Medical Research Center for Ischemic Tissue Regeneration, Yangsan, Gyeongsangnam-do, Republic of Korea; Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea.
Stem Cells. 2014 Mar;32(3):779-90. doi: 10.1002/stem.1578.
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 G-protein-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 ECFC-mediated 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.
内皮祖细胞 (ECFCs) 被招募到缺血性损伤部位，以促进新血管生成和受损组织的修复。然而，由于移植的 ECFCs 归巢和植入效率低，ECFCs 的治疗潜力受到限制。G 蛋白偶联的甲酰肽受体 (FPR) 2 已被牵涉到炎症和血管生成的调节中，而 FPR2 在 ECFCs 的归巢和植入以及缺血组织中的新血管生成中的作用尚未完全确定。本研究旨在探讨 WKYMVm（一种通过筛选合成肽文库分离的选择性 FPR2 激动剂）对 ECFCs 归巢能力和缺血组织血管再生的影响。WKYMVm 刺激体外人 ECFCs 的趋化性迁移、血管生成和增殖能力。小干扰 RNA 介导的 FPR2 沉默，但不是 FPR3 沉默，消除了 WKYMVm 诱导的 ECFCs 的迁移和血管生成。WKYMVm 肌肉内注射可减轻严重的后肢缺血，并促进缺血肢体的新血管生成。通过尾静脉移植到裸鼠体内的 ECFCs 整合到缺血后肢的毛细血管中，导致新血管生成增加和缺血肢体存活率提高。WKYMVm 肌肉内注射促进外源性给予的 ECFCs 归巢到缺血肢体，以及 ECFC 介导的血管再生。ECFCs 中 FPR2 表达的沉默导致 WKYMVm 诱导的外源性移植 ECFCs 归巢到缺血肢体、新血管生成和缺血肢体存活率降低。这些结果表明，WKYMVm 通过刺激 ECFCs 的归巢和新血管生成，通过 FPR2 依赖的机制促进缺血组织的修复。
