yong: None. C. Hsu: None. M. Guillou: None. S. Bao: None. C. Chanwantanpipat: None. D. Celermajer: None. J. Wu: None. M. Ng: None.
- © 2014 by American Heart Association, Inc.