Striking differences of distinct endothelial progenitor cell subtypes in coronary collateral formation and ischemia-mediated neovascularization

implications for therapeutic angiogenesis

Sui Ching G. Yuen, Kim H. Chan, Philippa Simpson, Zoe Clayton, Ashanti Dantanarayana, Laura Lecce, Louise Dunn, Andy Yong, Chi-Jen Hsu, Matt Guillou, Shisan Bao, Chirapan Chanwantanpipat, David Celermajer, Joseph Wu, Martin Ng

Research output: Contribution to journalMeeting abstract

Abstract

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.
Original languageEnglish
Article numberA14755
Number of pages1
JournalCirculation
Volume130
Issue numberSuppl 2
Publication statusPublished - 25 Nov 2014
Externally publishedYes
EventAmerican Heart Assocation 2014 - Chicago, United States
Duration: 15 Nov 201419 Nov 2014

Keywords

  • Progenitor cell
  • Angiogenesis
  • Endothelial progenitor cell
  • Ischemia reperfusion

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