WKYMVm-Induced Activation of Formyl Peptide Receptor 2 Stimulates Ischemic Neovasculogenesis by Promoting Homing of Endothelial Colony-Forming Cells

Abstract

Endothelial colony-forming cells (ECFCs) are recruited to the sites of ischemic injury in order to contribute to neovascularization and repair of injured tissues. However, therapeutic potential of ECFCs is limited due to low homing and engraftment efficiency of transplanted ECFCs. The Gprotein-coupled formyl peptide receptor (FPR) 2 has been implicated in regulation of inflammation and angiogenesis, while the role of FPR2 in homing and engraftment of ECFCs and neovascularization in ischemic tissues has not been fully defined. This study was undertaken to investigate the effects of WKYMVm, a selective FPR2 agonist isolated by screening synthetic peptide libraries, on homing ability of ECFCs and vascular regeneration of ischemic tissues. WKYMVm stimulated chemotactic migration, angiogenesis, and proliferation ability of human ECFCs in vitro. Small interfering RNA-mediated silencing of FPR2, but not FPR3, abrogated WKYMVm-induced migration and angiogenesis of ECFCs. Intramuscular injection of WKYMVm resulted in attenuation of severe hind limb ischemia and promoted neovascularization in ischemic limb. ECFCs transplanted via tail vein into nude mice were incorporated into capillary vessels in the ischemic hind limb, resulting in augmented neovascularization and improved ischemic limb salvage. Intramuscular injection of WKYMVm promoted homing of exogenously administered ECFCs to the ischemic limb and ECFCmediated vascular regeneration. Silencing of FPR2 expression in ECFCs resulted in abrogation of WKYMVm-induced in vivo homing of exogenously transplanted ECFCs to the ischemic limb, neovascularization, and ischemic limb salvage. These results suggest that WKYMVm promotes repair of ischemic tissues by stimulating homing of ECFCs and neovascularization via a FPR2-dependent mechanism. STEM CELLS 2014;32:779-790

Injectable PLGA microspheres encapsulating WKYMVM peptide for neovascularization

“…Human outgrowth endothelial cells (OECs) were isolated from human umbilical cord blood as previously described [12]. Cells were seeded on to the gelatin coated tissue culture plate (Millipore, Embryomax Ò , Ultrapure water with 0.1% gelatin) and maintained with endothelial cell basal medium-2 (EBM-2; Lonza, Walkersville, MD) supplemented with EGM™-2 singleQuots Ò except hydrocortisone.…”

“…Recently, several studies identified that the synthetic peptide WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met-NH2) can induce angiogenesis of endothelial cells via FPR-2 dependent stimulation of proliferation, migration, tube formation, and sprouting activity [10,11]. In addition, a recent study reported that the WKYMVm-induced activation of FPR-2 plays a role in ischemic tissue regeneration and neovascularization by homing and angiogenic activation of outgrowth endothelial cells (OECs) [12]. However, therapeutic activities of injected peptides may be diminished by several factors, including that of rapid degradation and secretion by the circulation system.…”

Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony–forming cells

“…ECFCs have shown promise for tissue regeneration. In mouse vascular injury models, they are rapidly recruited to the site of vascular injury or tissue ischemia after intravenous injection, where they initiate a vasculogenic response 8 , and they have been reported to enhance vascular repair and improve blood flow after myocardial infarction 9 , stroke 3,10 , ischemic retinopathy 2 and ischemic limb injury 8,11 , and to engraft and re-endothelialize denuded vascular segments or implanted grafts 12 . In elderly patients and subjects with peripheral arterial disease (PAD) and critical limb ischemia, ECFCs may become prone to replicative senescence, reducing their reparative potential.…”

Cellular behavior as a dynamic field for exploring bone bioengineering: A closer look at cell–biomaterial interface

“…Generally, stem cells are undifferentiated cells, with known proliferation potential, being able to self-renovate and differentiate in many lineages. This is why these cells have been appointed as a hope of cure for many diseases, especially concerning tissue regeneration [55][56][57]. Stem cells carry different features, depending on the moment of their harvesting.…”